# Advances in research on semi-synthesis, biotransformation and biological activities of novel derivatives from maslinic acid

Yosra Trabelsi, Mansour Znati, Hichem Ben Jannet, Jalloul Bouajila

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Yosra Trabelsi, Mansour Znati, Hichem Ben Jannet, Jalloul Bouajila. Advances in research on semi-synthesis, biotransformation and biological activities of novel derivatives from maslinic acid. Chemistry, 2024, 6 (5), pp.1146-1188. 10.3390/chemistry6050067. hal-04755135

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Review

# Advances in Research on Semi-Synthesis, Biotransformation and Biological Activities of Novel Derivatives from Maslinic Acid

Yosra Trabelsi<sup>1,2 ID</sup>, Mansour Znati<sup>1 ID</sup>, Hichem Ben Jannet<sup>1 ID</sup> and Jalloul Bouajila<sup>2,* ID</sup>

**Abstract:** Since ancient times, humans have turned to medicinal plants for treating various ailments and curing specific diseases, as these natural plants serve as the primary source of a range of phytochemicals, including triterpenes. Maslinic acid (MA), also known as (2α,3β)-2,3-dihydroxyolean-12-en-28-oic acid, is a pentacyclic triterpene acid present in numerous plants including olive, known for its high safety profile in humans. Recent experimental data increasingly suggests that MA exhibits diverse biological properties and therapeutic effects on various organ diseases, highlighting its significant potential for clinical applications due to its diverse potential pharmacological activities that promote health and resist various diseases, such as hypoglycemic, neuroprotective, anti-tumor, anti-inflammatory, antioxidant and multiple other biological activities. However, the undesirable pharmacokinetic properties of MA, such as high lipophilicity, pose a limitation to its application and development, impacting its bioavailability. Consequently, extensive research spanning decades has focused on structurally modifying MA to overcome these limitations and enhance its pharmacokinetic and therapeutic characteristics, leading to the identification of several potential lead compounds. In this review, we focus on the progress of research in recent years on MA with interest to its chemical and enzymatic modifications as well as the relationships between the modified structures or derivatives and their biological activities.

**Keywords:** maslinic acid derivatives; biotransformation; semi-synthesis; biological activities; structure-activity relationship

## 1. Introduction

The natural world is a rich reservoir of chemical diversity, holding immense potential for the discovery of bioactive natural products. Consistently, it has been found that roughly 60% of recently approved small molecule drugs have roots either in natural compounds or in their derivatives [1,2]. This underscores the indispensable role natural products continue to play in enhancing human health by offering a plethora of valuable compounds like paclitaxel, berberine and artemisinin widely known and utilized in nutritional products, health supplements and medications [3-7]. Triterpenoids are known for their vast range of different natural products, with over 20,000 varieties documented in the Plantae kingdom [4]. These compounds exhibit a diverse array of biological properties such as anti-diabetic, anti-bacterial, anti-cancer, hepatoprotective, hypolipidemic, antiviral and anti-inflammatory properties [5-8]. Certain pentacyclic triterpenoids with unique structures have garnered significant attention owing to their exceptional biological activities, such as MA [9], oleanolic acid [10], ursolic acid [11], and glycyrrhizic acid [12,13].

MA (Figure 1) is a pentacyclic triterpene acid widely found in a variety of plants including olive pomace [14], *Prunella vulgaris* [15], *Eriobotrya japonica* [16], *Plinia edulis* (Vell.) Sobral fruits [17], fruits of *Zizyphus jujuba* [18], leaves of *Orthosiphon stamineus* [19],

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**Citation:** Trabelsi, Y.; Znati, M.; Ben Jannet, H.; Bouajila, J. Advances in Research on Semi-Synthesis, Biotransformation and Biological Activities of Novel Derivatives from Maslinic Acid. *Chemistry* **2024**, *6*, 1146–1188. https://doi.org/10.3390/chemistry6050067

Academic Editor: George O'Doherty

Received: 12 July 2024

Revised: 13 September 2024

Accepted: 26 September 2024

Published: 30 September 2024

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**Copyright:** © 2024 by the authors.
Licensee MDPI, Basel, Switzerland.
This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).

<footnote n="1">¹ Medicinal Chemistry and Natural Products Team, Laboratory of Heterocyclic Chemistry, Natural Products and Reactivity (LR11ES39), Faculty of Science of Monastir, University of Monastir, Avenue of Environment, Monastir 5019, Tunisia; yosratrabelsi200@gmail.com (Y.T.); znatimansour@yahoo.fr (M.Z.); hichem.bjannet@gmail.com (H.B.J.)</footnote>

<footnote n="2">² Laboratoire de Génie Chimique, Université Paul Sabatier, CNRS, INPT, UPS, 31062 Toulouse, France</footnote>

<footnote>* Correspondence: jalloul.bouajila@univ-tlse3.fr</footnote>
*Hippophae rhamnoides* L [20], *Coleus tuberosus* [21], leaves of *Eriobotrya japonica* [22], *Ulmus davidiana* var. *japonica* [23], and *Lagerstroemia speciosa* leaves [24]. It is noteworthy that olive pomace has the highest content (Table 1) of MA (6.6 g/Kg).

<figure><img src="image_5.png" /><figcaption>**Figure 1.** Chemical structure of maslinic acid (1).</figcaption></figure>

<table><caption>**Table 1.** Content of MA in various sources.</caption><thead><tr><td>Source</td><td>Content (g/Kg)</td><td>Ref.</td></tr></thead><tbody><tr><td>Olive pomace</td><td>6.6</td><td>[14]</td></tr><tr><td>Plinia edulis (Vell.) Sobral fruits</td><td>6.5</td><td>[17]</td></tr><tr><td>Fruits of Zizyphus jujuba</td><td>8.65</td><td>[18]</td></tr><tr><td>Leaves of Orthosiphon stamineus</td><td>0.03</td><td>[19]</td></tr><tr><td>Hippophae rhamnoides L</td><td>0.09</td><td>[20]</td></tr><tr><td>Coleus tuberosus</td><td>0.043</td><td>[21]</td></tr><tr><td>Leaves of Eriobotrya japonica</td><td>1.7</td><td>[22]</td></tr><tr><td>Ulmus davidiana var. japonica</td><td>0.042</td><td>[23]</td></tr><tr><td>Lagerstroemia speciosa leaves</td><td>0.53</td><td>[24]</td></tr><tr><td>Eriobotrya japonica</td><td>0.012</td><td>[16]</td></tr><tr><td>Prunella vulgaris</td><td>0.007</td><td>[15]</td></tr></tbody></table>

MA is also present in olive oil, which serves as the traditional edible oil in Mediterranean coastal regions, known for its positive nutritional and health benefits. Moreover, olive oil is widely utilized in beauty care, further indicating the safety of MA for human consumption. Research reveals that the MA content varies across diverse types of olive oil; for example, extra virgin olive oil ranges from 20 to 98 mg/kg, high acid value olive oil contains 212 to 356 mg/kg of MA, with the highest MA content found in olive residue ranging from 212 to 1485 mg/kg in various regions [25]. Studies have indicated that even at high concentrations, MA does not induce discomfort or fatalities in animal models of disease treatment. In fact, the oral administration of a single dose of 1000 mg/kg of MA to mice did not have any negative effect on various organs [26]; as the same was observed for oleanolic acid, histopathological examination of organs after a high dose (1000 mg/kg) revealed no evidence of significant toxicological changes related to the oral administration of the oleanolic acid [27]. Subsequently, researchers delved into MA's pharmacological activity and potential molecular mechanisms for treating diseases and evaluated toxicological effects [28], revealing that MA possesses a wide array of pharmacological benefits, such as antiplatelet aggregation [29,30], hepatoprotective [31], anti-inflammatory, cardio-protective [32,33], anti-diabetic, anti-inflammatory, analgesic effects [34], anticancer [35-38], antimicrobial [39,40] and anti-hyperlipidemic [41,42]. Despite its intriguing properties, the
bioavailability of MA is significantly compromised due to its lipophilic core, which imparts unfavorable physicochemical characteristics and subsequently hinders its development as a viable therapeutic agent [43]. To address these limitations, various approaches have been explored, including chemical derivatization [44] and enzymatic modifications that have improved its pharmacokinetic and therapeutic properties. Yan et al. [45] provided an overview of recent research on derivatives generated from MA, emphasizing the biological properties of both MA and its derivatives. However, they have often overlooked the intricate details of the enzymatic modifications carried out on MA and the specific synthetic routes and pathways leading to these derivatives. Thus, this review addresses these gaps by providing an exhaustive examination of the enzymatic transformations such as biotransformations applied to MA, alongside a thorough analysis of the resulting bioactivities. Additionally, we delve deeper into semi-synthesis of different derivatives with greater focus on detailed synthetic routes and pathways for each derivative formed, ultimately elaborating a comprehensive understanding of the function-activity relationships, linking the molecular structures to their biological activities. This detailed insight not only advances the current knowledge of MA derivatives but also paves the way for future research and development in the field. In conclusion, this review can act as a comprehensive reference in both biology and organic chemistry for guiding future therapeutic evolution.

## 2. Biotransformations of MA (1) and Bioactivities of Derivatives

Over the years, many researchers have taken an interest in the enzymatic modification of MA (1). Therefore, biotransformations using a wide range of microorganisms have been investigated over the years, and these are shown in Table 2. Wang et al. [46] performed a study on the biotransformation of MA using five frequently employed microorganisms in food processing, namely *Streptomyces griseus*, *Streptomyces olivaceus*, *Bacillus subtilis*, *Penicillium griseofulvum* and *Bacillus megaterium*, with various yields. The anti-inflammatory activity of compounds 2–9 were assessed against NO production in LPS-induced and HMGB1-induced RAW 264.7 cells (Table 2). In the bioassay, it was observed that all metabolites exhibited non-cytotoxicity, whereas MA demonstrated a mild inhibitory effect on both models (HMGB1: >100 and cell viability: 104.39). In the context of HMGB1-activated inflammation, the majority of metabolites exhibited selective inhibitory effects. Notably, compounds 4, 6, and 8 demonstrated $IC_{50}$ values of 16.41, 10.77, and 11.52 µM, respectively. The analysis of the function-activity relationship indicated the influence of the substitution site and the number of hydroxyl groups, particularly the hydroxylation of angular methyl groups on the PT skeleton, on the anti-inflammatory potential of these compounds. Results show that compounds hydroxylated at C-15, C-7, and C-1 exhibited a moderate level of inhibition on the HMGB1 model, whereas significant inhibitory effects have been proven with hydroxylation at C-29, C-21 and C-23. Furthermore, when oxidizing the hydroxyl group at C-29 to the carboxyl group, the inhibitory effect diminished, while glycosylation at C-28 did not affect the inhibitory effect. Additionally, compounds with double bond rearrangement did not exhibit a great enhancement in the anti-inflammatory effect. On the other hand, no inhibitory effect was observed in the case of LPS-induced NO release, except for analog 3, which showed moderate inhibition ($IC_{50}$ = 24.40 µM). In summary, the study of the function-activity relationship of MA (1) transformation products provides valuable insights for the future development of highly effective and selective HMGB1 inhibitors. Another study [47] has shown that the action of *Rhizomucor miehei* on MA produces a C-30 hydroxylated metabolite 10, an 11α,12α-epoxy, 28,13β-olide metabolite 13, an 11-oxo derivative 12 and an olean-11-en-28,13β-olide derivative 11. An additional study [48] demonstrated that *Cunninghamella blakesleeana* CGMCC 3.910 catalyzed the MA biotransformation that led to these different metabolites: 2α,3β,7β,13β-tetrahydroxyolean-11-en-28-oic acid 17, 2α,3β,15α-trihydroxyolean-12-en-28-oic acid 15, 2α,3β,7β-trihydroxyolean-12-en-28-oic acid 14, and 2α,3β,7β,15α-tetrahydroxyolean-12-en-28-oic acid 16. Another experiment [49] showed the recombinant expression of three UDP-glucosyltransferases (UGTs), namely YojK, YjiC, and UGT109A3, from *B. subtilis*.
Their capacity to glycosylate MA in vitro was explored with the aim of producing MA-2-O-β-D-glucose.

<table><caption>**Table 2.** Examples of biotransformations carried out on MA (1) and anti-inflammatory potential of the resulted derivatives.</caption><thead><tr><th rowspan="3">Microorganism</th><th rowspan="3">Resulting Products</th><th rowspan="3">Yield (%)</th><th colspan="3">Anti-Inflammatory Activity: Inhibitory Effects on NO Production in LPS-Induced or HMGB1-Induced RAW 264.7 Cells <sup>1</sup></th><th rowspan="3">Ref.</th></tr><tr><th colspan="2">IC<sub>50</sub> (μM)</th><th rowspan="2">Cell Viability % (50 μM)</th></tr><tr><th>LPS</th><th>HMGB1</th></tr></thead><tbody><tr><td rowspan="2">Bacillus megaterium CGMCC 1.1741</td><td>2</td><td>28</td><td>&gt;100 <sup>2</sup></td><td>79.2</td><td>100.38</td><td rowspan="6">[46]</td></tr><tr><td>3</td><td>12</td><td>24.40</td><td>46</td><td>99.07</td></tr><tr><td rowspan="2">Streptomyces olivaceus CICC 23628</td><td>4</td><td>26</td><td>&gt;100 <sup>2</sup></td><td>16.41</td><td>104.19</td></tr><tr><td>5</td><td>5</td><td>&gt;100 <sup>2</sup></td><td>49.11</td><td>98.47</td></tr><tr><td rowspan="2">Penicillium griseofulvum CICC 40293</td><td>6</td><td>12</td><td>&gt;100 <sup>2</sup></td><td>10.77</td><td>94.69</td></tr><tr><td>6</td><td>12</td><td>&gt;100 <sup>2</sup></td><td>10.77</td><td>94.69</td></tr></tbody></table>
<table><caption>Table 2. *Cont.*</caption><thead><tr><th rowspan="3">Microorganism</th><th rowspan="3">Resulting Products</th><th rowspan="3">Yield (%)</th><th colspan="3">Anti-Inflammatory Activity: Inhibitory Effects on NO Production in LPS-Induced or HMGB1-Induced RAW 264.7 Cells <sup>1</sup></th><th rowspan="3">Ref.</th></tr><tr><th colspan="2">IC<sub>50</sub> (µM)</th><th rowspan="2">Cell Viability % (50 µM)</th></tr><tr><th>LPS</th><th>HMGB1</th></tr></thead><tbody><tr><td rowspan="2">Streptomyces griseus ATCC 1</td><td>7</td><td>10</td><td>&gt;100 <sup>2</sup></td><td>81.00</td><td>86.09</td><td></td></tr><tr><td>8</td><td>15</td><td>&gt;100 <sup>2</sup></td><td>11.52</td><td>96.55</td><td>[46]</td></tr><tr><td>Bacillus subtilis ATCC 6633</td><td>9</td><td>56</td><td>&gt;100 <sup>2</sup></td><td>&gt;100 <sup>2</sup></td><td>97.84</td><td></td></tr><tr><td rowspan="3">Rhizomucor miehei</td><td>10</td><td>11</td><td>-</td><td>-</td><td>-</td><td></td></tr><tr><td>11</td><td>0.5</td><td>-</td><td>-</td><td>-</td><td>[47]</td></tr><tr><td>12</td><td>1</td><td>-</td><td>-</td><td>-</td><td></td></tr></tbody></table>

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<table><caption>**Table 2. Cont.**</caption><thead><tr><th rowspan="3">Microorganism</th><th rowspan="3">Resulting Products</th><th rowspan="3">Yield (%)</th><th colspan="2">Anti-Inflammatory Activity: Inhibitory Effects on NO Production in LPS-Induced or HMGB1-Induced RAW 264.7 Cells <sup>1</sup></th><th rowspan="3">Ref.</th></tr><tr><th colspan="2">IC<sub>50</sub> (µM)</th></tr><tr><th>LPS</th><th>HMGB1</th></tr></thead><tbody><tr><td rowspan="5">Cunninghamella blakesleeana</td><td>13</td><td>0.2</td><td>-</td><td>-</td><td>-</td><td>[47]</td></tr><tr><td>14</td><td>37</td><td>-</td><td>-</td><td>-</td><td></td></tr><tr><td>15</td><td>3</td><td>-</td><td>-</td><td>-</td><td>[48]</td></tr><tr><td>16</td><td>3</td><td>-</td><td>-</td><td>-</td><td></td></tr><tr><td>17</td><td>2</td><td>-</td><td>-</td><td>-</td><td>-</td></tr><tr><td>Bacillus subtilis (UDP-glycosyltransferases UGTs: YojK, YjiC, and UGT109A3)</td><td>18</td><td>52 (YojK)<br>40 (YjiC)<br>39 (UGT109A3)</td><td>-</td><td>-</td><td>-</td><td>[49]</td></tr></tbody></table>

<footnote n="1">¹ DG as a positive control. ² Results showed NO inhibition.</footnote>
### 3. Chemical Modifications of MA (1) and Bioactivities

#### 3.1. Anticancer Derivatives

One of the most notable classes of plant secondary compounds is the pentacyclic triterpenoids, which are recognized for their potent anti-tumor properties and apparent absence of toxicity. Given these favorable characteristics, they are regarded as promising primary compounds for the development of novel multi-targeting anti-cancer agents [50].

MA's anti-cancer properties have been repeatedly highlighted in numerous recent studies that underscore its potential as a prospect for the creation of anti-cancer medications as well as anti-cancer agents. Seemingly, for the development of more potent anti-cancer treatments, the discovery of novel anti-tumor agents for boosting or reinstating apoptosis in malignant cancer cells is crucial [51]. Considering the substantial cytotoxicity exhibited by MA, structural modifications may facilitate the development of MA derivatives that possess improved $IC_{50}$ values across a range of cancer cell lines. Furthermore, numerous drug-related properties, such as solubility and bioavailability, can be significantly improved. Several MA analogs exhibiting potent anti-cancer activity are illustrated in Figures 2 and 3, with their synthetic routes detailed in Table 3.

<figure><img src="image_12.png" /><figcaption>**Figure 2.** MA derivatives as promising anti-cancer agents.</figcaption></figure>

<figure><img src="image_13.png" /><figcaption>**Figure 3.** MA analogs as anti-cancer agents.</figcaption></figure>
<table><caption>**Table 3.** Synthetic routes of derivatives with anti-cancer potential.</caption><thead><tr><th>Derivative</th><th>Synthetic Route</th></tr></thead><tbody><tr><td>19</td><td><img src="image_19.png" alt="Derivative 19: 1,3-Diphenyl-1H-imidazole-2-carbaldehyde with a red arrow indicating the Br atom, and a blue arrow indicating the N-atom at the 5-position of the imidazole ring. The structure is shown in a 2D plan view with the planes of the imidazole ring and the 2,4-dichloro phenyl ring clearly visible. The structure is followed by a red arrow indicating the direction of the Br atom's migration to the 5-position of the imidazole ring. The 3D structure is shown in a 3D plan view with the planes of the imidazole ring and the 2,4-dichloro phenyl ring clearly visible. The structure is then followed by a blue arrow indicating the migration of the Br atom from the 5-position of the imidazole ring to the 4-position of the phenyl ring. The 3D structure is shown in a 3D plan view with the planes of the imidazole ring and the 2,4-dichloro phenyl ring clearly visible. The structure is then followed by a red arrow indicating the final structure with the Br atom in the 4-position of the phenyl ring. The 3D structure is shown in a 3D plan view with the planes of the imidazole ring and the 2,4-dichloro phenyl ring clearly visible."></td></tr><tr><td>20</td><td><img src="image_20.png" alt="Derivative 20: 1,3-Diphenyl-1H-imidazole-2-carbaldehyde with a red arrow indicating the Br atom, and a blue arrow indicating the N-atom at the 5-position of the imidazole ring. The structure is shown in a 2D plan view with the planes of the imidazole ring and the 2,4-dichloro phenyl ring clearly visible. The structure is followed by a red arrow indicating the direction of the Br atom's migration to the 5-position of the imidazole ring. The 3D structure is shown in a 3D plan view with the planes of the imidazole ring and the 2,4-dichloro phenyl ring clearly visible. The structure is then followed by a blue arrow indicating the migration of the Br atom from the 5-position of the imidazole ring to the 4-position of the phenyl ring. The 3D structure is shown in a 3D plan view with the planes of the imidazole ring and the 2,4-dichloro phenyl ring clearly visible. The structure is then followed by a red arrow indicating the final structure with the Br atom in the 4-position of the phenyl ring. The 3D structure is shown in a 3D plan view with the planes of the imidazole ring and the 2,4-dichloro phenyl ring clearly visible."></td></tr><tr><td>21</td><td><img src="image_21.png" alt="Derivative 21: 1,3-Diphenyl-1H-imidazole-2-carbaldehyde with a blue arrow indicating the direction of the Br atom's migration to the 5-position of the imidazole ring. The structure is shown in a 2D plan view with the planes of the imidazole ring and the 2,4-dichloro phenyl ring clearly visible. The structure is then followed by a red arrow indicating the direction of the Br atom's migration to the 5-position of the imidazole ring. The 3D structure is shown in a 3D plan view with the planes of the imidazole ring and the 2,4-dichloro phenyl ring clearly visible. The structure is then followed by a blue arrow indicating the migration of the Br atom from the 5-position of the imidazole ring to the 4-position of the phenyl ring. The 3D structure is shown in a 3D plan view with the planes of the imidazole ring and the 2,4-dichloro phenyl ring clearly visible. The structure is then followed by a red arrow indicating the final structure with the Br atom in the 4-position of the phenyl ring. The 3D structure is shown in a 3D plan view with the planes of the imidazole ring and the 2,4-dichloro phenyl ring clearly visible."></td></tr><tr><td>22</td><td><img src="image_22.png" alt="Derivative 22: 1,3-Diphenyl-1H-imidazole-2-carbaldehyde with a red arrow indicating the direction of the Br atom's migration to the 5-position of the imidazole ring. The structure is shown in a 2D plan view with the planes of the imidazole ring and the 2,4-dichloro phenyl ring clearly visible. The structure is then followed by a blue arrow indicating the direction of the Br atom's migration to the 5-position of the imidazole ring. The 3D structure is shown in a 3D plan view with the planes of the imidazole ring and the 2,4-dichloro phenyl ring clearly visible. The structure is then followed by a blue arrow indicating the migration of the Br atom from the 5-position of the imidazole ring to the 4-position of the phenyl ring. The 3D structure is shown in a 3D plan view with the planes of the imidazole ring and the 2,4-dichloro phenyl ring clearly visible. The structure is then followed by a red arrow indicating the final structure with the Br atom in the 4-position of the phenyl ring. The 3D structure is shown in a 3D plan view with the planes of the imidazole ring and the 2,4-dichloro phenyl ring clearly visible."></td></tr><tr><td>23 (a-d)</td><td><img src="image_23.png" alt="Derivative 23: 1,3-Diphenyl-1H-imidazole-2-carbaldehyde with a red arrow indicating the direction of the Br atom's migration to the 5-position of the imidazole ring. The structure is shown in a 2D plan view with the planes of the imidazole ring and the 2,4-dichloro phenyl ring clearly visible. The structure is then followed by a blue arrow indicating the direction of the Br atom's migration to the 5-position of the imidazole ring. The 3D structure is shown in a 3D plan view with the planes of the imidazole ring and the 2,4-dichloro phenyl ring clearly visible. The structure is then followed by a blue arrow indicating the migration of the Br atom from the 5-position of the imidazole ring to the 4-position of the phenyl ring. The 3D structure is shown in a 3D plan view with the planes of the imidazole ring and the 2,4-dichloro phenyl ring clearly visible. The structure is then followed by a red arrow indicating the final structure with the Br atom in the 4-position of the phenyl ring. The 3D structure is shown in a 3D plan view with the planes of the imidazole ring and the 2,4-dichloro phenyl ring clearly visible."></td></tr></tbody></table>
<table><caption>**Table 3. Cont.**</caption><thead><tr><th>Derivative</th><th>Synthetic Route</th></tr></thead><tbody><tr><td>27 (a-c)</td><td><img src="image_0_1.png" alt="Synthetic Route for 27 (a-c)"></td></tr><tr><td>27d, 27e</td><td><img src="image_0_2.png" alt="Synthetic Route for 27d, 27e"></td></tr></tbody></table>

Chouaïb et al. [52] investigated the effects of MA and corresponding triazole analogs on cancer cell lines, specifically human SW480 (Colon) and mouse EMT-6 (Breast). Their research revealed that MA displayed notable anti-proliferative effects on both SW480 cancer cells and EMT-6, leading to cell survival rates of 9% and 5% at 100 µM, respectively. The study also highlighted that the 1.4-regioisomers, particularly compound **20**, exhibited superior anti-proliferative activity in comparison with the 1.5-regioisomers. Remarkably, it is worth highlighting that compound **20** demonstrated the highest activity against SW480 and EMT-6, with cell viabilities of 34 and 13% at 100 µM. In the case of the 1.4-regioisomers, derivative **19** showed the most potent activity against both cell lines EMT-6 and SW480, with cell viabilities of 10% and 6% at 30 µM. This observed activity was linked to the attachment of the triazole to the aryl group concerning the triterpene moiety in the cellular environment. In a separate experimental investigation, it was discovered that MA and its analog, compound **21**, displayed activity in damaging the cell membrane of tumor cells, particularly A2780 cells. In fact, the IC₅₀ values for MA and its analogs in A2780 cells were 19.5 and 10.6 µM, respectively. It was found that derivative **21** formed crystals with cholesterol in the cell membrane, or in close proximity to it, during cell culture. Subsequently, compound **21** penetrated the cell membrane, interacting with the lipid raft containing cholesterol, leading to alterations in the cell membrane structure, reduction in cell volume, and initiation of apoptosis [53].

The study by Medina-O'Donnell et al. [54] highlighted the potential of PEG polymer for conjugation of pro-drugs, owing to its great solubility in aqueous environments. In fact, ex-
periments revealed the substantial anti-cancer potential of diamine and PEGylated-diamine derivatives **22** of MA. Within non-tumor HPF cell lines, all MA diamine conjugates demonstrated cell viability levels ranging from 81% to 94%. Interestingly, MA diamine derivatives possessing the longest and shortest diamine chains exhibited the most pronounced cytotoxic effects in tumor cell lines, with IC₅₀ values spanning from 0.76 µM to 1.76 µM. On the other hand, these conjugates demonstrated effectiveness that was 20- and 140-fold greater than the original precursors in B16-F10 cell lines [55]. Parra et al. [51] illustrated that MA and its derivatives possess the capability to hinder the development of B16F10 melanoma cells by triggering apoptosis. MA conversion into the sodium salt derivative **23a** underwent a series of steps. Additionally, MA diacetyl analog underwent a transformation into the related amide analog initially using thionyl chloride in DCM, followed by NH₃/MeOH, to be transitioned into the nitrile derivative **23b** through thionyl chloride/DCM treatment, after which a further deacetylation yielded **23c**. Moreover, compound **23d**, formed by treating MA through DMF and benzyl chloride, displayed notable anti-tumor properties. The assessment of these following specific compounds for their pro-apoptotic effects at a concentration of 1 µM gives the following values: **23b** at 68.62%, **23d** at 87.50%, **23c** at 78.75% and **23a** at 56.67%. Another study emphasized the significant anti-melanoma effects of MA and the corresponding acetylated derivative (EM2, **24**) [56]. On the other hand, MA displayed an IC₅₀ equal to 13.7 µM, while compound **24** exhibited stronger toxicity with a lower IC₅₀ value of 1.5 µM in 518A2 cells and an IC₅₀ value of 33.8 µM in the nonmalignant mouse fibroblast cell line (or else NiH 3T3). Specifically, in A2780 ovarian cancer cells, the EC₅₀ value of analog **24** was notably reduced to 0.5 µM. Moreover, it is noteworthy that the anti-proliferative activity in A2780 ovarian cancer cells was enhanced (EC₅₀ equal to 0.5 µM for compound **24**). This evaluation was suggested to be in relation with the derivatization occurred at MA's C-28 position [57]. In summary, structural modifications conducted on compound **24** highlighted the importance of the acetyl groups and the presence of (2b, 3b)-configurated centers with the aim of achieving enhanced cytotoxicity along with ideal discrimination between cancerous cells and non-cancerous mouse fibroblasts. Consequently, the substitution of the MA benzylamide function with a phenylurea fragment led to the formation of derivative **25**, contributing to the improvement of EC₅₀ values of 0.9 µM (for A2780 ovarian cancer cells) and EC₅₀ > 120 µM for fibroblasts (NIH 3T3), ultimately inducing apoptosis [58]. In another study, Serbian et al. [59] carried out a reaction between MA and benzoyl chlorides that afforded the 3-O-acylated and 2-O-acylated MA analogs. These compounds were biologically screened using the SRB or (sulforhodamine B) assays, and it was shown that cancer cell cytotoxicity increased in comparison with the parent compound MA. Additionally, when treating A2780 cells with MA during 96 h, the EC₅₀ value was equal to 19.5 µM. Notably, the EC₅₀ values of compounds **26a-f** consistently remained below 10 µM. The acetylation of MA led to acetates **27a**. Subsequent reactions involved treating **27a** through oxalyl chloride and a reaction with piperazine in a later step, resulting in the formation of amides **27b**. Thereafter, violet-colored compounds **27c** were formed through a reaction of **27b** with rhodamine B. Compound **27c** exhibited approximately a 1000-fold higher cytotoxicity compared to the parent compound, and its selectivity for FSi (introduced as EC₅₀ NIH 3T3 compared to EC₅₀ A2780 tumor cell line) was enhanced by 50 times. Remarkably, rhodamine B showed no signs of cytotoxicity at concentrations up to 30 µM. Hence, compound **27c** stands out as one of the most potent triterpenoic acid derivatives discovered thus far, exhibiting cytotoxicity in nano-molar concentrations. Its cytotoxic effects are comparable to those of well-known cytotoxic drugs such as paclitaxel or doxorubicin [60]. An interesting study by Vega-Granados et al. [61] highlighted the potential of MA-coumarin conjugates as anti-cancer candidates against three cancer cell lines (B16-F10, HT29, and Hep G2) respectively compared with three non-tumor cell lines (HPF, IEC-18, and WRL68). Their research revealed that the most pronounced cytotoxic activity was exhibited by **27e** where the two molecules of coumarin-3-carboxylic acid are coupled through the C-2 and C-3 hydroxy groups of MA. It is noteworthy that compound **27e**, with IC₅₀ = 0.6, 1.1, and 0.9 µM, respectively, in two of the three cancer cell lines, was
between 110- and 30-fold greater potency than the parent compound MA (1), showing cell viability percentages of approximately 90% observed in all non-tumor cells. Notably, results indicated that compound **27d** showed cell viability percentages spanning from 61 to 88% for the non-tumor cells (HPF, IEC-18, and WRL68), at the corresponding IC₅₀ concentration of the respective cancer cell line.

## 3.2. Anti-Inflammatory Derivatives

Chouaïb et al. [62] reported that MA derivatives conjugated with an isoxazole have been synthesized and assessed for their anti-inflammatory properties. In fact, the synthesis was carried out using various dipolarophiles **a-e** under microwave irradiation in anhydrous DMF (Table 4). The synthesis of isoxazole derivatives **28-33** was performed with a regiospecific method in the presence of Et₃N and CuI. This approach utilized diverse aromatic hydroximyl chlorides and propargyl-(2,3)-2,3-dihydroxyolean-12-en-28-oate **a** under microwave irradiation for 5-10 min, achieving yields spanning from 84 to 96% (Scheme 1). The in vitro anti-inflammatory test demonstrated a strong inhibitory effect for all derivatives compared to the parent compound **1** (Table 5). It is noteworthy that among all synthesized analogs, derivative **33**, featuring a furfuryl moiety on the isoxazole fragment, exhibited the highest anti-inflammatory activity (% IL-1β production = 4; 100 µM). Notably, compounds **29, 30, 31** and **32** also displayed enhanced activity (% IL-1β production = 33-55; 30-100 µM) in comparison with MA (1) (% IL-1β production = 109, 30 µM). Consequently, this suggests that halogens contribute more significantly to the activity than other substituents, with the observed activity appearing to depend on the nature of the substituents rather than their electronic effects [62].

<table><caption>**Table 4.** Synthesis of dipolarophiles **a-e** from MA.</caption><thead><tr><th>Derivatives</th><th>Method A (82%) <sup>1</sup></th><th>(%) <sup>2</sup></th><th>Method B (99%) <sup>1</sup></th><th>(%) <sup>2</sup></th></tr></thead><tbody><tr><td>a</td><td></td><td>44</td><td></td><td>25</td></tr><tr><td>b</td><td>NaH (2 eq) <sup>3</sup></td><td>5</td><td>NaH (4 eq) <sup>3</sup></td><td>0</td></tr><tr><td>c</td><td>Propargyl bromide (3 eq) <sup>3</sup></td><td>15</td><td>Propargyl bromide (4 eq) <sup>3</sup></td><td>23</td></tr><tr><td>d</td><td>2 h</td><td>11</td><td>8 h</td><td>20</td></tr><tr><td>e</td><td></td><td>7</td><td></td><td>31</td></tr></tbody></table>

<figure><img src="image_14.png" /><figcaption>**Scheme 1.** Route of synthesis to 3,5-Disubstituted isoxazoles **28-33** synthesis.</figcaption></figure>

<footnote n="1">¹ Mixture yield, stemming from MA as a precursor. ² Isolated yield of compounds (a-e) following column chromatography eluted with PE-EtOAc, stemming from the MA. ³ Compared to the starting material (MA).</footnote>
<table><caption>**Table 5.** Effect of MA and derivatives **28–33** on viability and inflammatory cytokine (IL-1β) production in LPS-stimulated PBMCs.</caption><thead><tr><th></th><th></th><th>Concentration (μM)</th><th>% PBMCs <sup>1</sup></th><th>% IL-1β Production <sup>2</sup></th><th>Ref.</th></tr></thead><tbody><tr><td colspan="2">DMSO 0.33% + LPS</td><td></td><td>100</td><td>100</td><td></td></tr><tr><td colspan="2">DEXA <sup>3</sup> + LPS</td><td>1</td><td>81</td><td>32</td><td></td></tr><tr><td colspan="2">PRED <sup>4</sup> + LPS</td><td>70</td><td>67</td><td>43</td><td></td></tr><tr><td colspan="2">ZVAD <sup>5</sup> + LPS</td><td>5</td><td>110</td><td>42</td><td></td></tr><tr><td colspan="2">Code</td><td></td><td></td><td></td><td></td></tr><tr><td colspan="2">MA</td><td>100</td><td>14</td><td>Nd <sup>6</sup></td><td></td></tr><tr><td colspan="2"></td><td>30</td><td>53</td><td>109</td><td></td></tr><tr><td></td><td>R</td><td>Time (min)</td><td>Yield (%)</td><td></td><td></td></tr><tr><td rowspan="2">28</td><td>[Chemical Structure]</td><td>5</td><td>96</td><td>100</td><td>89</td><td>82</td></tr><tr><td></td><td></td><td></td><td>30</td><td>32</td><td>Nd</td></tr><tr><td rowspan="2">29</td><td>[Chemical Structure]</td><td>6</td><td>90</td><td>100</td><td>87</td><td>55</td></tr><tr><td></td><td></td><td></td><td>30</td><td>74</td><td>Nd</td></tr><tr><td rowspan="2">30</td><td>[Chemical Structure]</td><td>6</td><td>92</td><td>100</td><td>23</td><td>Nd</td></tr><tr><td></td><td></td><td></td><td>30</td><td>57</td><td>33</td></tr><tr><td rowspan="2">31</td><td>[Chemical Structure]</td><td>8</td><td>88</td><td>100</td><td>44</td><td>Nd</td></tr><tr><td></td><td></td><td></td><td>30</td><td>72</td><td>52</td></tr><tr><td rowspan="2">32</td><td>[Chemical Structure]</td><td>5</td><td>95</td><td>100</td><td>58</td><td>Nd</td></tr><tr><td></td><td></td><td></td><td>30</td><td>42</td><td>44</td></tr><tr><td rowspan="2">33</td><td>[Chemical Structure]</td><td>10</td><td>84</td><td>100</td><td>78</td><td>4</td></tr><tr><td></td><td></td><td></td><td>30</td><td>85</td><td>Nd</td></tr></tbody></table>

[62]

In a follow-up to their prior research, Chouaïb et al. [52] synthesized MA-triazole conjugates and assessed their anti-inflammatory properties. Bis-alkynes c or d, copper iodide, and triethylamine were added at rt. The appropriate azide was then introduced to the mixture, which was subsequently subjected to microwave irradiation for a few minutes, resulting in the formation of compounds **34–37** (Scheme 2) as well as compounds **38–42** (Scheme 3). Moreover, tri-alkyne e and the appropriate azide were dissolved in H₂O. To this mixture, copper iodide and trimethylamine were added. The reaction mixture was irradiated with microwaves for 5–10 min to afford compounds **43–46** (Scheme 4). Furthermore, the 1,5-regioisomers **47–52** were produced through mixing a solution of alkyne a in DMF with Cp*RuCl(PPh₃)₂* at rt. Then, the appropriate aryl azide was added, and the reaction mixture was subjected to microwave irradiation for a few minutes (Scheme 5). As a result, 1,4-regioisomers **53–58** were formed under solvent-free conditions through mixing dipolarophile a, copper(I) iodide and Et₃N at rt. Subsequently, the appropriate aryl azide was added to this mixture, and the reaction mixture was subjected to microwave irradiation for a few minutes (Scheme 6). The study revealed

<footnote n="1">¹ The anti-inflammatory activity of the tested compounds was assessed using LPS-stimulated human peripheral blood mono-nuclear cells (PBMCs) with LPS (lipopolysaccharide). ² %IL-1β production: indicates the anti-inflammatory activity compared to the starting material (MA). ³ Dexamethasone (DEXA, 1 mM). ⁴ Prednisolone (PRED, 70 mM). ⁵ ZVAD (5 mM). ⁶ Non-determined.</footnote>
that stronger inhibitory properties have been proven for all the formed triazoles compared to their precursor **1**. Notably, incorporating triazole moieties into compound **1** significantly enhanced its anti-inflammatory efficacy. Among the bis-1,4-disubstituted triazoles **34–37** (Table 6), only compounds **34** and **35** demonstrated relatively significant effects, with % IL-1β production = 71 and 56, respectively, in 100 µM compared with the other derivatives and MA (1). Furthermore, the % IL-1β production observed for the bis-1,4-disubstituted triazoles **38–42** (Table 7) indicated that a higher activity is noticed in cases where the aromatic ring possesses electron-donating groups, which is not the case with electron-withdrawing groups or without substitutions that showed moderate activity. Specifically, analogs **41** and **39** showed the best results (% IL-1β production = 52 and 34, respectively; 100 µM). The placement of the triazole at either C-3 (derivatives **38–42**) or C-2 (derivatives **34–37**) within MA (1) plays a critical role in determining its effectiveness. In fact, this is evident in instances like **36** and **41** with % IL-1β production equal to 100 and 52, respectively, at 100 µM, in cases where the same aromatic system (m-MePh) is attached to the triazole. In contrast, compounds **46** (featuring a naphthyl fragment on the triazole moiety) and **45** (m-Me), outlined in Table 8, exhibited significant effects (% IL-1β production = 34 and 23, respectively; 30 µM) on reducing PBMCs in comparison with MA and other conjugates. This discovery underscores the significance of both the quantity and potentially the positioning of triazole moieties in enhancing the anti-inflammatory properties of MA (1) [52]. Results outlined in Table 9 showed also that in the series of 1,5-regioisomers, derivatives **50** and **51** demonstrated pronounced activity (% IL-1β production 42 and 46, respectively; 100 µM), while compound **49** with (p-Br) showed the highest inhibition with % IL-1β production value equal to 21 in 100 µM. Additionally, the results depicted in Table 10 indicated that most of the tested 1,4-regioisomers **53–58** displayed significant anti-inflammatory effects. Among them, **56** (p-Br) was the most potent derivative showing a % IL-1β production value equal to 21 at 100 µM. Upon comparing the % IL-1β production values of derivatives **47–52** with those of derivatives **53–58**, which share identical substitutions at the triazole ring, it becomes evident that the latter exhibit greater activity (% IL-1β production = 40–91 and 21–82, respectively; 100 µM). Nevertheless, a noteworthy observation emerged during the examination of the regiochemistry in two conjugates from each series, **47–52** and **53–58**, which share the same substituent. This is exemplified in compounds **56** (p-Br substituted) (% IL-1β production = 21; 100 µM) and **49** (p-Br substituted) (% IL-1β production = 61; 100 µM) where activity is reversed due to the regiochemistry. This study highlights the noteworthiness of the triazole’s regiochemistry and the type of aryl group linked to it in influencing the observed activity [52].

<figure><img src="image_15.png" /><figcaption>**Scheme 2.** CuAAC Synthesis of Bis-1,4-Disubstituted Triazoles **34–37**.</figcaption></figure>

<figure><img src="image_16.png" /><figcaption>**Scheme 3.** bis-1,4-disubstituted triazoles **38–42** prepared by the Cu(I) catalyzed synthesis.</figcaption></figure>
<figure><img src="image_17.png" /><figcaption>**Scheme 4.** Tri-1,4-disubstituted triazoles **43–46** prepared by the Cu(I)-catalyzed synthesis.</figcaption></figure>

<figure><img src="image_18.png" /><figcaption>**Scheme 5.** Synthesis of the 1,5-triazolyl and **47–52** conjugates.</figcaption></figure>

<figure><img src="image_19.png" /><figcaption>**Scheme 6.** Synthesis of the 1,4-triazolyl **53–58** conjugates.</figcaption></figure>

<table><caption>**Table 6.** Effect of MA and derivatives **34–37** on viability and inflammatory cytokine (IL-1β) production in LPS-stimulated PBMCs.</caption><thead><tr><th></th><th>Concentration (μM)</th><th>% PBMCs <sup>1</sup></th><th>% IL-1β Production <sup>2</sup></th><th>Ref.</th></tr></thead><tbody><tr><td>DMSO 0.33% + LPS</td><td></td><td>100</td><td>100</td><td></td></tr><tr><td>DEXA <sup>3</sup> + LPS</td><td>1</td><td>81</td><td>32</td><td></td></tr><tr><td>PRED <sup>4</sup> + LPS</td><td>70</td><td>67</td><td>43</td><td></td></tr><tr><td>ZVAD <sup>5</sup> + LPS</td><td>5</td><td>110</td><td>42</td><td></td></tr><tr><td>Code</td><td></td><td></td><td></td><td></td></tr><tr><td>MA</td><td></td><td>100</td><td>14</td><td></td></tr><tr><td></td><td></td><td>30</td><td>53</td><td>[52]</td></tr><tr><td>R</td><td>Time (min)</td><td>Yield (%)</td><td></td><td></td></tr><tr><td rowspan="2">34</td><td rowspan="2">4</td><td>100</td><td>92</td><td>71</td></tr><tr><td>30</td><td>92</td><td>Nd <sup>6</sup></td></tr><tr><td rowspan="2">35</td><td rowspan="2">6</td><td>100</td><td>98</td><td>56</td></tr><tr><td>30</td><td>94</td><td>Nd</td></tr></tbody></table>
<table><caption>**Table 6. Cont.**</caption><thead><tr><th></th><th></th><th></th><th>Concentration (µM)</th><th>% PBMCs <sup>1</sup></th><th>% IL-1β Production <sup>2</sup></th><th>Ref.</th></tr></thead><tbody><tr><td rowspan="2">36</td><td rowspan="2">[Image of 36]</td><td rowspan="2">6</td><td>100</td><td>66</td><td>100</td><td rowspan="4">[52]</td></tr><tr><td>30</td><td>93</td><td>Nd</td></tr><tr><td rowspan="2">37</td><td rowspan="2">[Image of 37]</td><td rowspan="2">5</td><td>100</td><td>97</td><td>95</td></tr><tr><td>30</td><td>80</td><td>Nd</td></tr></tbody></table>

¹ The anti-inflammatory activity of the tested compounds was assessed using LPS-stimulated human peripheral blood mono-nuclear cells (PBMCs) with LPS (lipopolysaccharide). ² %IL-1β production: indicates the anti-inflammatory activity compared to the starting material (MA). ³ Dexamethasone (DEXA, 1 mM). ⁴ Prednisolone (PRED, 70 mM). ⁵ ZVAD (5 mM). ⁶ Non-determined.

<table><caption>**Table 7.** Effect of MA and derivatives **38–42** on viability and inflammatory cytokine (IL-1β) production in LPS-stimulated PBMCs.</caption><thead><tr><th></th><th></th><th></th><th>Concentration (µM)</th><th>% PBMCs <sup>1</sup></th><th>% IL-1β Production <sup>2</sup></th><th>Ref.</th></tr></thead><tbody><tr><td colspan="2">DMSO 0.33% + LPS</td><td></td><td>100</td><td>100</td><td>100</td><td></td></tr><tr><td colspan="2">DEXA <sup>3</sup> + LPS</td><td></td><td>1</td><td>81</td><td>32</td><td></td></tr><tr><td colspan="2">PRED <sup>4</sup> + LPS</td><td></td><td>70</td><td>67</td><td>43</td><td></td></tr><tr><td colspan="2">ZVAD <sup>5</sup> + LPS</td><td></td><td>5</td><td>110</td><td>42</td><td></td></tr><tr><td colspan="2">Code</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td rowspan="2">MA</td><td></td><td></td><td>100</td><td>100</td><td>14</td><td rowspan="4">[52]</td></tr><tr><td></td><td></td><td>30</td><td>30</td><td>53</td></tr><tr><td>R</td><td>Time (min)</td><td>Yield (%)</td><td></td><td></td><td></td></tr><tr><td>38</td><td>[Image of 38]</td><td>4</td><td>96</td><td>100</td><td>88</td><td>82</td></tr><tr><td colspan="2"></td><td></td><td>30</td><td>82</td><td>Nd <sup>6</sup></td><td></td></tr><tr><td>39</td><td>[Image of 39]</td><td>4</td><td>98</td><td>100</td><td>74</td><td>34</td></tr><tr><td colspan="2"></td><td></td><td>30</td><td>88</td><td>Nd</td><td></td></tr><tr><td>40</td><td>[Image of 40]</td><td>7</td><td>90</td><td>100</td><td>71</td><td>74</td></tr><tr><td colspan="2"></td><td></td><td>30</td><td>91</td><td>Nd</td><td></td></tr><tr><td>41</td><td>[Image of 41]</td><td>6</td><td>96</td><td>100</td><td>81</td><td>52</td></tr><tr><td colspan="2"></td><td></td><td>30</td><td>83</td><td>Nd</td><td></td></tr><tr><td>42</td><td>[Image of 42]</td><td>6</td><td>94</td><td>100</td><td>95</td><td>91</td></tr><tr><td colspan="2"></td><td></td><td>30</td><td>93</td><td>Nd</td><td></td></tr></tbody></table>

¹ The anti-inflammatory activity of the tested compounds was assessed using LPS-stimulated human peripheral blood mono-nuclear cells (PBMCs) with LPS (lipopolysaccharide). ² %IL-1β production: indicates the anti-inflammatory activity compared to the starting material (MA). ³ Dexamethasone (DEXA, 1 mM). ⁴ Prednisolone (PRED, 70 mM). ⁵ ZVAD (5 mM). ⁶ Non-determined.
<table><caption>**Table 8.** Effect of MA and derivatives **43–46** on viability and inflammatory cytokine (IL-1β) production in LPS-stimulated PBMCs.</caption><thead><tr><th></th><th></th><th>Concentration (μM)</th><th>% PBMCs <sup>1</sup></th><th>% IL-1β Production <sup>2</sup></th><th>Ref.</th></tr></thead><tbody><tr><td colspan="2">DMSO 0.33% + LPS</td><td></td><td>100</td><td>100</td><td></td></tr><tr><td colspan="2">DEXA <sup>3</sup> + LPS</td><td>1</td><td>81</td><td>32</td><td></td></tr><tr><td colspan="2">PRED <sup>4</sup> + LPS</td><td>70</td><td>67</td><td>43</td><td></td></tr><tr><td colspan="2">ZVAD <sup>5</sup> + LPS</td><td>5</td><td>110</td><td>42</td><td></td></tr><tr><td colspan="2">Code</td><td></td><td></td><td></td><td></td></tr><tr><td rowspan="2">MA</td><td></td><td></td><td>100</td><td>14</td><td></td></tr><tr><td></td><td></td><td>30</td><td>53</td><td></td></tr><tr><td></td><td>R</td><td>Time (min)</td><td>Yield (%)</td><td></td><td></td></tr><tr><td rowspan="2">43</td><td rowspan="2">[Chemical Structure]</td><td rowspan="2">5</td><td>98</td><td>100</td><td>73</td><td rowspan="2">[52]</td></tr><tr><td>98</td><td>100</td><td>73</td><td>43</td></tr><tr><td rowspan="2">44</td><td rowspan="2">[Chemical Structure]</td><td rowspan="2">8</td><td>95</td><td>100</td><td>83</td><td rowspan="2">Nd <sup>6</sup></td></tr><tr><td>95</td><td>100</td><td>83</td><td>47</td></tr><tr><td rowspan="2">45</td><td rowspan="2">[Chemical Structure]</td><td rowspan="2">10</td><td>96</td><td>100</td><td>85</td><td rowspan="2">Nd <sup>6</sup></td></tr><tr><td>96</td><td>100</td><td>85</td><td>23</td></tr><tr><td rowspan="2">46</td><td rowspan="2">[Chemical Structure]</td><td rowspan="2">8</td><td>98</td><td>100</td><td>63</td><td rowspan="2">Nd <sup>6</sup></td></tr><tr><td>98</td><td>100</td><td>63</td><td>34</td></tr></tbody></table>

<table><caption>**Table 9.** Effect of MA and derivatives **47–52** on viability and inflammatory cytokine (IL-1β) production in LPS-stimulated PBMCs.</caption><thead><tr><th></th><th></th><th>Concentration (μM)</th><th>% PBMCs <sup>1</sup></th><th>% IL-1β Production <sup>2</sup></th><th>Ref.</th></tr></thead><tbody><tr><td colspan="2">DMSO 0.33% + LPS</td><td></td><td>100</td><td>100</td><td></td></tr><tr><td colspan="2">DEXA <sup>3</sup> + LPS</td><td>1</td><td>81</td><td>32</td><td></td></tr><tr><td colspan="2">PRED <sup>4</sup> + LPS</td><td>70</td><td>67</td><td>43</td><td></td></tr><tr><td colspan="2">ZVAD <sup>5</sup> + LPS</td><td>5</td><td>110</td><td>42</td><td></td></tr><tr><td colspan="2">Code</td><td></td><td></td><td></td><td></td></tr><tr><td rowspan="2">MA</td><td></td><td></td><td>100</td><td>14</td><td rowspan="2">[52]</td></tr><tr><td></td><td></td><td>30</td><td>53</td></tr><tr><td></td><td>R</td><td>Time (min)</td><td>Yield (%)</td><td></td><td></td></tr><tr><td rowspan="2">47</td><td rowspan="2">[Chemical Structure]</td><td rowspan="2">4</td><td>98</td><td>100</td><td>87</td><td rowspan="2">Nd <sup>6</sup></td></tr><tr><td>98</td><td>100</td><td>87</td><td>91</td></tr><tr><td colspan="2"></td><td></td><td>30</td><td>93</td><td>Nd <sup>6</sup></td></tr></tbody></table>

<footnote n="1">¹ The anti-inflammatory activity of the tested compounds was assessed using LPS-stimulated human peripheral blood mono-nuclear cells (PBMCs) with LPS (lipopolysaccharide). ² %IL-1β production: indicates the anti-inflammatory activity compared to the starting material (MA). ³ Dexamethasone (DEXA, 1 mM). ⁴ Prednisolone (PRED, 70 mM). ⁵ ZVAD (5 mM). ⁶ Non-determined.</footnote>
<table><caption>**Table 9. Cont.**</caption><thead><tr><th></th><th></th><th></th><th>Concentration (µM)</th><th>% PBMCs <sup>1</sup></th><th>% IL-1β Production <sup>2</sup></th><th>Ref.</th></tr></thead><tbody><tr><td rowspan="2">48</td><td rowspan="2">[Image of 48]</td><td rowspan="2">6</td><td>100</td><td>76</td><td>60</td><td rowspan="6">[52]</td></tr><tr><td>30</td><td>74</td><td>Nd</td></tr><tr><td rowspan="2">49</td><td rowspan="2">[Image of 49]</td><td rowspan="2">4</td><td>100</td><td>94</td><td>61</td></tr><tr><td>30</td><td>87</td><td>Nd</td></tr><tr><td rowspan="2">50</td><td rowspan="2">[Image of 50]</td><td rowspan="2">8</td><td>100</td><td>75</td><td>42</td></tr><tr><td>30</td><td>93</td><td>Nd</td></tr><tr><td rowspan="2">51</td><td rowspan="2">[Image of 51]</td><td rowspan="2">6</td><td>100</td><td>51</td><td>46</td></tr><tr><td>30</td><td>99</td><td>Nd</td></tr><tr><td rowspan="2">52</td><td rowspan="2">[Image of 52]</td><td rowspan="2">6</td><td>100</td><td>93</td><td>76</td></tr><tr><td>30</td><td>95</td><td>Nd</td></tr></tbody></table>

<table><caption>**Table 10.** Effect of MA and derivatives **53–58** on viability and inflammatory cytokine (IL-1β) production in LPS-stimulated PBMCs.</caption><thead><tr><th></th><th></th><th>Concentration (µM)</th><th>% PBMCs <sup>1</sup></th><th>% IL-1β Production <sup>2</sup></th><th>Ref.</th></tr></thead><tbody><tr><td colspan="2">DMSO 0.33% + LPS</td><td>100</td><td>100</td><td>100</td><td></td></tr><tr><td colspan="2">DEXA <sup>3</sup> + LPS</td><td>1</td><td>81</td><td>32</td><td></td></tr><tr><td colspan="2">PRED <sup>4</sup> + LPS</td><td>70</td><td>67</td><td>43</td><td></td></tr><tr><td colspan="2">ZVAD <sup>5</sup> + LPS</td><td>5</td><td>110</td><td>42</td><td></td></tr><tr><td colspan="2">Code</td><td></td><td></td><td></td><td></td></tr><tr><td rowspan="2">MA</td><td></td><td>100</td><td>14</td><td></td><td rowspan="6">[52]</td></tr><tr><td></td><td>30</td><td>53</td><td></td></tr><tr><td colspan="2">R</td><td>Time (min)</td><td>Yield (%)</td><td></td></tr><tr><td rowspan="2">53</td><td rowspan="2">[Image of 53]</td><td rowspan="2">2</td><td>100</td><td>92</td><td>62</td></tr><tr><td>30</td><td>91</td><td>Nd <sup>6</sup></td></tr><tr><td rowspan="2">54</td><td rowspan="2">[Image of 54]</td><td rowspan="2">2</td><td>100</td><td>71</td><td>65</td></tr><tr><td>30</td><td>75</td><td>Nd</td></tr></tbody></table>

<footnote n="1">¹ The anti-inflammatory activity of the tested compounds was assessed using LPS-stimulated human peripheral blood mono-nuclear cells (PBMCs) with LPS (lipopolysaccharide). ² %IL-1β production: indicates the anti-inflammatory activity compared to the starting material (MA). ³ Dexamethasone (DEXA, 1 mM). ⁴ Prednisolone (PRED, 70 mM). ⁵ ZVAD (5 mM). ⁶ Non-determined.</footnote>
<table><caption>**Table 10. Cont.**</caption><thead><tr><th></th><th></th><th></th><th></th><th>Concentration (µM)</th><th>% PBMCs <sup>1</sup></th><th>% IL-1β Production <sup>2</sup></th><th>Ref.</th></tr></thead><tbody><tr><td rowspan="2">55</td><td rowspan="2">[Chemical Structure]</td><td rowspan="2">4</td><td rowspan="2">94</td><td>100</td><td>83</td><td>82</td><td rowspan="6">[52]</td></tr><tr><td>30</td><td>55</td><td>Nd</td></tr><tr><td rowspan="2">56</td><td rowspan="2">[Chemical Structure]</td><td rowspan="2">4</td><td rowspan="2">94</td><td>100</td><td>92</td><td>21</td></tr><tr><td>30</td><td>74</td><td>Nd</td></tr><tr><td rowspan="2">57</td><td rowspan="2">[Chemical Structure]</td><td rowspan="2">2</td><td rowspan="2">96</td><td>100</td><td>88</td><td>59</td></tr><tr><td>30</td><td>97</td><td>Nd</td></tr><tr><td rowspan="2">58</td><td rowspan="2">[Chemical Structure]</td><td rowspan="2">2</td><td rowspan="2">95</td><td>100</td><td>97</td><td>53</td></tr><tr><td>30</td><td>88</td><td>Nd</td></tr></tbody></table>

### 3.3. Glycogen Phosphorylase Inhibitors Derivatives

Wen et al. [63] conducted a study wherein they reported a newly synthesized MA series of analogs that were assessed for their enzymatic inhibition properties against rabbit muscle glycogen phosphorylase a (GPa), which is readily available commercially and bears substantial similarity in sequence to the GPa of human liver. Throughout the synthesis, the methyl ester **59** was accompanied by treatment of MA (**1**) with iodomethane in the presence of K₂CO₃ in DMF at rt. The same was reported for MA esters **60** and **61**, which were produced in good yields by treating **1** with ethyl bromoacetate and N-chloromethylpyrazole. Ester **61** was subsequently transformed into **62** by hydrolysis of **61** with an aqueous solution of 4 N NaOH in THF without modifying the C-28 bond (Scheme 7). The reaction of MA (**1**) with 1,4-dibromobutane or 1,2-dibromoethane in DMF with K₂CO₃ at rt produced derivatives **63** and **64** (Scheme 8). Subsequently, heating **63** in refluxing EtOH with Et₃N resulted in the formation of compound **65**. The reaction of **63** or **64** with corresponding amines afforded conjugates **66–71**. In fact, stirring a mixture of **63**, triethylamine, in DMF with presence of K₂CO₃ at rt led to **66** (Scheme 8). The reduction of compound **72** with NaBH₄ produced compounds **74** and **76**. Similarly, the reduction of **73** afforded **75** and **77** (Scheme 9).

<figure><img src="image_20.png" /><figcaption>**Scheme 7.** Route of synthesis of MA derivatives **59–62**. i: RX (ethyl bromoacetate, CH₃I or N-chloromethylpyrazole), DMF, K₂CO₃; ii: 4 N NaOH, THF.</figcaption></figure>

<footnote n="1">¹ The anti-inflammatory activity of the tested compounds was assessed using LPS-stimulated human peripheral blood mono-nuclear cells (PBMCs) with LPS (lipopolysaccharide). ² %IL-1β production: indicates the anti-inflammatory activity compared to the starting material (MA). ³ Dexamethasone (DEXA, 1 mM). ⁴ Prednisolone (PRED, 70 mM). ⁵ ZVAD (5 mM). ⁶ Non-determined.</footnote>
<table><caption>**Table 12.** Effects of MA analogs **63–71** on rabbit muscle GPa (glycogen phosphorylase a).</caption><thead><tr><th>Code</th><th>R</th><th>Yield (%)</th><th>GPa Inhibition Assay Results<br>RMGPa<sup>1</sup> IC<sub>50</sub> (µM)</th></tr></thead><tbody><tr><td>63</td><td><b>-Br</b><br>n = 2</td><td>-</td><td>50</td></tr><tr><td>64</td><td><b>-Br</b><br>n = 4</td><td>-</td><td>7</td></tr><tr><td>65</td><td><b>-OH</b><br>n = 2</td><td>78</td><td>153</td></tr><tr><td>66</td><td><b>-N(C<sub>2</sub>H<sub>5</sub>)<sub>2</sub></b><br>n = 2</td><td>82</td><td>51</td></tr><tr><td>67</td><td><b>-N</b><br>n = 2</td><td>-</td><td>31</td></tr><tr><td>68</td><td><b>-N</b><br>n = 2</td><td>-</td><td>43</td></tr><tr><td>69</td><td><b>-N(C<sub>2</sub>H<sub>5</sub>)<sub>2</sub></b><br>n = 4</td><td>-</td><td>62</td></tr><tr><td>70</td><td><b>-N</b><br>n = 4</td><td>-</td><td>580</td></tr></tbody></table>

### 3.4. Antibacterial and Antifungal Derivatives

Blanco-Cabra et al. [40] reported that a series of MA C-28 amide conjugates have been synthesized and tested for their in vitro antibacterial efficacy and toxicity properties. First, after activation of the MA carboxyl group with TBTU, the MA-TBTU derivatives were obtained by adding TBTU in the presence of DIEA in anhydrous THF at room temperature. Second, the MA-TBTU derivatives were dissolved in CH₂Cl₂ and reacted with the corresponding diamine reagents (DAD, HDA, and PDA) in the presence of potassium carbonate, forming both monomers (MA-PDA, MA-HDA, MA-DAD) and dimers (MA-PDA-MA, MA-HDA-MA, MA-DAD-MA). Conversely, the reaction of MA-TBTU derivatives with N,N-dimethyl-1,3-propanediamine exclusively produced MA-DMPA (Scheme 10). The study showed that MA-HDA derivatives possessed enhanced in vitro antimicrobial effectiveness and lower toxicity than the original compound MA (1) on the other side (Table 14). This decrease is evident from a reduction in the minimum inhibitory concentration (MIC) against most Gram-positive bacteria assessed, highlighting their effectiveness, especially against Methicillin-Resistant S. aureus (MRSA) and S. aureus. Additionally, in the *Galleria mellonella* animal infection model, MA-HDA exhibited heightened in vivo activity [40]. In the context of planktonic bacterial growth, the MA amide derivatives were assessed for their antibacterial effect. The results presented in Table 14 depict the antibacterial efficacy in terms of MIC₅₀ (the minimal inhibitory concentration 50%). As a result, it was proven that among all examined derivatives, MA-HDA was the most potent conjugate showing enhanced activity, consistently keeping or enhancing MA's antimicrobial properties through most tested strains, with specific significance noted against S. aureus and MRSA (66% reduction in MIC₅₀ with MIC₅₀ values of 25 µM), which represents a substantial improvement compared to the original compound (MA, MIC₅₀ of 0.15 µM). An analogous pattern was noted in case of MA-DAD (reducing MRSA with MIC₅₀ by 66%). It was demonstrated that the in vitro toxicity, quantified in Table 14 as the concentration required to achieve a 50% reduction in cell viability (CC₅₀), shows that the MA-DAD and HDA derivatives exhibited no greater toxicity than their precursor. This is noteworthy, considering its improved antimicrobial activity against certain bacterial strains. Next, these derivatives were evaluated for their efficacy and in vivo toxicity in *Galleria mellonella*. In

<footnote n="1">¹ Rabbit muscle glycogen phosphorylase a.</footnote>
fact, *G. mellonella* represents the toxicity evaluation model (lethal dose) of the newly tested antimicrobial derivatives [64]. The evaluation involved determining the compound dose per kilogram that resulted in a 50% mortality rate in greater wax moth larvae, referred to as LD₅₀ (the lethal dose 50). It is worth noting that selectivity indexes (SI), whether in cells or *G. mellonella*, underscored the heightened efficacy of the MA-HDA derivative against *S. aureus* growth in relation with their toxicity (SI = 17.9 or 661). It was notable that the SI calculation and the choice of *G. mellonella* as a model of an invertebrate animal for in vivo toxicity assessment is pivotal. The selectivity index experiences a substantial boost when calculated using LD₅₀ rather than CC₅₀ (refer to Table 14). In certain instances, in vivo toxicity can markedly differ; for instance, the in vitro toxicity of MA-HDA was enhanced, while its in vivo toxicity diminished compared to the parent compound MA.

<table><caption>**Table 13.** Effects of MA analogs 72–77 on rabbit muscle GPa (glycogen phosphorylase a).</caption><thead><tr><th>Code</th><th>R</th><th>Yield (%)</th><th>GPa Inhibition Assay Results<br>RMGPa<sup>1</sup> IC<sub>50</sub> (µM)</th></tr></thead><tbody><tr><td>72</td><td>-Ac</td><td>-</td><td>29</td></tr><tr><td>73</td><td>-TBDMS</td><td>-</td><td>Nd<sup>2</sup></td></tr><tr><td>74</td><td>-Ac</td><td>75</td><td>80</td></tr><tr><td>75</td><td>-TBDMS</td><td>74</td><td>1707</td></tr><tr><td>76</td><td>-Ac</td><td>14</td><td>63</td></tr><tr><td>77</td><td>-TBDMS</td><td>19</td><td>580</td></tr></tbody></table>

In another study, Chouaïb et al. [65] synthesized a series of MA C-2 and C-3 esters that were assessed for their antifungal and antibacterial potential. The condensation of MA (1) with multiple acid chlorides in presence of DMAP led to bis-acylated esters **85–89** and mono-acylated esters **90–94**. The treatment of MA (1) with cyclic anhydrides produced exclusively the bis-esters **95–99** (Scheme 11). Results showed that derivatives with sulfur moiety (**85** and **90**; MIC = 5 µg/mL) and chlorine atoms demonstrated a pronounced antibacterial potential (Table 14). The sulfur triterpenoid **85** exhibited the highest antifungal activity, showing good effectiveness against *Trichoderma harzianum*, *Aspergillus niger*, *Penicillium italicum*, *Penicillium digitatum* and *Aspergillus flavus*. However, compound **90** was the most active against *Aspergillus niger* (MIC = 19 µg/mL). It is noteworthy that the fungus *Penicillium italicum* had the highest sensitivity to the derivative with sulfur atom **85** (inhibition zone = 24 mm) as outlined in Table 15.

<figure><img src="image_21.png" /><figcaption>**Scheme 10.** Synthesis of pentacyclic dihydroxyterpene carboxylic acid (MA) derivatives **78–84**. Reagents and conditions: Diisopropylethylamine (DIEA), THF, CH₂Cl₂, rt, TBTU (O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate), HDA (hexane-1,6-diamine), PDA (propane-1,3-diamine), and DAD (decane-1,10-diamine), K₂CO₃, DMPA.</figcaption></figure>

<footnote n="1">¹ Rabbit muscle glycogen phosphorylase a. ² Not determined.</footnote>
<table><caption>**Table 14.** Antibacterial activity, in vitro and in vivo toxicity of MA amine derivatives **78–84**.</caption><thead><tr><th rowspan="3">Code</th><th rowspan="3">Compound</th><th rowspan="3">Yield (%)</th><th colspan="10">MIC<sub>50</sub> (µM)</th></tr><tr><th colspan="5">Gram-Positive</th><th colspan="5">Gram-Negative</th></tr><tr><th>S. aureus</th><th>S. aureus MRSA</th><th>S. epidermidis</th><th>S. mutans</th><th>S. faecalis</th><th>E. coli</th><th>P. aeruginosa</th><th>CC<sub>50</sub><sup>1</sup> (µM/mL)</th><th>LD<sub>50</sub><sup>2</sup> (µM/mL)</th></tr></thead><tbody><tr><td>1</td><td>MA</td><td>-</td><td>0.03<br><b>20.9/504</b><sup>4</sup></td><td>0.15</td><td>0.05<br><b>12.5/302</b></td><td>0.03<br><b>20.9/504</b></td><td>0.03<br><b>20.9/504</b></td><td>NA<sup>3</sup></td><td>NA</td><td>0.66</td><td>0.64</td></tr><tr><td>78</td><td>MA-PDA</td><td>63</td><td>0.37</td><td>0.37</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td><td>0.37</td><td>0.58</td><td>-</td></tr><tr><td>79</td><td>MA-HDA</td><td>64</td><td>0.02<br><b>17.9/661</b></td><td>0.04<br><b>10.7/397</b></td><td>0.03<br><b>13.4/496</b></td><td>0.09<br><b>5.4/198</b></td><td>0.14</td><td>NA</td><td>NA</td><td>0.50</td><td>0.75</td></tr><tr><td>80</td><td>MA-DAD</td><td>62</td><td>0.03<br><b>10.5</b></td><td>0.03<br><b>8.4</b></td><td>0.01<br><b>21</b></td><td>0.03<br><b>8.4</b></td><td>0.03<br><b>8.4</b></td><td>NA</td><td>NA</td><td>0.39</td><td>-</td></tr><tr><td>81</td><td>MA-DMPA</td><td>90</td><td>0.13</td><td>0.15</td><td>0.13</td><td>0.15</td><td>0.13</td><td>NA</td><td>NA</td><td>NC<sup>5</sup></td><td>-</td></tr><tr><td>82</td><td>MA-PDA MA</td><td>27</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td><td>0.11</td><td>-</td></tr><tr><td>83</td><td>MA-HDA-MA</td><td>28</td><td>NA</td><td>NA</td><td>100</td><td>100</td><td>NA</td><td>NA</td><td>NA</td><td>0.29</td><td>-</td></tr><tr><td>84</td><td>MA-DAD-MA</td><td>30</td><td>NA</td><td>NA</td><td>0.04</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td><td>0.30</td><td>-</td></tr></tbody></table>

<figure><img src="image_22.png" /><figcaption>**Scheme 11.** Synthesis of pentacyclic dihydroxyterpene carboxylic acid (MA) derivatives **85–99**. i: Chloride acid, Py Anhy, N,N-dimethyl-4-aminopyridine (DMAP), reflux, 4H; ii: Cyclic anhydrid, DMSO, 40°C, DMAP, 24h.</figcaption></figure>

<table><caption>**Table 15.** Antifungal activity of MA esters derivatives **85–99**.</caption><thead><tr><th rowspan="3">Code</th><th rowspan="3">Compound</th><th rowspan="3">Yield (%)</th><th colspan="8">MIC<sub>50</sub> (µM)<sup>1</sup></th></tr><tr><th colspan="2">Gram-Positive</th><th colspan="2">Gram-Negative</th><th colspan="5">Zone of Inhibition (mm)</th></tr><tr><th>S. aureus</th><th>S. faecalis</th><th>E. coli</th><th>P. aeruginosa</th><th>A. flavus</th><th>A. niger</th><th>P. digitatum</th><th>P. italicum</th><th>T. harzianum</th></tr></thead><tbody><tr><td>1</td><td>MA</td><td>-</td><td>15</td><td>30</td><td>15</td><td>15</td><td>NI<sup>2</sup></td><td>9</td><td>NI</td><td>13</td><td>9.5</td></tr><tr><td>85</td><td></td><td>59</td><td>5</td><td>10</td><td>10</td><td>25</td><td>9</td><td>13.5</td><td>11.5</td><td>24</td><td>26</td></tr></tbody></table>

<footnote n="1">¹ Cytotoxicity (CC₅₀) was evaluated on human alveolar epithelial A459 cells. ² Lethal doses LD₅₀ were evaluated in *Galleria mellonella* larvae. ³ No activity. ⁴ Selectivity index (SI), calculated as CC₅₀/MIC₅₀ and LD₅₀/MIC₅₀ (in bold). ⁵ NC, non-cytotoxic.</footnote>
<table><caption>Table 15. *Cont.*</caption><thead><tr><th rowspan="3">Code</th><th rowspan="3">Compound</th><th rowspan="3">Yield (%)</th><th colspan="8">MIC<sub>50</sub> (µM)<sup>1</sup></th></tr><tr><th colspan="4">Gram-Positive</th><th colspan="4">Gram-Negative</th><th colspan="4">Zone of Inhibition (mm)</th></tr><tr><th>S. aureus</th><th>S. faecalis</th><th>E. coli</th><th>P. aeruginosa</th><th>A. flavus</th><th>A. niger</th><th>P. digitatum</th><th>P. italicum</th><th>T. harzianum</th></tr></thead><tbody><tr><td>86</td><td></td><td>48</td><td>15</td><td>5</td><td>15</td><td>5</td><td>NI</td><td>NI</td><td>NI</td><td>NI</td><td>9.5</td></tr><tr><td>87</td><td></td><td>55</td><td>5</td><td>5</td><td>5</td><td>5</td><td>NI</td><td>NI</td><td>15</td><td>NI</td><td>9.5</td></tr><tr><td>88</td><td></td><td>45</td><td>5</td><td>5</td><td>5</td><td>5</td><td>NI</td><td>NI</td><td>NI</td><td>NI</td><td>NI</td></tr><tr><td>89</td><td></td><td>52</td><td>150</td><td>100</td><td>300</td><td>150</td><td>NI</td><td>NI</td><td>NI</td><td>NI</td><td>NI</td></tr><tr><td>90</td><td></td><td>33</td><td>15</td><td>10</td><td>10</td><td>15</td><td>NI</td><td>19</td><td>15.5</td><td>14</td><td>16</td></tr><tr><td>91</td><td></td><td>32</td><td>100</td><td>25</td><td>15</td><td>10</td><td>NI</td><td>19.0</td><td>NI</td><td>NI</td><td>13</td></tr><tr><td>92</td><td></td><td>31</td><td>10</td><td>5</td><td>5</td><td>15</td><td>12</td><td>NI</td><td>NI</td><td>NI</td><td>NI</td></tr><tr><td>93</td><td></td><td>39</td><td>5</td><td>5</td><td>5</td><td>5</td><td>NI</td><td>NI</td><td>NI</td><td>NI</td><td>10</td></tr><tr><td>94</td><td></td><td>28</td><td>NI</td><td>NI</td><td>NI</td><td>NI</td><td>NI</td><td>NI</td><td>NI</td><td>13</td><td>NI</td></tr><tr><td>95</td><td></td><td>81</td><td>30</td><td>30</td><td>50</td><td>50</td><td>NI</td><td>NI</td><td>NI</td><td>NI</td><td>16</td></tr><tr><td>96</td><td></td><td>88</td><td>300</td><td>50</td><td>50</td><td>90</td><td>NI</td><td>NI</td><td>9</td><td>NI</td><td>9.5</td></tr></tbody></table>

<figure><img src="image_23.png" /></figure>

<figure><img src="image_24.png" /></figure>

<figure><img src="image_25.png" /></figure>

<figure><img src="image_26.png" /></figure>

<figure><img src="image_27.png" /></figure>

<figure><img src="image_28.png" /></figure>

<figure><img src="image_29.png" /></figure>

<figure><img src="image_30.png" /></figure>

<figure><img src="image_31.png" /></figure>

<figure><img src="image_32.png" /></figure>

<figure><img src="image_33.png" /></figure>
<table><caption>**Table 15. Cont.**</caption><thead><tr><th rowspan="3">Code</th><th rowspan="3">Compound</th><th rowspan="3">Yield (%)</th><th colspan="8">MIC<sub>50</sub> (µM) <sup>1</sup></th></tr><tr><th colspan="2">Gram-Positive</th><th colspan="4">Gram-Negative</th><th colspan="4">Zone of Inhibition (mm)</th></tr><tr><th>S. aureus</th><th>S. faecalis</th><th>E. coli</th><th>P. aeruginosa</th><th>A. flavus</th><th>A. niger</th><th>P. digitatum</th><th>P. italicum</th><th>T. harzianum</th></tr></thead><tbody><tr><td>97</td><td><img src="97_molecule.png" alt="Chemical structure of 97"></td><td>82</td><td>300</td><td>30</td><td>50</td><td>25</td><td>15</td><td>NI</td><td>13</td><td>NI</td><td>NI</td></tr><tr><td>98</td><td><img src="98_molecule.png" alt="Chemical structure of 98"></td><td>76</td><td>50</td><td>50</td><td>25</td><td>50</td><td>19</td><td>NI</td><td>NI</td><td>NI</td><td>17</td></tr><tr><td>99</td><td><img src="99_molecule.png" alt="Chemical structure of 99"></td><td>78</td><td>50</td><td>100</td><td>100</td><td>50</td><td>NI</td><td>NI</td><td>NI</td><td>NI</td><td>NI</td></tr><tr><td colspan="2">IMIPENEM</td><td>-</td><td>15</td><td>15</td><td>25</td><td>5</td><td>-</td><td>-</td><td>-</td><td>-</td><td>-</td></tr><tr><td colspan="2">FONG <sup>3</sup></td><td>-</td><td>-</td><td>-</td><td>-</td><td>-</td><td>40</td><td>28</td><td>45</td><td>43</td><td>34</td></tr></tbody></table>

### 3.5. *Derivatives with Herbicide Activity*

In their study, Nejma et al. [66] conducted the semi-synthesis of novel hybrid compounds by employing a 1,3-dipolar cycloaddition method that included phthalimide-based azides and propargylated MA **100** (Scheme 12). By employing CuAAC cycloaddition conditions using microwave irradiation, the reaction selectively produced various 1,4-disubstituted triazole derivatives **101–107** in different yields, within 5 min as a maximum reaction time. The efficacy of these 1,4-disubstituted triazole compounds in inhibiting seed germination and consequently impeding plant growth was assessed, demonstrating encouraging properties that could act as templates for developing effective and valuable herbicides. Following the synthesis of the MA-based analogs, their impact on regulating seed germination and the initial development phases of *Lactuca sativa* L. as the target plant was investigated. Results outlined in Table 16 demonstrated notable herbicidal potential, with inhibition reaching up to 100%. Within the series based on MA, MA (1) displayed a minimal inhibition percentage equal to 5.56%. Conversely, MA propargylation demonstrated a contrasting impact. Therefore, this compound can serve as a reference in the development of triazolophthalimide hybrid compounds based on MA. The herbicidal impacts of the synthesized triazoles **101–107** (Table 16) exhibited increased efficacy in comparison to propargylated MA **100**. These analogs notably hindered total germination, ranging from 91.79 to 100%. Based on the existing literature and the effects of propargylated MA **100**, the herbicidal potential of compounds **101–107** was primarily attributed to the additional triazolomethyl phthalimide component [67]. Notably, it is crucial to highlight that the presence of compound **105** resulted in 100% complete inhibition of seed germination. In the phthalimide series, as hypothesized previously, the increased inhibitory effect on germination seen in this study is likely caused by the presence of the thiol moiety within the structure of the hybrid compound. In conclusion, MA shows minimal inhibitory effects on *Lactuca sativa* L. seeds germination in comparison to propargylated MA **100** which appears to enhance their growth. Significantly, the transition in the activity of propargylated MA **100** from promoting to inhibiting germination in the synthesized compounds is clearly attributed to the presence of the methyltriazolo and phthalimide moieties. The significant impacts of these new hybrid molecules mainly stem from the connection between MA and phthalimide components through the triazole viaduct.

<footnote n="1">¹ MIC (µg/mL): minimum inhibitory concentration, ² NI: No inhibition zone detected. ³ FONG: Carbendazim 0.5 mg/mL.</footnote>
<figure><img src="image_34.png" /><figcaption>**Scheme 12.** Synthesis of MA 1,4-triazolyl derivatives **100–107**. i: NaH, 80%; ii: sodium ascorbate, CuSO₄·5H₂O (condition a); CuI, MW-250 W, 39–56% (condition b).</figcaption></figure>

### 3.6. Anti-Diabetic Derivatives

Zeng et al. [68] investigated the synthesis of a series of derivatives coupling MA with amino acids, followed by the in vitro assessment of their inhibitory activity against α-glucosidase. The precursor MA (1) was first converted into the 2α, 3β-O-diacetate by treatment with Ac₂O. This intermediate was then reacted with oxalyl chloride and subsequently condensed with the appropriate amino acid methyl/ethyl ester hydrochlorides (like L-valine, γ-aminobutyric acid, glycine). The final products, **108** and **109–121**, were obtained through a simple hydrolysis (Scheme 13). Results showed that all newly synthesized derivatives exhibited varying α-glucosidase inhibitory effect in comparison to acarbose in cases of using the DMSO or EtOH-H₂O system as solvents (Table 17). Specifically, both the derivatives and acarbose demonstrated a reduced inhibitory effect compared to that of the precursor MA (1). Notably, among the presented derivatives, those with a C-28 amide side chain featuring two free carboxyl groups (113: IC₅₀ = 382 µM) displayed higher inhibitory activity than acarbose (IC₅₀ = 484 µM) in both EtOH and DMSO systems, except for derivative 112. Within the ethanol-water system, the majority of derivatives displayed slightly reduced inhibitory effect compared to acarbose. Notably, compounds with only one free carboxyl group on the C-28 amide side chain displayed lower inhibitory potential compared to those featuring two free carboxyl groups on the C-28 amide side chain (IC₅₀ values equal to 608 and 798 µM for **116** and **117**, respectively). Interestingly, the lack of a free hydroxyl group on the C-28 amide side chain did not impact the inhibitory effects.

<figure><img src="image_35.png" /><figcaption>**Scheme 13.** Synthesis of MA derivatives **108–121**. i: (CH₃CO)₂O, Pyridine, 18h, rt; ii: (COCl)₂, CH₂Cl₂, rt; iii: amino acid methyl (ethyl) ester hydrochloride, Et₃N, CH₂Cl₂; iv: 4 N NaOH, CH₃OH.</figcaption></figure>
<table><caption>**Table 16.** Effects of 1,4-triazolyl derivatives **100–107** of MA on root length (R<sup>L</sup>), shoot length (S<sup>L</sup>) and total inhibition (G<sup>T</sup>) of *Lactuca sativa* L.</caption><thead><tr><th></th><th></th><th>G<sup>T</sup> (1)</th><th>R<sup>L</sup> (2)</th><th>S<sup>L</sup> (3)</th></tr></thead><tbody><tr><td>Control</td><td></td><td>01.89</td><td>98.57</td><td>98.94</td></tr><tr><td>Code</td><td></td><td></td><td></td><td></td></tr><tr><td>MA</td><td></td><td>5.56</td><td>97.81</td><td>95.70</td></tr><tr><td>100</td><td></td><td>0.00</td><td>100</td><td>100</td></tr><tr><td></td><td>R</td><td colspan="3">Yield (%)</td></tr><tr><td></td><td></td><td>Condition (a)</td><td>Condition (b)</td><td></td></tr><tr><td>101</td><td>-O</td><td>36</td><td>56</td><td>91.79</td></tr><tr><td>102</td><td>-OH</td><td>34</td><td>55</td><td>96.00</td></tr><tr><td>103</td><td>-OAc</td><td>32</td><td>52</td><td>92.44</td></tr><tr><td>104</td><td>EtOAc</td><td>33</td><td>56</td><td>94.85</td></tr><tr><td>105</td><td>EtSH</td><td>34</td><td>56</td><td>100.00</td></tr><tr><td>106</td><td>EtOMe</td><td>31</td><td>47</td><td>95.79</td></tr><tr><td>107</td><td>EtOMe</td><td>29</td><td>39</td><td>98.21</td></tr></tbody></table>

<table><caption>**Table 17.** In vitro evaluation of the inhibitory effect of MA derivatives **108–121** on α-glucosidase in different measurement systems.</caption><thead><tr><th rowspan="2">Code</th><th rowspan="2">R</th><th rowspan="2">Yield (%)</th><th colspan="2">IC<sub>50</sub> (μM)</th><th rowspan="2">Ref.</th></tr><tr><th>EtOH (5%)/H<sub>2</sub>O</th><th>DMSO (5%)</th></tr></thead><tbody><tr><td>108</td><td>-</td><td>70</td><td>987</td><td>-</td><td></td></tr><tr><td>109</td><td>-CH(CH<sub>3</sub>)C<sub>2</sub>H<sub>5</sub></td><td>65</td><td>847</td><td>-</td><td></td></tr><tr><td>110</td><td>-CH(CH<sub>3</sub>)<sub>2</sub></td><td>68</td><td>NI<sup>1</sup></td><td>NI</td><td></td></tr><tr><td>111</td><td>-CHOHCH<sub>3</sub></td><td>65</td><td>998</td><td>-</td><td></td></tr><tr><td>112</td><td>-CH<sub>2</sub>CH<sub>2</sub>COOH</td><td>62</td><td>495</td><td>486</td><td></td></tr><tr><td>113</td><td>-CH<sub>2</sub>COOH</td><td>64</td><td>382</td><td>438</td><td></td></tr><tr><td>114</td><td>-H</td><td>75</td><td>1000</td><td>-</td><td></td></tr><tr><td>115</td><td>-CH<sub>2</sub>OH</td><td>68</td><td>1321</td><td>-</td><td></td></tr><tr><td>116</td><td>-CH<sub>2</sub>CH(CH<sub>3</sub>)<sub>2</sub></td><td>66</td><td>608</td><td>-</td><td>[68]</td></tr><tr><td>117</td><td>-CH<sub>2</sub>C<sub>6</sub>H<sub>5</sub></td><td>63</td><td>798</td><td>-</td><td></td></tr><tr><td>118</td><td>-CH<sub>3</sub></td><td>69</td><td>987</td><td>-</td><td></td></tr><tr><td>119</td><td>-NCH<sub>2</sub>CH<sub>3</sub>CH<sub>3</sub>CH</td><td>71</td><td>NI</td><td>-</td><td></td></tr><tr><td>120</td><td>-CH<sub>2</sub>C<sub>6</sub>H<sub>4</sub>-p-OH</td><td>73</td><td>684</td><td>-</td><td></td></tr><tr><td>121</td><td>-CH<sub>2</sub>CH<sub>2</sub>SCH<sub>3</sub></td><td>62</td><td>598</td><td>-</td><td></td></tr><tr><td>Acarbose</td><td>-</td><td>-</td><td>484</td><td>447</td><td></td></tr><tr><td>MA</td><td>-</td><td>-</td><td>-</td><td>283</td><td></td></tr></tbody></table>

<footnote>(1) Total inhibition of *Lactuca sativa* L. (2) Root length. (3) Shoot length.</footnote>

<footnote n="1">¹ NI: No inhibition.</footnote>
In another study, Huang et al. [69] reported the synthesis of a series of MA derivatives by coupling the piperazine-L-amino acid complex at the C-28 site of the parent compound **1**. Firstly, MA (**1**) was acetylated by reacting with acetic anhydride. This intermediate was then reacted with oxalyl chloride and condensed with piperazines successively in the presence of trimethylamine. After reactions of dehydration and condensation using *N*-benzyloxycarbonyl-L-amino acid, the target compounds **122–131** were obtained by both reduction and hydrolysis reactions (Scheme 14). The final derivatives were tested in vitro for their α-glucosidase inhibitory activity (Table 18). The results indicate that the α-glucosidase inhibitory activity of compound **126** is close to that of the reference acarbose in the EtOH-H₂O system. In comparison to the ethanol-water system, the DMSO system yielded lower IC₅₀ values for the derivatives. Among all the synthesized derivatives, compound **126**, which includes a piperazine-L-aspartic conjugate, showed a similar α-glucosidase inhibitory effect (IC₅₀ = 591 µM) to acarbose (IC₅₀ = 347 µM). Upon inspecting the molecular structure, the presence of a free carboxyl group on the amino acid's branched chain in compound **126** was found to be crucial in improving its α-glucosidase inhibitory activity. Furthermore, it was noted that conjugates resulting from the combination of triterpenoid acid (MA) with serine (**128** IC₅₀ = 2754 µM) and threonine (**129** IC₅₀ = 2579 µM) displayed comparable α-glucosidase inhibitory properties to other derivatives. Notably, these two compounds, which feature an additional hydroxyl group in the side chain, did not lead to an enhancement in α-glucosidase inhibitory activity.

<figure><img src="image_36.png" /><figcaption>**Scheme 14.** The synthetic pathway of pentacyclic triterpenoid acid (MA) derivatives **122–131**. I: Ac₂O, Py; ii: oxalyl chloride, Et₃N; iii: piperazines, Et₃N; iv: EDCI (1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide); v: H₂, CH₃OH; vi: CH₃OH/THF, 4 N NaOH, 25°C.</figcaption></figure>

Liu's research [70] revealed another noteworthy discovery, demonstrating that within the class of pentacyclic tricarboxylic acid-piperazine analogs, a range of C28-modified analogs of MA with saturated nitrogen heterocycle segments (such as 1-deoxynojirimycin or piperazines) was prepared. MA was initially reacted with α,ω-bromoalkanes. The resulting intermediate was then subjected to a nucleophilic substitution reaction with 1-DNJ to produce MA-DNJ analogs **132–149** (Scheme 15). Further, MA (**1**) was acetylated using acetic anhydride. The resulting intermediate was then reacted with oxalyl chloride and piperazines in the presence of Et₃N. The final products **140–142** were obtained through a subsequent hydrolysis reaction (Scheme 16). This process entailed merging two bioactive components via a covalent link, generating a unique hybrid biological entity following the concept of active splicing. Subsequently, the α-glucosidase inhibitory activity of these synthesized compounds was assessed in vitro. The results revealed that certain analogs like **142**: IC₅₀ = 768.5, **133**: IC₅₀ = 1468.4 and **141**: IC₅₀ = 499.6 µM) exhibited higher inhibitory activity against α-glucosidase in comparison with the precursor MA (IC₅₀ = 2540.6 µM). Specifically, compound **141** (IC₅₀ = 499.6 µM) demonstrated stronger inhibitory activity
than acarbose (IC₅₀ = 606 µM). To explore the inhibitory impact of the synthesized analogs on α-glucosidase, all final products were dissolved in DMSO for in vitro inhibition experiments. As outlined in Table 19, most compounds exhibit significant inhibitory effects against α-glucosidase. In the initial series of triterpenic acid-DNJ derivatives (132–139), a lower IC₅₀ value than the primary compound MA (1) (IC₅₀ = 2540.6 µM) were observed for compounds 132 (IC₅₀ = 2041.4 µM), 133 (IC₅₀ = 1468.4 µM), and 134 (IC₅₀ = 1718.4 µM) containing an alkyl chain linker (2–4 carbon atoms). However, with the introduction of a longer hydrophobic carbon chain (comprising 4–8 carbon atoms) into the compound structure, the inhibitory activity of the analogs decreased compared to the parent compound MA (1), as observed in compounds like 137 (IC₅₀ = 3068.4 µM) and 135 (IC₅₀ = 3660.4 µM). The combination of pentacyclic dihydroxytriterpenecarboxylic acid MA (1) with piperazines (specifically 140–142, part of the second series of derivatives) resulted in compounds where the piperazine component with one free hydroxyl (141: IC₅₀ = 499.6 µM) and amino groups (142: IC₅₀ = 768.5 µM) exhibited notably higher inhibitory activity than MA alone (IC₅₀ = 2540.6 µM) as depicted in Table 20. Particularly noteworthy is that compound 141 displayed superior hypoglycemic activity compared to acarbose (IC₅₀ = 606 µM). These results emphasize that incorporating a free hydroxyl or an amino group into the piperazine substructure of the pentacyclic triterpene acid derivatives can increase the modified compounds' α-glucosidase inhibition effect, which is the case of 141 compared to 140 and 142 compared to 140.

<table><caption>**Table 18.** In vitro evaluation of the inhibitory effect of MA derivatives 122–131 on α-glucosidase in different measurement systems.</caption><thead><tr><th rowspan="2">Code</th><th rowspan="2">R</th><th rowspan="2">Yield (%)</th><th colspan="2">IC<sub>50</sub> (µM)</th><th rowspan="2">Ref.</th></tr><tr><th>EtOH (5%)/H<sub>2</sub>O</th><th>DMSO (5%)</th></tr></thead><tbody><tr><td>122</td><td>-H</td><td>83</td><td>3638</td><td>-</td><td></td></tr><tr><td>123</td><td>-CH<sub>2</sub>C<sub>6</sub>H<sub>5</sub></td><td>86</td><td>4072</td><td>-</td><td></td></tr><tr><td>124</td><td>-CH(CH<sub>3</sub>)<sub>2</sub></td><td>85</td><td>NI<sup>1</sup></td><td>NI</td><td></td></tr><tr><td>125</td><td>-CH<sub>3</sub></td><td>88</td><td>2754</td><td>-</td><td></td></tr><tr><td>126</td><td>-CH<sub>2</sub>COOH</td><td>87</td><td>591</td><td>-</td><td></td></tr><tr><td>127</td><td>-CH<sub>2</sub>CH<sub>2</sub>CH<sub>2</sub>NH<sub>2</sub></td><td>89</td><td>NI</td><td>NI</td><td rowspan="5">[69]</td></tr><tr><td>128</td><td>-CH<sub>2</sub>OH</td><td>87</td><td>2754</td><td>-</td></tr><tr><td>129</td><td>-CHOHCH<sub>3</sub></td><td>89</td><td>2579</td><td>-</td></tr><tr><td>130</td><td>-H</td><td>78</td><td>1505</td><td>1505</td></tr><tr><td>131</td><td>-CH<sub>3</sub></td><td>72</td><td>1506</td><td>1193</td></tr><tr><td>Acarbose</td><td>-</td><td>-</td><td>374</td><td>493</td><td></td></tr><tr><td>MA</td><td>-</td><td>-</td><td>-</td><td>83</td><td></td></tr></tbody></table>

<figure><img src="image_37.png" /><figcaption>**Scheme 15.** Synthesis of derivatives of pentacyclic dihydroxyterpene carboxylic acid 132–139. i: K₂CO₃, 25°C; ii: K₂CO₃, DMF, N₂, KI, 50 °C.</figcaption></figure>

<footnote n="1">¹ NI: No inhibition.</footnote>
<figure><img src="image_38.png" /><figcaption>**Scheme 16.** Synthesis of derivatives of pentacyclic dihydroxyterpene carboxylic acid **140–142**. i: Ac₂O, Py; ii: Et₃N, oxalyl chloride; iii: piperazines, Ac₂O; iv: 4 N NaOH, CH₃OH/THF, rt.</figcaption></figure>

<table><caption>**Table 19.** In vitro evaluation of the inhibitory effect of MA derivatives **132–139** on α-glucosidase in different measurement systems.</caption><thead><tr><th rowspan="2">Code</th><th rowspan="2">R</th><th rowspan="2">Yield (%)</th><th colspan="2">IC<sub>50</sub> (µM)</th><th rowspan="2">Ref.</th></tr><tr><th>EtOH (5%)/H<sub>2</sub>O</th><th>DMSO (5%)</th></tr></thead><tbody><tr><td>132</td><td>n = 2</td><td>52</td><td>-</td><td>2041.4</td><td rowspan="10">[70]</td></tr><tr><td>133</td><td>n = 3</td><td>50</td><td>-</td><td>1468.4</td></tr><tr><td>134</td><td>n = 4</td><td>50</td><td>-</td><td>1718.4</td></tr><tr><td>135</td><td>n = 5</td><td>50</td><td>-</td><td>3660.4</td></tr><tr><td>136</td><td>n = 6</td><td>45</td><td>-</td><td>NI<sup>1</sup></td></tr><tr><td>137</td><td>n = 8</td><td>47</td><td>-</td><td>3068.4</td></tr><tr><td>138</td><td>n = 10</td><td>50</td><td>-</td><td>/<sup>2</sup></td></tr><tr><td>139</td><td>n = 12</td><td>54</td><td>-</td><td>/<sup>2</sup></td></tr><tr><td>Acarbose</td><td>-</td><td>-</td><td>-</td><td>606</td></tr><tr><td>MA</td><td>-</td><td>-</td><td>-</td><td>2540.6</td></tr></tbody></table>

<table><caption>**Table 20.** In vitro evaluation of the inhibitory effect of MA derivatives **140–142** on α-glucosidase in different measurement systems.</caption><thead><tr><th rowspan="2">Code</th><th rowspan="2">R</th><th rowspan="2">Yield (%)</th><th colspan="2">IC<sub>50</sub> (µM)</th><th rowspan="2">Ref.</th></tr><tr><th>EtOH (5%)/H<sub>2</sub>O</th><th>DMSO (5%)</th></tr></thead><tbody><tr><td>140</td><td>NH</td><td>57</td><td>-</td><td>NI<sup>1</sup></td><td rowspan="4">[70]</td></tr><tr><td>141</td><td>N-(CH<sub>2</sub>)<sub>2</sub>OH</td><td>62</td><td>-</td><td>499.6</td></tr><tr><td>142</td><td>N-(CH<sub>2</sub>)<sub>2</sub>NH<sub>2</sub></td><td>66</td><td>-</td><td>768.5</td></tr><tr><td>Acarbose</td><td>-</td><td>-</td><td>-</td><td>606</td></tr><tr><td>MA</td><td>-</td><td>-</td><td>-</td><td>2540.6</td></tr></tbody></table>

In another study, Xu et al. [71] investigated the synthesis of a series of compounds by glycosylation of MA with monosaccharides and disaccharides. MA was initially transformed

<footnote n="1">¹ NI: No inhibition. ² The derivatives are insoluble in the solvent system used for measurement.</footnote>

<footnote n="1">¹ NI: No inhibition.</footnote>
into its benzyl ester. The resulting intermediate was then glycosylated using TMSOTf (cat) at the C(2α)-OH and C(3β)-OH positions. Finally, compounds **143–148** were synthesized through transesterification with NaOMe in methanol (Scheme 17). Hence, the solubility and inhibitory activity of α-glucosidase assay of these newly synthesized compounds showed that MA bis-disaccharide glycoside demonstrated higher water solubility and α-glucosidase inhibitory potential than the bis-monosaccharide glycoside (Table 21). It is noteworthy that compound **148** exhibited the highest α-glucosidase inhibitory activity (IC₅₀ = 684 µM). This result highlights the importance of the presence of the lactose group at C-3 and C-2, which helped improve and enhance the water solubility as well as the inhibitory activity.

<figure><img src="image_39.png" /><figcaption>**Scheme 17.** Synthesis of derivatives of pentacyclic dihydroxyterpene carboxylic acid **143–148**. i: BnBr, K₂CO₃, DMF; ii: CH₂Cl₂, TMSOTf, rt; iii: H₂, EtOAc, Pd-C; iv: MeOH, NaOMe.</figcaption></figure>

<table><caption>**Table 21.** In vitro evaluation of the inhibitory effect of MA derivatives **143–148** on α-glucosidase in different measurement systems.</caption><thead><tr><th rowspan="2">Code</th><th rowspan="2">R</th><th rowspan="2">Yield (%)</th><th colspan="2">IC<sub>50</sub> (µM)</th><th rowspan="2">Ref.</th></tr><tr><th>EtOH (5%)/H<sub>2</sub>O</th><th>DMSO (5%)</th></tr></thead><tbody><tr><td>143</td><td><img src="image_143.png" alt="Chemical structure of 143"></td><td>88.3</td><td>7865</td><td>-</td><td></td></tr><tr><td>144</td><td><img src="image_144.png" alt="Chemical structure of 144"></td><td>86.7</td><td>5362</td><td>-</td><td></td></tr><tr><td>145</td><td><img src="image_145.png" alt="Chemical structure of 145"></td><td>80.6</td><td>7837</td><td>-</td><td></td></tr><tr><td>146</td><td><img src="image_146.png" alt="Chemical structure of 146"></td><td>88.2</td><td>NI<sup>1</sup></td><td>NI</td><td>[71]</td></tr><tr><td>147</td><td><img src="image_147.png" alt="Chemical structure of 147"></td><td>70.9</td><td>684</td><td>705</td><td></td></tr><tr><td>148</td><td><img src="image_148.png" alt="Chemical structure of 148"></td><td>80.2</td><td>2940</td><td>-</td><td></td></tr><tr><td>MA</td><td></td><td>-</td><td>-</td><td>103</td><td></td></tr><tr><td>Acarbose</td><td></td><td>-</td><td>478</td><td>449</td><td></td></tr></tbody></table>

<footnote n="1">¹ NI: No inhibition.</footnote>
### 3.7. Inhibitors of Protein Tyrosine Phosphatase 1B Derivatives

Qui et al. [72] investigated the synthesis of a series of derivatives coupling MA (1) with fused heterocyclic rings (indole, pyrazine, thiazole, pyrimidin, pyrazole and isoxazole) at the C-2 and C-3 positions. The final quinoxaline derivative **149** was afforded by the reaction of the diketone with phenylenediamine and the final product, **150**, was then obtained through a dehydro-aromatization reaction with $MnO_2$. In addition, compound **152** was synthesized through an MeI scavenger (Scheme 18). Compounds **153** and **154** were obtained through a similar process as compound **152**, with the key difference being that the demethylation of the C-28 methyl ester was carried out in anhydrous DMF but in the presence of LiI, without the use of n-octylamine (Scheme 19). Compounds **160-163** were prepared by reacting the pyrazole derivative **159** with acetyl chloride, hexanoyl chloride, nicotinoyl chloride, and isonicotinoyl chloride, respectively (Scheme 20). Further, these newly synthesized derivatives were assessed for their inhibitory activities on PTP1B, TCPTP, and PTPs (Tables 22-24). The inhibitory effect of some conjugates was tested on various other PTPs which negatively regulate insulin dephosphorylation, such as src homology phosphatase-1 (SHP-1), leukocyte antigen-related phosphatase (LAR) and src homology phosphatase-2 (SHP-2). Results showed that the inhibition potential of most of the newly synthesized derivatives was increased significantly. It is noteworthy that derivatives **155** and **162** (Table 24) were the most potent PTP1B inhibitors, showing great activity in comparison with the parent compound **1** ($IC_{50}$ = 0.61 and 0.64 µM, respectively). We can highlight that derivative **162** was the most selective compound showing a 6.9-fold preference for PTP1B over TCPTP.

<figure><img src="image_40.png" /><figcaption>**Scheme 18.** Synthesis of MA derivatives **149-150**. i: BnCl, DMF, $K_2CO_3$, 92%; ii: PCC, DCM, 90%; iii: mCPBA, $H_2SO_4$, MeOH-DCM, 80%; iv: H2, Pd/C, MeOH, 98%; v: NaOH, MeOH, 97%; vi: EtOH, phenylenediamine, 56%; vii: EtOH, ethylene diamine, 95%; viii: DMF, $MnO_2$, KOH.</figcaption></figure>

<table><caption>**Table 22.** Inhibitory activities of MA derivatives **149-150** on PTP1B, TCPTP and PTPs.</caption><thead><tr><th rowspan="2">Code</th><th rowspan="2">Yield (%)</th><th colspan="5">IC<sub>50</sub> (µM)</th><th rowspan="2">TCPTP/PTP1B <sup>1</sup></th></tr><tr><th>PTP1B</th><th>TCPTP</th><th>LAR <sup>2</sup></th><th>SHP-1 <sup>3</sup></th><th>SHP-2 <sup>4</sup></th></tr></thead><tbody><tr><td>1</td><td>-</td><td>5.93</td><td>19.47</td><td>&gt;40</td><td>&gt;40</td><td>&gt;40</td><td>3.3</td></tr><tr><td>149</td><td>56</td><td>1.43</td><td>5.88</td><td>&gt;40</td><td>&gt;40</td><td>&gt;40</td><td>4.1</td></tr><tr><td>150</td><td>28</td><td>1.79</td><td>8.31</td><td>&gt;40</td><td>&gt;40</td><td>&gt;40</td><td>4.6</td></tr></tbody></table>

<footnote n="1">¹ TCPTP/PTP1B, the ratio of $IC_{50}$ of TCPTP and PTP1B. ² LAR: leukocyte antigen-related phosphatase. ³ SHP-1: src homology phosphatase-1. ⁴ SHP-2: src homology phosphatase-2.</footnote>
<figure><img src="image_41.png" /><figcaption>**Scheme 19.** Synthesis of MA derivatives **151–154**. i: PCC, DCM, 85%; ii: TEA, N,N-dimethylformamide dimethyl acetal, toluene, 78%; iii: guanidine hydrochloride, EtOH, NaOEt, 70%; iv: ethanimidamide hydrochloride or methanimidamide, Ac₂O, EtOH, NaOEt, R = Me, 74%; R = H, 78%; v: anhydrous DMF, LiI; vi: anhydrous DMF, n-octylamine LiI.</figcaption></figure>

<figure><img src="image_42.png" /><figcaption>**Scheme 20.** Synthesis of MA derivatives **155–163**. i: TFA, C₆H₅NHNH₂, HOAc; ii: pyridinium tribromide, DCM, HOAc, 82%; iii: anhydrous EtOH, thiourea; iv: MeONa, benzene, HCOOEt, 94%; v: EtOH/H₂O, hydroxylamine hydrochloride; vi: EtOH/H₂O, phenylhydrazine hydrochloride; vii: EtOH/H₂O, hydrazine hydrochloride; viii: anhydrous DMF, py, RCOCI.</figcaption></figure>
<table><caption>**Table 23.** Inhibitory activities of MA derivatives **151–154** on PTP1B, TCPTP and PTPs.</caption><thead><tr><th rowspan="2">Code</th><th rowspan="2">Yield (%)</th><th colspan="5">IC<sub>50</sub> (µM)</th></tr><tr><th>PTP1B</th><th>TCPTP</th><th>LAR <sup>2</sup></th><th>SHP-1 <sup>3</sup></th><th>SHP-2 <sup>4</sup></th></tr></thead><tbody><tr><td>151</td><td>12</td><td>5.44</td><td>Nd <sup>5</sup></td><td>-</td><td>-</td><td>-</td></tr><tr><td>152</td><td>78</td><td>1.78</td><td>5.51</td><td>-</td><td>-</td><td>3.1</td></tr><tr><td>153</td><td>74</td><td>2.73</td><td>8.19</td><td>&gt;40</td><td>&gt;40</td><td>&gt;40</td></tr><tr><td>154</td><td>80</td><td>2.61</td><td>6.50</td><td>-</td><td>-</td><td>2.5</td></tr></tbody></table>

<table><caption>**Table 24.** Inhibitory activities of MA derivatives **155–163** on PTP1B, TCPTP and PTPs.</caption><thead><tr><th rowspan="2">Code</th><th rowspan="2">Yield (%)</th><th colspan="5">IC<sub>50</sub> (µM)</th></tr><tr><th>PTP1B</th><th>TCPTP</th><th>LAR <sup>2</sup></th><th>SHP-1 <sup>3</sup></th><th>SHP-2 <sup>4</sup></th></tr></thead><tbody><tr><td>155</td><td>55</td><td>0.61</td><td>1.60</td><td>-</td><td>-</td><td>2.6</td></tr><tr><td>156</td><td>63</td><td>1.92</td><td>6.44</td><td>&gt;40</td><td>&gt;40</td><td>3.4</td></tr><tr><td>157</td><td>85</td><td>2.60</td><td>8.44</td><td>&gt;40</td><td>&gt;40</td><td>3.3</td></tr><tr><td>158</td><td>65</td><td>1.39</td><td>3.80</td><td>&gt;40</td><td>&gt;40</td><td>2.7</td></tr><tr><td>159</td><td>80</td><td>1.65</td><td>5.99</td><td>&gt;40</td><td>&gt;40</td><td>3.6</td></tr><tr><td>160</td><td>82</td><td>1.48</td><td>4.93</td><td>-</td><td>-</td><td>3.3</td></tr><tr><td>161</td><td>85</td><td>1.75</td><td>5.56</td><td>-</td><td>-</td><td>3.2</td></tr><tr><td>162</td><td>77</td><td>0.64</td><td>4.39</td><td>-</td><td>-</td><td>6.9</td></tr><tr><td>163</td><td>80</td><td>0.81</td><td>3.62</td><td>-</td><td>-</td><td>4.5</td></tr><tr><td>164 <sup>5</sup></td><td>-</td><td>3.89</td><td>6.24</td><td>-</td><td>-</td><td>1.6</td></tr></tbody></table>

### 3.8. Derivatives as Inhibitors of Acylcholinesterases

In this study, Schwartz et al. [73] investigated the synthesis of new MA conjugates that were assessed for their potential as cholinesterase inhibitors. The first group of compounds **165–191** (Scheme 21), representing MA esters, were synthesized by reacting MA with alkyl bromides in the presence of potassium carbonate in anhydrous DMF. The second group of compounds **192–207** (Scheme 22) includes various MA derivatives (**192**, **193**), its methyl esters (**194**, **195**), and amides (**196–207**), featuring either free or acetylated hydroxyl groups at the C-2 and C-3 positions. Acetylations were performed in pyridine using Ac₂O, while the sulfamates **194** and **195** were derived from methyl ester **165** and sodium hydride in THF, followed by the addition of sulfamoyl chloride. The synthesis of amides began with 2,3-diacetyl MA, which was first reacted with thionyl chloride, followed by the addition of an amine. The evaluation of these derivatives as cholinesterase inhibitors demonstrated that compound **177** was a marvelous inhibitor for AChE, being the most active analog with an inhibition constant equal to 1.6 µM in comparison with the parent compound MA that showed no inhibition (Table 25).

<table><caption>**Table 25.** IC₅₀ values in SRB assays, with NiH 3T3 or nonmalignant murine embryonic fibroblasts and Kᵢ (inhibition constants in µM for AChE).</caption><thead><tr><th>Compound</th><th>MA</th><th>168</th><th>173</th><th>174</th><th>177</th><th>178</th><th>181</th><th>189</th></tr></thead><tbody><tr><td>IC<sub>50</sub> (µM)</td><td>16.6</td><td>13.4</td><td>21.6</td><td>12.3</td><td>12.9</td><td>33.1</td><td>14.1</td><td>17.3</td></tr><tr><td>K<sub>i</sub> (AChE)</td><td>&gt;100</td><td>16.8</td><td>34.8</td><td>6.01</td><td>1.6</td><td>22.4</td><td>4.78</td><td>2.03</td></tr></tbody></table>

<footnote n="1">¹ TCPTP/PTP1B, the ratio of IC₅₀ of TCPTP and PTP1B. ² LAR: leukocyte antigen-related phosphatase. ³ SHP-1: src homology phosphatase-1. ⁴ SHP-2: src homology phosphatase-2. ⁵ Nd: Not determined.</footnote>

<footnote n="1">¹ TCPTP/PTP1B, the ratio of IC₅₀ of TCPTP and PTP1B. ² LAR: leukocyte antigen-related phosphatase. ³ SHP-1: src homology phosphatase-1. ⁴ SHP-2: src homology phosphatase-2. ⁵ Positive control chloroacetimidate.</footnote>
<figure><img src="image_43.png" /><figcaption>**Scheme 21.** MA structures and corresponding esters **165–191**.</figcaption></figure>

<figure><img src="image_44.png" /><figcaption>**Scheme 22.** Structures of 2,3-substituted MA esters **192–195** and amides **196–207** (Prg: Propargyl and all: Allyl).</figcaption></figure>

### 3.9. Antiviral Derivatives

Parra et al. [74] investigated the synthesis of MA conjugates that comprise amino acids and peptides. Derivatives (**208–219**) were prepared by condensing MA (**1**) and the corresponding amino acid (α-amino acids: glycine (Gly), L-alanine (Ala) and L-valine (Val)); or λ-aminobutyric acid (GABA), 6-aminohexanoic acid (6AHA) and 11-aminoundecanoic acid (11AUA) with the carboxylic group protected as methyl ester. The condensations were carried out at rt in anhydrous dichloromethane in the presence of N,N'-dicyclohexylcarbodiimide (DCC), N-hydroxybenzotriazole (HOBt), and triethylamine (TEA). Hence, analogs **208–213** with the corresponding amino acid methyl ester moiety were obtained. Subsequently, the saponification of compounds **208–213** with NaOH/MeOH/THF at room temperature led to **214–219** (Scheme 23). In order to find out the anti-HIV properties of these novel compounds, MT-2 cells were infected with the pseudotyped HIV-1 clone pNL4-3 using the VSV envelope, which avoids HIV-1's normal entrance mechanism into these cells facilitating strong HIV-1 replication. After being integrated into the host firefly, luciferase gene expression is mediated by chromosomes; as a result, the rate of viral replication in infected cells is correlated with luciferase activity. Consequently, 24 h after cellular infection with the VSV-pseudotyped HIV-1 clone, high
luciferase activity levels were found. Pretreating MT-2 cells with MA (1) and derivatives 30 min before infection led to a dose-dependent inhibition of the luciferase activity, with compounds 211 and 219 being the most potent inhibitors of HIV-1 (Table 26). The amount of luciferase activity in cell extracts was measured and the results depicted in Table 26 are shown as a percentage of activation when compared to 100% activation in untreated infected cells.

<figure><img src="image_45.png" /><figcaption>**Scheme 23.** The synthetic pathway of pentacyclic triterpenoid acid (MA) derivatives 208–219.</figcaption></figure>

In another study, Soltane et al. [75] screened the inhibitory activity of previously synthesized MA derivatives [52,62] (Figure 4) on highly pathogenic coronaviruses (anti-SARS-CoV-2 activity). Subsequently, half maximal cytotoxic concentration, or “CC₅₀,” was computed for each analog individually in order to determine the appropriate doses at which to characterize the antiviral activity. Out of the evaluated panel conjugates, compound 230 bearing the isoxazole side chain moiety with a p-chlorophenyl substitution showed a promising in vitro activity against SARS-CoV-2 with IC₅₀ value equal to 4.12 µM (Table 27).

<figure><img src="image_46.png" /><figcaption>**Figure 4.** MA derivatives 220–230 screened for their anti-SARS-CoV-2 activity.</figcaption></figure>
In another study, Serra et al. [76] have tested the antiviral activity of compound **231** (Figure 5). The results showed that this conjugate exhibited a modest inhibition, as outlined in Table 28. In fact, to inhibit the cytopathic effect, the number of viruses infecting the cells in multi-well plates was kept low—approximately one virus per three cells. After incubating the cells for two to three days with and without the substances under study (100 µg/mL), morphological alterations in the cells were observed using a light microscope.

<table><caption>**Table 26.** Effects of MA and the derivatives **208–219** on recombinant virus replication.</caption><thead><tr><th>Code</th><th>Dose (10 µM)</th><th>Dose (25 µM)</th><th>Ref.</th></tr></thead><tbody><tr><td colspan="4">Infection Percentage: Untreated Cells = 100% Infection</td></tr><tr><td>MA</td><td>56.3</td><td>6.7</td><td></td></tr><tr><td>208</td><td>75.5</td><td>56.3</td><td></td></tr><tr><td>209</td><td>63.6</td><td>8.9</td><td></td></tr><tr><td>210</td><td>72.0</td><td>11.1</td><td></td></tr><tr><td>211</td><td>32.5</td><td>12.0</td><td></td></tr><tr><td>212</td><td>69.6</td><td>36.8</td><td rowspan="8">[74]</td></tr><tr><td>213</td><td>66.9</td><td>35.6</td></tr><tr><td>214</td><td>162.1</td><td>130.7</td></tr><tr><td>215</td><td>124.2</td><td>60.9</td></tr><tr><td>216</td><td>102.8</td><td>121.2</td></tr><tr><td>217</td><td>126.4</td><td>93.8</td></tr><tr><td>218</td><td>146.4</td><td>79.3</td></tr><tr><td>219</td><td>56.7</td><td>21.5</td></tr></tbody></table>

<table><caption>**Table 27.** Cytotoxic data for the screened MA derivatives **220–230**.</caption><thead><tr><th>Code</th><th>MA</th><th>220</th><th>221</th><th>222</th><th>223</th><th>224</th><th>225</th><th>226</th><th>227</th><th>228</th><th>229</th><th>230</th></tr></thead><tbody><tr><td>CC<sub>50</sub></td><td>97.3</td><td>157.2</td><td>90.6</td><td>208.8</td><td>97.4</td><td>185.3</td><td>218.1</td><td>513.8</td><td>356.4</td><td>405.4</td><td>324.2</td><td>141.6</td></tr><tr><td>IC<sub>50</sub> (µM)</td><td>99.8</td><td>236.3</td><td>85.2</td><td>135</td><td>108</td><td>131.9</td><td>134.7</td><td>116.1</td><td>158.9</td><td>136.7</td><td>218.6</td><td>4.1</td></tr></tbody></table>

<figure><img src="image_47.png" /><figcaption>**Figure 5.** MA derivative **231** tested for antiviral activity.</figcaption></figure>

<table><caption>**Table 28.** Observed inhibition of viral cytopathic effects by compound **231**.</caption><thead><tr><th colspan="7">Virus Inhibition</th></tr><tr><th>Polio 1<sup>1</sup></th><th>HSV<sub>1</sub><sup>2</sup></th><th>HSV<sub>2</sub><sup>3</sup></th><th>VV<sup>4</sup></th><th>VSV<sup>5</sup></th><th>SWN<sup>6</sup></th><th>Rotavirus</th></tr></thead><tbody><tr><td>—</td><td>—</td><td>±</td><td>—</td><td>±</td><td>—</td><td>—</td></tr></tbody></table>

### 3.10. *Derivatives Synthesized with No Activity Assessed*

García-Granados et al. [77] have investigated the synthesis of a wide range of derivatives from the MA-A-ring (Figure 6). Various derivatives of methyl maslinate were synthesized using standard reaction procedures (Schemes 24–26). Among these derivatives, those

<footnote n="1">¹ Polio 1: Poliovirus type Sabin 1. ² HSV: Herpes simplex virus type 1. ³ HSV2: Herpes simplex virus type 2. ⁴ VV: Vaccinia virus. ⁵ VSV: Vesicular stomatitis virus. ⁶ SWN: Influenza A virus swine strain.</footnote>
with good leaving groups in the A-ring of the oleanene skeleton were employed in several rearrangements described below. Jones reagent was utilized to oxidize the hydroxyl group at C-3 in compound **233**, producing the 3-oxo derivative **242**. Similarly, the hydroxyl group at C-2 in compound **234** was oxidized to yield the 2-oxo derivative **233** (Scheme 24). To synthesize oleanene derivatives with short carbon chains in the A-ring, oxo derivatives **242** and **243** were treated with triphenylmethylphosphonium bromide and sec-butyllithium under Wittig reaction conditions. The Wittig reaction with 3-oxo derivative **242** resulted in the formation of products **241**, **244**, and **245** (Scheme 24). Compound **239** was treated under reflux for 30 min with AcOH/AcOK, to afford **251** and **252** (Scheme 25). Compound **241**, previously obtained from the oxidation of methyl maslinate, was a byproduct of this reaction. Additionally, product **237** was treated under reflux for 30 min with AcOH/AcOK, leading to compounds **232** (25%), **233** (15%), **247** (5%), **248** (45%), and **249** (5%) (Scheme 26).

<figure><img src="image_48.png" /><figcaption>**Figure 6.** MA derivatives.</figcaption></figure>

<figure><img src="image_49.png" /><figcaption>**Scheme 24.** Reaction pathway for compound **233** and **234**.</figcaption></figure>
<figure><img src="image_50.png" /><figcaption>**Scheme 25.** Reaction pathway suggested for compound 239.</figcaption></figure>

<figure><img src="image_51.png" /><figcaption>**Scheme 26.** Reaction pathway suggested for compound 237.</figcaption></figure>

**4. Conclusions**

Multiple recent evaluations have consistently shown that derivatives of MA exhibit a range of impressive biological activities. These derivatives have been confirmed to possess significant therapeutic potential, emerging as promising agents in the treatment of multiple diseases, particularly cancer, diabetes, and inflammatory conditions. This comprehensive review delves into and summarizes diverse synthetic pathways, chemical structures, biological properties, and function-activity relationships associated with analogs derived from MA. Structural modifications of MA extend beyond the traditionally targeted four "active" sites, namely C28 -COOH, C2-OH, C12 = C13 double bond and C3-OH. For instance, earlier studies compellingly demonstrated the potent inhibitory effect of MA derivatives against α-glucosidase. Systematic exploration of the structure-activity relationship (SAR) revealed that incorporating piperazines and piperazine-L-amino moieties at C-28, as well as amides at C-28, enhanced inhibitory potency against α-glucosidase. Furthermore, numerous MA derivatives have been synthesized and assessed for their anti-tumor activities. Among them, diamine and PEGylated diamine conjugates showed conspicuous potential. Notably, in tumor cell lines, the MA diamine conjugate with the shortest and longest diamine chains demonstrated the most potent cytotoxic effects, with IC₅₀ values ranging from 0.76 to 1.76 mM. It is clearly notable also that regarding the GPa inhibition, compound **64** was the most potent GPa inhibitor with IC₅₀ = 7 µM. Therefore, a distinct inclination towards hydrophobic groups at C-28 is noticeable in enzyme inhibition, posing a challenge for optimizing leads using MA and similar triterpenoids, as drug design typically favors good water solubility. Interestingly, the derivative MA-HDA exhibited enhanced antimicrobial activity, notably reducing MIC₅₀ against MRSA by 66%. Additionally, several MA conjugates have demonstrated increased inhibitory activity on germination of *Lactuca sativa* L., which was possibly attributed to the thiol group within the hybrid compound structure. Moreover, it was crystal clear that many of the MA derivatives conjugated with triazoles or isoxazoles exhibited potent anti-inflammatory activity (the derivative
featuring a furfuryl fragment on the isoxazole moiety demonstrated the most significant anti-inflammatory properties, with a % IL-1β production of 4 at a concentration of 100 µM). Furthermore, MA derivatives have demonstrated exceptional efficacy as protein tyrosine phosphatase 1B inhibitors. Notably, we can highlight that derivative **162** exhibited the highest selectivity ($IC_{50}$ value of 0.64 µM) with a 6.9-fold preference for PTP1B over T-cell protein tyrosine phosphatase (TCPTP). Additionally, it is noteworthy that compound **177** emerged as an outstanding acetylcholinesterase (AChE) inhibitor, boasting an inhibition constant of 1.68 µM, surpassing the activity of the parent compound MA. Further, in terms of antiviral activity, compounds **211**, with an R group of γ-aminobutyric acid (GABA), and **219**, with an R group of 11-aminoundecanoic acid (11AUA), were identified as the most potent inhibitors of HIV-1 as they exhibited doses equal to 32.5 and 56.7, respectively, at 10 µM. It is worth highlighting also that compound **230**, which incorporates an isoxazole side chain moiety with a *p*-chlorophenyl substitution, exhibited significant *in vitro* activity against SARS-CoV-2, with an $IC_{50}$ value of 4.12 µM. The synthesis and design of structurally and functionally diverse MA analogs have paved the way for compounds that exhibit strong affinity and selectivity for specific molecular therapeutic targets. The literature strongly suggests that MA derivatives hold potential as complementary and alternative therapies for various diseases, warranting further exploration. In summary, the emphasis of this review sheds light on the different synthesis routes of multiple MA derivatives and brings to light their biological activities as well as diving into their structure-activity relationships.

The assessment carried out aims to provide guidance to researchers to target synthesis routes or structures of derivatives with interesting activity to go further, for example, towards in vivo tests and clinical trials.

**Author Contributions:** Y.T. carried out the practical tasks and drafting of the manuscript. M.Z., H.B.J. and J.B. were involved in the correction of the manuscript, the orientation of the work, and the coordination of the project. All authors have read and agreed to the published version of the manuscript.

**Funding:** Campus France PHC-UTIQUE PROJECT (reference 22G1202), E-mail: gestion.phcmaghreb@campusfrance.org.

**Institutional Review Board Statement:** Not applicable.

**Informed Consent Statement:** Not applicable.

**Data Availability Statement:** The study did not report any data.

**Conflicts of Interest:** The authors declare no conflicts of interest.

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