Third-generation analogues of Guttiferone A

David Hozain, Kevin Cottet, Yann Fromentin, Annabelle Dugay, Florence
Souquet, Elisabeth Mouray, Philippe Grellier, Didier Buisson, Raimundo
Gonçalves de Oliveira Junior, Marie-Christine Lallemand

► To cite this version:

David Hozain, Kevin Cottet, Yann Fromentin, Annabelle Dugay, Florence Souquet, et al. Third-generation analogues of Guttiferone A. Bioorganic and Medicinal Chemistry Letters, 2025, 122, pp.130186. 10.1016/j.bmcl.2025.130186. hal-05104946

HAL Id: hal-05104946

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Submitted on 10 Jun 2025

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Third-generation analogues of Guttiferone A

David Hozain<sup>a</sup>, Kevin Cottet<sup>a</sup>, Yann Fromentin<sup>a</sup>, Annabelle Dugay<sup>a</sup>, Florence Souquet<sup>a</sup>, Elisabeth Mouray<sup>b</sup>, Philippe Grellier<sup>b</sup>, Didier Buisson<sup>b</sup>, Raimundo Gonçalves de Oliveira Junior<sup>a, *, 1</sup>, Marie-Christine Lallemand<sup>a, 1</sup>

<figure><img src="image_3.png" /></figure>

ARTICLE INFO

Keywords:

Guttiferone a

Antiparasitic activity

Plasmodium falciparum

Trypanosoma brucei

Dioxolane derivatives

A B S T R A C T

This study introduces third-generation derivatives of guttiferone A, designed to enhance both bioactivity and selectivity against *Plasmodium falciparum* and *Trypanosoma brucei*. Following an optimized synthetic route, two dioxolane derivatives of 3,16-oxyguttiferone A were prepared: 14-monodioxolane-3,16-oxyguttiferone A (3) and 13,14-bisdioxolane-3,16-oxyguttiferone A (4). Biological evaluation revealed compound 3 to be the most effective, with a selectivity index (SI) of 457.1 against *Trypanosoma brucei brucei* strain and 57.1 against *P. falciparum*, significantly outperforming its precursors. Compound 4 also demonstrated substantial activity with an SI of 143.8 against *T. brucei*. These results highlight the potential of targeted structural modifications, particularly monodioxolane substitution, to improve the pharmacological profile of guttiferone A derivatives.

Guttiferones are polycyclic polyprenylated acylphloroglucinol (PPAP) derivatives widely recognized for their complex chemical structures and notable bioactive properties. These compounds are predominantly isolated from the latex of *Symphonia globulifera*, a tropical plant traditionally used in folk medicine to treat parasitic diseases.<sup>1-3</sup> Structurally, guttiferones feature a bicyclo[3.3.1]nonane-2,4,9-trione core with long lipophilic side chains, which are characteristic of PPAPs.<sup>4</sup> Among the guttiferones, guttiferone A has attracted particular attention due to its diverse biological activities, especially its potent antiparasitic effects.<sup>5-7</sup> Previous studies have demonstrated its efficacy against *Plasmodium falciparum*, *Leishmania donovani*, and *Trypanosoma brucei*, highlighting its potential as a candidate for novel antiparasitic drug development.<sup>8</sup>

Xanthone derivatives (first-generation analogues) of guttiferone A
were obtained *via* electrosynthesis⁹ and by biotransformation after

screening microorganisms from a culture collection¹⁰ or endophytes
isolated from *S. globulifera*.¹¹ Among these, the compound 3,16-oxygut-
tiferone A demonstrated a slight improvement in antiparasitic activity
against *P. falciparum* compared to guttiferone A.¹⁰

Esters and ether derivatives of guttiferone A (second-generation analogues) were then synthetized and have shown strong antiparasitic activity against *P. falciparum*, *T. brucei*, and *L. donovani*, with IC₅₀ values in the range of 1–5 µM.¹² A catechol-bisdioxolane derivative (Fig. 1) exhibited promising activity against *T. brucei* and *P. falciparum*, with a selectivity index (SI) greater than 20 when tested on VERO cells. However, the IC₅₀ values and SI for these molecules remain significantly less satisfactory compared to those of standard drugs such as pentamidine (*T. brucei*) and chloroquine (*P. falciparum*).¹²

This short communication presents third-generation analogues of
guttiferone A (Fig. 1), combining the structural modifications intro-

<footnote><sup>a</sup> UMR CNRS 8038 CiTCOM, PNAS Team, Université Paris Cité, 75006 Paris, France</footnote>

<footnote><sup>b</sup> UMR CNRS 7245 MCAM, Muséum National d'Histoire Naturelle, 75005 Paris, France</footnote>

<footnote>* Corresponding authors.
*E-mail address:* raimundo.goncalves-de-oliveira-junior@u-paris.fr (R.G. de Oliveira Junior).</footnote>

<footnote n="1">¹ Both authors equally contributed to the supervision of the work.</footnote>
<figure><img src="image_4.png" /><figcaption>Fig. 1. Examples of first, second, and third-generations analogues of guttiferone A with antiparasitic potential.</figcaption></figure>

duced in previous studies that enhanced its antiparasitic activity, particularly against *P. falciparum* and *Trypanosoma brucei brucei* strains. Dioxolane derivatives of 3,16-oxyguttiferone A were synthesized and evaluated for their *in vitro* bioactivity. The compounds described herein are novel and exhibit enhanced pharmacological effects with improved selectivity.

The synthesis of third-generation analogues was undertaken following the pathway outlined in Fig. 2. Two synthetic routes were considered: cyclization followed by functionalization of the catechol core (route a), or functionalization of the catechol core followed by cyclization (route b). Previous studies demonstrated that cyclization could be problematic if the hydroxyl groups of the catechol moiety are substituted.⁹,¹³,¹⁴ Thus, we opted for route a. Using an established cyclization methodology,¹⁴ sufficient quantities of 3,16-oxyguttiferone A (2) were prepared. This intermediate was subsequently subjected to an alkylation reaction. The experimental conditions were based on the Dias procedure¹³ for catechol modulation, which we further optimized. Specifically, a mixture of cesium carbonate (10 %) and potassium carbonate (10 equivalents) in anhydrous acetone, along with 2-(2-bromoethyl)-1,3-dioxolane (5 equivalents), was used. As anticipated, the reaction yielded two products: **3** (14-monodioxolane-3,16-oxyguttiferone A) and **4** (13,14-bisdioxolane-3,16-oxyguttiferone A).

Mass spectrometry data for compounds **3** and **4** showed molecular ion peaks at *m/z* 701.4049 [M + H]⁺ and 801.4581 [M + H]⁻, respectively. These values correspond to the loss of two protons relative to the intramolecular oxidation of guttiferone A (leading to 3,16-oxyguttiferone A), along with the incorporation of one (**3**) or two (**4**) ethyl-dioxolane units. The ¹H NMR spectra (Table 1) were consistent with the 3,16-oxyguttiferone core. As expected, singlets corresponding to H-12 (7.45 ppm for 3 and 7.53 ppm for 4) and H-15 (7.22 ppm for 3 and 7.25 ppm for 4) confirmed the formation of the xanthone core.¹¹ Multiplets observed at ~3.80–4.00 ppm, attributed to protons of the dioxolane ring, along with signals at 2.18–2.24 ppm and 4.33 ppm, assigned to ethyl groups, confirmed the presence of one (**3**) or two (**4**) ethyl-dioxolane substituents on the catechol ring. Additionally, characteristic ¹³C NMR signals at δC 101.8 (**3**) and 102.9, 103.0 (**4**) were observed, typical of CH groups within a di-oxygenated dioxolane ring, further confirming the substitution pattern. These findings are consistent with previously reported mono- and bis-dioxolane derivatives.¹²

Final structural confirmation of the analogues was achieved through complete NMR characterization and mass spectrometry (details in the supplementary material).

All molecules were then evaluated for their *in vitro* antiparasitic activities against *P. falciparum* and *Trypanosoma brucei brucei* strain. Additionally, alongside cytotoxicity assessments in VERO cells. As shown in Table 2, compounds **3** and **4** exhibited strong antiparasitic activity, particularly against *T. brucei*. **3** demonstrated a SI of 457.1, while **4** showed an SI of 143.8. Both derivatives displayed lower IC₅₀ values compared to guttiferone A (**1**) and 3,16-oxyguttiferone A (**2**, a first-generation analogue). Notably, compounds **3** and **4** were more potent and selective than second-generation compounds, such as 13,14-bisdioxolane-guttiferone A (IC₅₀ 1.8–2.0 µM, SI = 20.8–22.8).¹² However, their selectivity indices remain significantly lower than those observed for the standard drugs (chloroquine, IC₅₀ = 0.111 µM, SI = 189.2 for *P. falciparum*; pentamidine, IC₅₀ = 0.005 µM, SI = 11,400 for *T. brucei*), highlighting the need for further chemical modifications in third-generation analogues.¹²

Based on our findings and previous studies, we propose that the combined chemical modifications – intramolecular cyclization and alkylation – enhance both bioactivity and selectivity. The third-generation derivatives, particularly compound **3**, which contains a single dioxolane unit, exhibited a significant improvement in SI compared to earlier analogues.¹² Although the specific targets involved in the antiparasitic activity of guttiferone A and its derivatives remain unknown, we hypothesize that intramolecular oxidation, leading to the formation of xanthone derivatives with more planar and rigid structures, may improve interactions with potential biological targets.

These preliminary findings highlight the potential of these structural modifications in developing more selective and potent antiparasitic agents. The next phase of this study will involve screening the most bioactive compounds from the first-, second- and third-generation derivatives against key targets expressed in parasitic strains. Future studies will further explore structure-activity relationships (SAR), with a particular focus on optimizing the mono-alkylated compound (**3**) due to its superior activity against both *P. falciparum* and *T. brucei*, as well as its enhanced selectivity.
<figure><img src="image_5.png" /><figcaption>**Fig. 2.** Chosen *route a* for the synthesis of third-generation derivatives (3 and 4). Reagents and conditions: (i) 2-(2-bromoethyl)-1,3-dioxolane (5 eq.), K₂CO₃ (10 eq.), Cs₂CO₃ (10 %), anhydrous acetone, 60 °C.</figcaption></figure>
<table><caption>**Table 1**

¹H NMR (400 MHz) and ¹³C NMR (75 MHz) spectroscopic data for compounds 3 and 4 in CD₃OD.</caption><thead><tr><th rowspan="2">Position</th><th colspan="2">Compound 3</th><th colspan="2">Compound 4</th></tr><tr><th>δ<sub>C</sub></th><th>δ<sub>H</sub> (J in Hz)</th><th>δ<sub>C</sub></th><th>δ<sub>H</sub> (J in Hz)</th></tr></thead><tbody><tr><td>1</td><td>194.2</td><td></td><td>194.0</td><td></td></tr><tr><td>2</td><td>119.0</td><td></td><td>119.0</td><td></td></tr><tr><td>3</td><td>179.8</td><td></td><td>179.8</td><td></td></tr><tr><td>4</td><td>65.1</td><td></td><td>65.1</td><td></td></tr><tr><td>5</td><td>52.0</td><td></td><td>52.0</td><td></td></tr><tr><td>6</td><td>41.7</td><td>1.88, 1H, m</td><td>41.7</td><td>1.84, 1H, m</td></tr><tr><td>7</td><td>39.1</td><td>2.10, 2H, m</td><td>39.0</td><td>2.10, 2H, m</td></tr><tr><td>8</td><td>66.9</td><td></td><td>66.9</td><td></td></tr><tr><td>9</td><td>207.3</td><td></td><td>207.2</td><td></td></tr><tr><td>10</td><td>174.5</td><td></td><td>174.3</td><td></td></tr><tr><td>11</td><td>118.9</td><td></td><td>118.5</td><td></td></tr><tr><td>12</td><td>109.7</td><td>7.45, 1H, s</td><td>107.4</td><td>7.53, 1H, s</td></tr><tr><td>13</td><td>148.0</td><td></td><td>149.7</td><td></td></tr><tr><td>14</td><td>155.1</td><td></td><td>156.6</td><td></td></tr><tr><td>15</td><td>103.0</td><td>7.22, 1H, s</td><td>102.2</td><td>7.25, 1H, s</td></tr><tr><td>16</td><td>150.9</td><td></td><td>151.9</td><td></td></tr><tr><td>17</td><td>27.4</td><td>2.88, 1H, m; 2.99, 1H, m</td><td>27.4</td><td>2.86, 1H, m; 3.00, 1H, m</td></tr><tr><td>18</td><td>119.7</td><td>4.62, 1H, m</td><td>119.6</td><td>4.62, 1H, m</td></tr><tr><td>19</td><td>136.3</td><td></td><td>136.3</td><td></td></tr><tr><td>20</td><td>25.9</td><td>1.41, 3H, s</td><td>25.9</td><td>1.39, 3H, s</td></tr><tr><td>21</td><td>18.6</td><td>1.74, 3H, s</td><td>18.7</td><td>1.73, 3H, s</td></tr><tr><td>22</td><td>20.5</td><td>1.30, 3H, s</td><td>20.6</td><td>1.29, 3H, s</td></tr><tr><td>23</td><td>38.0</td><td>1.53, 2H, m</td><td>38.0</td><td>1.50, 2H, m</td></tr><tr><td>24</td><td>30.2</td><td>1.78, 1H, m; 1.88, 1H, m</td><td>30.2</td><td>1.77, 1H, m, 1.90, 1H, m</td></tr><tr><td>25</td><td>124.5</td><td>4.85, 1H, m</td><td>124.5</td><td>4.85, 1H, m</td></tr><tr><td>26</td><td>134.1</td><td></td><td>134.2</td><td></td></tr><tr><td>27</td><td>26.1</td><td>1.64, 3H, s</td><td>26.2</td><td>1.63, 3H, s</td></tr><tr><td>28</td><td>18.0</td><td>1.37, 3H, s</td><td>18.0</td><td>1.38, 3H, s</td></tr><tr><td>29</td><td>30.4</td><td>2.52, 2H, m</td><td>30.4</td><td>2.52, 2H, m</td></tr><tr><td>30</td><td>120.8</td><td>5.22, 1H, t (7.5)</td><td>120.8</td><td>5.22, 1H, t (7.5)</td></tr><tr><td>31</td><td>135.6</td><td></td><td>135.6</td><td></td></tr><tr><td>32</td><td>26.0</td><td>1.70, 3H, s</td><td>26.1</td><td>1.69, 3H, s</td></tr><tr><td>33</td><td>18.1</td><td>1.70, 3H, s</td><td>18.1</td><td>1.69, 3H, s</td></tr><tr><td>34</td><td>24.0</td><td>2.01, 2H, m</td><td>24.0</td><td>2.00, 2H, m</td></tr><tr><td>35</td><td>125.0</td><td>5.13, 1H, m</td><td>125.0</td><td>5.10, 1H, m</td></tr><tr><td>36</td><td>133.0</td><td></td><td>133.0</td><td></td></tr><tr><td>37</td><td>26.3</td><td>1.70, 3H, s</td><td>26.4</td><td>1.69, 3H, s</td></tr><tr><td>38</td><td>17.8</td><td>1.64, 3H, s</td><td>17.9</td><td>1.63, 3H, s</td></tr><tr><td>39</td><td>66.7</td><td>4.33, 2H, m</td><td>66.7</td><td>4.33, 2H, m</td></tr><tr><td>40</td><td>34.3</td><td>2.24, 2H, m</td><td>34.7</td><td>2.18, 2H, m</td></tr><tr><td>41</td><td>101.8</td><td>5.13, 1H, m</td><td>103.0</td><td>5.10, 1H, m</td></tr><tr><td>42</td><td>66.0</td><td>4.00, 2H, m</td><td>66.0</td><td>3.99, 2H, m</td></tr><tr><td>43</td><td>66.0</td><td>3.90, 2H, m</td><td>66.0</td><td>3.87, 2H, m</td></tr><tr><td>44</td><td></td><td></td><td>66.4</td><td>4.22, 2H, t (6.5)</td></tr><tr><td>45</td><td></td><td></td><td>34.5</td><td>2.18, 2H, m</td></tr><tr><td>46</td><td></td><td></td><td>102.9</td><td>5.10, 1H, m</td></tr><tr><td>47</td><td></td><td></td><td>66.0</td><td>3.99, 2H, m</td></tr><tr><td>48</td><td></td><td></td><td>66.0</td><td>3.87, 2H, m</td></tr></tbody></table>

<table><caption>**Table 2**

Trypanocidal and antiplasmodial activities of guttiferone A (1), 3,16-oxyguttiferone A (2) and third-generation derivatives (3 and 4).</caption><thead><tr><th rowspan="2">Compound</th><th colspan="3">VERO cells*</th><th colspan="2">P. falciparum**</th><th colspan="2">T. brucei***</th></tr><tr><th>IC<sub>50</sub> (µM)</th><th>IC<sub>50</sub> (µM)</th><th>SI</th><th>IC<sub>50</sub> (µM)</th><th>SI</th><th>IC<sub>50</sub> (µM)</th><th>SI</th></tr></thead><tbody><tr><td>1</td><td>7.05 ± 0.36</td><td>3.32 ± 0.45</td><td>2.1</td><td>3.9 ± 0.2</td><td>1.8</td><td></td><td></td></tr><tr><td>2</td><td>3.0 ± 1.1</td><td>0.89 ± 0.21</td><td>3.4</td><td>1.8 ± 0.5</td><td>1.7</td><td></td><td></td></tr><tr><td>3</td><td>32 ± 5.1</td><td>0.56 ± 0.08</td><td>57.1</td><td>0.07 ± 0.01</td><td>457.1</td><td></td><td></td></tr><tr><td>4</td><td>23 ± 2.6</td><td>1.5 ± 0.4</td><td>15.3</td><td>0.16 ± 0.01</td><td>143.8</td><td></td><td></td></tr><tr><td>Chloroquine</td><td>21.0</td><td>0.111</td><td>189.2</td><td>-</td><td>-</td><td></td><td></td></tr><tr><td>Pentamidine</td><td>57.0</td><td>-</td><td>-</td><td>0.005</td><td>11,400</td><td></td><td></td></tr></tbody></table>

SI: Selectivity Index.

* VERO cells: Monkey African Green kidney cells.

** *P. falciparum*: The chloroquine-resistant strain FcB1/Colombia of *Plasmodium falciparum*.

*** *T. brucei*: Bloodstream forms of *Trypanosoma brucei brucei* strain 90-13.

### CRediT authorship contribution statement

**David Hozain:** Writing – original draft, Methodology, Investigation, Formal analysis, Data curation. **Kevin Cottet:** Methodology, Investigation, Formal analysis. **Yann Fromentin:** Methodology, Investigation, Data curation. **Annabelle Dugay:** Methodology, Investigation, Formal analysis. **Florence Souquet:** Methodology, Investigation, Formal analysis. **Elisabeth Mouray:** Methodology, Investigation, Formal analysis, Data curation. **Philippe Grellier:** Writing – review & editing, Validation, Methodology, Investigation, Formal analysis, Data curation. **Didier Buisson:** Writing – review & editing, Validation, Methodology, Investigation, Conceptualization. **Raimundo Gonçalves de Oliveira Junior:** Writing – original draft, Visualization, Supervision, Methodology, Investigation, Conceptualization. **Marie-Christine Lallemand:** Writing – original draft, Visualization, Validation, Supervision, Resources, Project administration, Investigation, Conceptualization.

### Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

### Acknowledgments

The authors would like to thank Cyril Colas from the *Fédération de Recherche ICOA/CBM (FR2708)*" for HRMS analysis. Financial supports of this work by Université Paris Cité (grant to DH) are equally acknowledged.

### Appendix A. Supplementary data

Supplementary data to this article can be found online at https://doi.org/10.1016/j.bmcl.2025.130186.

### Data availability

Data will be made available on request.

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