# Synthesis and cytotoxicity studies of novel N-arylbenzo[h]quinazolin-2-amines

Battini Veeraiah, Kishore Ramineni, Dabbugoddu Brahmaiah, Nangunoori Sampath Kumar, Hélène Solhi, Rémy Le Guével, Chada Raji Reddy, Frédéric Justaud, René Grée

► To cite this version:

Battini Veeraiah, Kishore Ramineni, Dabbugoddu Brahmaiah, Nangunoori Sampath Kumar, Hélène Solhi, et al.. Synthesis and cytotoxicity studies of novel N-arylbenzo[h]quinazolin-2-amines. Beilstein Journal of Organic Chemistry, 2024, 20, pp.2592-2598. 10.3762/bjoc.20.218. hal-04772032

HAL Id: hal-04772032

https://hal.science/hal-04772032v1

Submitted on 7 Nov 2024

HAL is a multi-disciplinary open access
archive for the deposit and dissemination of sci-
entific research documents, whether they are pub-
lished or not. The documents may come from
teaching and research institutions in France or
abroad, or from public or private research centers.

L'archive ouverte pluridisciplinaire HAL, est
destinée au dépôt et à la diffusion de documents
scientifiques de niveau recherche, publiés ou non,
émanant des établissements d'enseignement et de
recherche français ou étrangers, des laboratoires
publics ou privés.

<figure><img src="image_1.png" /></figure>

Distributed under a Creative Commons Attribution 4.0 International License
<figure><img src="image_2.png" /></figure>

# Synthesis and cytotoxicity studies of novel N-arylbenzo[h]quinazolin-2-amines

Battini Veeraiah¹, Kishore Ramineni*¹, Dabbugoddu Brahmaiah², Nangunoori Sampath Kumar², Hélène Solhi³, Rémy Le Guevel³, Chada Raji Reddy⁴, Frédéric Justaud⁵ and René Grée*⁵

Full Research Paper

Open Access

Address:

¹Anurag University, Ghatkesar, Hyderabad 500088, TS, India,

²Chemveda Life Sciences India Pvt. Ltd., #B-11/1, IDA Uppal, Hyderabad-500039, Telangana, India,

³Univ Rennes, Plateform ImPACcell, BIOSIT, F-35000 Rennes, France. ⁴CSIR-Indian Institute of Chemical Technology, Uppal Road, Tarnaka, Hyderabad 500007, TS, India and ⁵Univ Rennes, CNRS, ISCR (Institut des Sciences Chimiques de Rennes), UMR 6226, F-35000 Rennes, France

Email:

Kishore Ramineni* - rkishorehs@anurag.edu.in; René Grée* - rene.gree@univ-rennes.fr

Keywords:

Buchwald–Hartwig coupling; cytotoxicity; heterocycles; Pd catalysis; quinazolines

Beilstein J. Org. Chem. **2024**, *20*, 2592–2598.
https://doi.org/10.3762/bjoc.20.218

Received: 14 July 2024

Accepted: 24 September 2024

Published: 14 October 2024

Associate Editor: I. Baxendale

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

© 2024 Veeraiah et al.; licensee Beilstein-Institut.

License and terms: see end of document.

## Abstract

In this paper, we report a short and efficient synthesis of novel N-arylbenzo[h]quinazoline-2-amines. We have prepared a focused library of nineteen representative examples which have been submitted to cytotoxicity assays against a representative panel of eight cancer cell lines and several molecules gave attractive results in this area.

## Introduction

Nitrogen-containing heterocyclic molecules are ubiquitous in living systems. Among them, quinazolines, and especially the 4-aminoquinazolines (type A molecules, Figure 1), are recognized as a “privileged scaffold” in bioorganic and medicinal chemistry [1]. On the other hand, the 2-anilinoquinazolines have been less studied but our groups have developed recently the synthesis of new molecules of this family and discovered a compound (DB18) with a potent inhibition (at 10–30 nM) of the

CLK1, CLK2 and CLK4 kinases, and a remarkable selectivity since it does not show any action (at 100 µM) against the closely related DYRKs kinases [2,3]. Very recently, this skeleton proved to be also very useful in the research of antimicrobial agents [4], and the closely related dihydropteridinone derivatives were found as potent inhibitors of vaccinia-related kinase 1 and casein kinase 1δ/ε [5]. In addition, it is worth mentioning that closely related compounds like 2-(aryl-

<footnote>* Corresponding author</footnote>
amino)benzo[h]quinazolin-4-ones [6-8] and N2-aryl-
benzo[h]quinazoline-2,4-diamines [9-11] are well identified
scaffolds for bioactive molecules. Thus, it appeared interesting
to explore novel molecules with extended aromatic units around
this basic quinazoline core and our first choice was N-aryl-
benzo[h]quinazoline-2-amines with the general structure C as
indicated in Figure 1.

Very limited studies have been devoted to the synthesis of this
core structure and, to the best of our knowledge, only one mole-
cule of this type was obtained in low yield as a secondary prod-
uct during studies on the use of the Friedländer annulation reac-
tion starting from naphthylamines [12]. Therefore, the goal of
this paper is to describe a short and efficient synthesis for this
type of novel skeleton and to prepare a focused library for these
targets C. Further, we will report results on their cytotoxic ac-
tivities.

Results and Discussion
Chemical synthesis

For the preparation of our targets, we selected a flexible
strategy which should allow us to introduce the molecular
diversity on the anilino moiety in the last step through a palla-
dium-catalyzed reaction (Scheme 1).

Therefore, we prepared first the core structure **3** in two steps
from the commercially available fluoronaphthalene **1**. Metalla-
tion, followed by trapping with DMF afforded the known alde-
hyde **2** in 65% yield [13]. Then, reaction with guanidinium
carbonate in DMA at high temperature [12], gave the desired
intermediate 2-aminobenzo[h]quinazoline (**3**). In a final step,
classical Buchwald–Hartwig coupling [14–17] with bromoben-
zene under the conditions described recently [18], gave the first
target **4a** (R = H) in 69% yield. In a similar way, we prepared a
designed library with eighteen additional members **4b** to **4s**

<figure><img src="image_4.png" /><figcaption>**Figure 1:** Aminoquinazolines and our new target molecules.</figcaption></figure>

<figure><img src="image_5.png" /><figcaption>**Scheme 1:** Synthesis of the desired targets 4.</figcaption></figure>
(Figure 2) having in the different *ortho*, *meta* and *para* positions either methyl groups, halogens (F, Cl) or methoxy groups. We have also prepared compounds with two substituents or with three fluorine atoms. All these compounds have been obtained in fair yields (51–70%) and they have spectral and analytical data in agreement with the indicated structures, as given in the experimental section and Supporting Information File 1.

## Cytotoxicity studies

Next, we performed a cytotoxicity screening of the nineteen molecules **4a–s**, at 25 µM, investigating seven representative cancer cell lines: hepatocellular carcinoma HuH-7, colorectal adenocarcinoma CaCo-2, breast carcinoma MDA-MB-231 and MDA-MB-468, colorectal carcinoma HCT-116, prostate carcinoma PC3 and breast carcinoma MCF7. In parallel, human skin fibroblasts were used as reference for non-tumor cells and

<figure><img src="image_6.png" /><figcaption>**4a** (69%)</figcaption></figure>

<figure><img src="image_7.png" /><figcaption>**4b** (65%)</figcaption></figure>

<figure><img src="image_8.png" /><figcaption>**4c** (66%)</figcaption></figure>

<figure><img src="image_9.png" /><figcaption>**4d** (52%)</figcaption></figure>

<figure><img src="image_10.png" /><figcaption>**4e** (65%)</figcaption></figure>

<figure><img src="image_11.png" /><figcaption>**4f** (60%)</figcaption></figure>

<figure><img src="image_12.png" /><figcaption>**4g** (58%)</figcaption></figure>

<figure><img src="image_13.png" /><figcaption>**4h** (66%)</figcaption></figure>

<figure><img src="image_14.png" /><figcaption>**4i** (64%)</figcaption></figure>

<figure><img src="image_15.png" /><figcaption>**4j** (65%)</figcaption></figure>

<figure><img src="image_16.png" /><figcaption>**4k** (65%)</figcaption></figure>

<figure><img src="image_17.png" /><figcaption>**4l** (67%)</figcaption></figure>

<figure><img src="image_18.png" /><figcaption>**4m** (51%)</figcaption></figure>

<figure><img src="image_19.png" /><figcaption>**4n** (67%)</figcaption></figure>

<figure><img src="image_20.png" /><figcaption>**4o** (70%)</figcaption></figure>

<figure><img src="image_21.png" /><figcaption>**4p** (63%)</figcaption></figure>

<figure><img src="image_22.png" /><figcaption>**4q** (65%)</figcaption></figure>

<figure><img src="image_23.png" /><figcaption>**4r** (66%)</figcaption></figure>

<figure><img src="image_24.png" /><figcaption>**4s** (65%)</figcaption></figure>

<caption>**Figure 2:** Target molecules 4 prepared with the yields for the last step.</caption>
roscovitine (ROSCO), doxorubicin (DOXO) and Taxol as positive controls. For details see: ref. [2] and Supporting Information File 1, Table S1.

Compounds **4a–f**, **4h**, **4i**, **4k**, **4l**, **4o** and **4q** that induced a more than 30% decrease of cell population for at least one cell line were further investigated.

The determination of IC₅₀ confirmed that, although most molecules have low to no activity, a few of them exhibited significant cytotoxicity against several cell lines (Table 1). This is the case in particular for **4a** which has demonstrated low micro-molar toxicities (IC₅₀ from 1.7 to 6 µM) against HuH-7, Caco-2, MDA-MB-468 and HCT-116 cells, with low to no action, on the other cells. Similarly, the *meta*-fluoro analogue **4i** is active only on Caco-2, MDA-MB-468, HCT-116 and MCF7 (IC₅₀ from 2 to 6 µM) while the *meta*-methoxy **4f** and *ortho*-fluoro **4h** show significant toxicity only on Caco-2 (IC₅₀ 4.3 and 4.6 µM, respectively). Further, the *para*-methyl compound **4d** acts on HCT-116 only (IC₅₀ 5 µM). On the other hand, all molecules exhibited no effect on normal human fibroblasts at the highest

concentration tested (25 µM). For these more potent molecules, further studies will be required to rationalize their activities and selectivities and explore their mechanism(s) of action.

## Conclusion

In conclusion, we have designed a short and versatile strategy for the preparation of new *N*-arylbenzo[h]quinazoline-2-amines and it was exemplified through the preparation of a focused chemical library with 19 members. In addition, the cytotoxicity assays afforded interesting results demonstrating that the substitution on the anilino part can have significant effects on their bioactivity. Two molecules (**4a** and **4i**) exhibited a relatively broad cytotoxicity on four cancer cell lines among the seven assayed. On the other hand, two others (**4f** and **4h**) were active only on Caco-2, while another one (**4d**) only on HCT-116. Thus, the results obtained with these compounds indicate that such a novel heterocyclic scaffold, which has not been used earlier, should offer attractive potentialities in bioorganic and medicinal chemistry. Extension of these studies are ongoing in our laboratories and corresponding results will be reported in due course.

<table><caption>**Table 1:** Cytotoxic studies (IC₅₀ determination) of selected quinazolines **4**.ᵃ</caption><thead><tr><th>cells<br>compounds</th><th>HuH-7<br>IC<sub>50</sub> µM</th><th>Caco-2<br>IC<sub>50</sub> µM</th><th>MDA-MB-231<br>IC<sub>50</sub> µM</th><th>MDA-MB-468<br>IC<sub>50</sub> µM</th><th>HCT-116<br>IC<sub>50</sub> µM</th><th>PC3<br>IC<sub>50</sub> µM</th><th>MCF7<br>IC<sub>50</sub> µM</th><th>Fibro<br>IC<sub>50</sub> µM</th></tr></thead><tbody><tr><td>DMSO</td><td>NE</td><td>NE</td><td>NE</td><td>NE</td><td>NE</td><td>NE</td><td>NE</td><td>NE</td></tr><tr><td>roscovitine</td><td>12</td><td>14</td><td>15</td><td>13</td><td>7</td><td>10</td><td>11</td><td>16</td></tr><tr><td>doxorubicin</td><td>0.03</td><td>NE</td><td>0.03</td><td>0.03</td><td>0.04</td><td>0.06</td><td>0.07</td><td>NE</td></tr><tr><td>Taxol</td><td>0.009</td><td>0.07</td><td>0.02</td><td>0.006</td><td>0.003</td><td>0.004</td><td>0.02</td><td>NE</td></tr><tr><td><strong>4a</strong></td><td><strong>1.7</strong><br>(±0.4)</td><td><strong>4.7</strong><br>(±1.3)</td><td><strong>29</strong><br>(±5.5)</td><td><strong>6</strong><br>(±2.0)</td><td><strong>4</strong><br>(±0.4)</td><td><strong>34.5</strong><br>(±4.5)</td><td><strong>13</strong><br>(±3.6)</td><td>NE</td></tr><tr><td><strong>4b</strong></td><td>NE</td><td>NE</td><td>NE</td><td>NE</td><td>NE</td><td>NE</td><td>NE</td><td>NE</td></tr><tr><td><strong>4c</strong></td><td>NE</td><td>28<br>(±7.0)</td><td>NE</td><td>22<br>(±3.2)</td><td>18<br>(±1.3)</td><td>NE</td><td>30<br>(±3.0)</td><td>NE</td></tr><tr><td><strong>4d</strong></td><td>NE</td><td>NE</td><td>NE</td><td>31<br>(±6.0)</td><td><strong>5</strong><br>(±1.9)</td><td>30<br>(±8.5)</td><td>NE</td><td>NE</td></tr><tr><td><strong>4e</strong></td><td>NE</td><td>20<br>(±4.1)</td><td>25<br>(±2.3)</td><td>25<br>(±4.1)</td><td>26<br>(±11)</td><td>NE</td><td>22<br>(±4.6)</td><td>NE</td></tr><tr><td><strong>4f</strong></td><td>23<br>(±3.9)</td><td><strong>4.3</strong><br>(±1.7)</td><td>NE</td><td>33<br>(±6.9)</td><td>10<br>(±1.0)</td><td>26<br>(±6.0)</td><td>NE</td><td>NE</td></tr><tr><td><strong>4h</strong></td><td>NE</td><td><strong>4.6</strong><br>(±1.6)</td><td>NE</td><td>NE</td><td>NE</td><td>NE</td><td>NE</td><td>NE</td></tr><tr><td><strong>4i</strong></td><td>17<br>(±3.7)</td><td><strong>2</strong><br>(±0.6)</td><td>17<br>(±2.1)</td><td><strong>4</strong><br>(±2.1)</td><td><strong>6</strong><br>(±0.2)</td><td>11<br>(±0.2)</td><td><strong>3</strong><br>(±0.8)</td><td>NE</td></tr><tr><td><strong>4k</strong></td><td>NE</td><td>NE</td><td>NE</td><td>NE</td><td>NE</td><td>NE</td><td>NE</td><td>NE</td></tr><tr><td><strong>4l</strong></td><td>22<br>(±4.7)</td><td>17<br>(±5.1)</td><td>NE</td><td>26<br>(±4.5)</td><td>24<br>(±3.3)</td><td>26<br>(±2.2)</td><td>18<br>(±2.5)</td><td>NE</td></tr><tr><td><strong>4o</strong></td><td>24<br>(±5.1)</td><td>16<br>(±3.5)</td><td>NE</td><td>20<br>(±3.0)</td><td>23<br>(±13)</td><td>21<br>(±2.0)</td><td>21<br>(±1.2)</td><td>NE</td></tr><tr><td><strong>4q</strong></td><td>16<br>(±2.3)</td><td>14<br>(±2.9)</td><td>20<br>(±3.0)</td><td>19<br>(±3.1)</td><td>13<br>(±4.4)</td><td>19<br>(±5.2)</td><td>14<br>(±0.6)</td><td>NE</td></tr></tbody></table>

<footnote>ᵃIC₅₀ determination of effects of quinazolines on seven representative tumor cell lines and normal human fibroblasts. IC₅₀ (µM) were calculated from dose-response curves after 48 h exposure (mean of triplicates). NE: no effect.</footnote>
Experimental
Chemical synthesis
General information

All reactions were performed in heat gun-dried round-bottomed
flasks under a dry argon or nitrogen atmosphere. Air and moisture-sensitive compounds were introduced via syringes or
cannula, using standard inert atmosphere techniques. In addition, the gas stream was passed through glass cylinder filled
with P₂O₅ to remove any traces of residual moisture. Reactions
were monitored by thin-layer chromatography (TLC) using
E. Merck silica gel plates and components were visualized by
illumination with short wavelength UV light and/or staining
(ninhydrin or basic KMnO₄). All aldehydes were distilled right
before use. All aryl bromides and other reagents were used as
they were received from commercial suppliers, unless otherwise noted. THF and Et₂O were dried over sodium-benzo-
phenone and distilled prior to use.

¹H NMR spectra were recorded at 300 and 400 MHz, and
¹³C NMR spectra at 75 and 100 MHz, in CDCl₃ or DMSO-d₆
using TMS (tetramethylsilane) as an internal standard. Multiplicity was tabulated using standard abbreviations: s for singlet,
d for doublet, dd for doublet of doublets, t for triplet, q for
quadruplet, ddd for doublet of doublets of doublets and m for
multiplet (br means broad). When necessary, in particular in
order to have better accuracy on small coupling constants, resolution in ¹H NMR was enhanced using Traficante. All compounds were purified by flash column chromatography on silica
gel unless otherwise noted.

Melting points were obtained using an Electrothermal IA9200
series digital apparatus with thin-wall glass tube used to hold
mp samples for capillary mp determination. FTIR spectra were
recorded on a Bruker Alpha apparatus with spectra further
analysed with spectragraph 1.2.4 version. The absorption bands
were reported in cm⁻¹. High-resolution mass spectra were re-
corded in the Centre Régional de Mesures Physiques de l'Ouest,
Rennes (CRMPO), on a Maxis 4G.

Representative synthesis: preparation of compound
**4a**

**Step 1:** Synthesis of 1-fluoro-2-naphthaldehyde (2): To a stirred solution of compound **1** (3.0 g, 0.02 mol) in THF (60 mL) was added *n*-butyllithium (1.6 M, 12.8 mL, 0.02 mol) at –78 °C. The mixture was stirred at –78 °C for 2 h, and then dry DMF (3.3 mL, 0.041 mol) was added. After stirring for 2 h at –78 °C, the mixture was quenched with water and the crude product was extracted with ethyl acetate (30 mL × 3). The combined organic phase was dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to afford crude compound **2** as pale-yellow solid (65% yield). Its NMR data

are in agreement with literature [5]. ¹H NMR (400 MHz, DMSO-d₆, δ ppm) 10.49 (s, 1H), 8.26 (d, *J* = 8.4 Hz, 1H), 8.10 (d, *J* = 8.0 Hz, 1H), 7.90 (d, *J* = 8.8 Hz, 1H), 7.84–7.74 (m, 3H).

**Step 2: Synthesis of benzo[h]quinazolin-2-amine (3):** To a stirred solution of guanidinium carbonate (2.0 g, 0.011 mol) in DMA (15 mL) was added compound **2** (1.5 g, 0.008 mol). Then the reaction mixture was heated to stir at 150 °C for 16 h. After completion of the reaction (TLC), the mixture was poured into ice water, a solid was formed, filtered and dried to get compound **3** as a brown colored solid (63% yield). ¹H NMR (400 MHz, DMSO-d₆, δ ppm) 9.06 (s, 1H), 8.91 (d, *J* = 8.0 Hz, 1H), 7.93 (d, *J* = 7.6 Hz, 1H), 7.76–7.64 (m, 3H), 7.56 (d, *J* = 8.8 Hz, 1H), 6.99 (br s, 2H); ¹³C NMR (75 MHz, DMSO-d₆, δ ppm) 162.18, 161.31, 152.03, 136.05, 130.07, 129.07, 128.36, 126.72, 124.51, 124.38, 122.67, 116.44; ¹H-¹³C NMR ((300, 75) MHz, DMSO-d₆, δ ppm) (9.09 161.23), (8.95 124.31), (7.95 128.17), (7.76 129.93), (7.69 126.77), (7.61 124.66), (7.58 122.55); FTIR (KBr 1%, cm⁻¹) *v*: 3440, 3316, 3192, 1625, 1611, 1598, 1571, 1496, 1471, 1460, 1410, 801, 763; HRESIMS (*m/z*): [M + H]⁺ calcd for C₁₂H₁₀N₃, 196.0869; found, 196.0872 (1 ppm); mp: 193–195 °C (lit. 194–196 °C [12]).

**Step 3: Representative procedure for the preparation of compounds 4:** To the stirred solution of benzo[h]quinazolin-2-amine (3a, 0.256 mmol, 1.0 equiv) in 1,4-dioxane (4 mL) was added bromobenzene (0.384 mmol, 1.5 equiv), Xanthphos (0.051 mmol, 0.2 equiv) and cesium carbonate (0.769 mmol, 3 equiv). This mixture was degassed for 15 minutes under N₂ atmosphere. Pd₂(dba)₃ (0.0256 mmol, 0.1 equiv) was added and the reaction mixture was stirred for 16 h at 100 °C. After cooling to room temperature, the mixture was filtered through Celite and washed with EtOAc (2 × 10 mL). The filtrate was evaporated under reduced pressure and the crude product was purified by using 60–120 silica mesh column chromatography using 10–20% ethyl acetate in hexane as eluent afforded target compound 4a (69% yield).

**Compound 4a: N-phenylbenzo[h]quinazolin-2-amine:** 69% yield (off white solid). ¹H NMR (400 MHz, DMSO-d₆, δ ppm) 10.01 (br s, 1H, NH), 9.29 (s, 1H), 9.03 (dd, *J* = 7.2, 0.8 Hz, 1H), 8.07–8.01 (m, 3H), 7.84–7.72 (m, 3H), 7.43 (d, *J* = 2.0 Hz, 1H), 7.41 (t, *J* = 7.6 Hz, 1H), 7.05 (t, *J* = 6.8 Hz, 1H); ¹³C NMR (75 MHz, DMSO-d₆, δ ppm) δ 161.2, 158.1, 151.2, 141.0, 136.1, 130.5, 129.2, 129.1, 128.6, 127.4, 124.5, 124.4, 124.3, 122.1, 119.3, 117.6; FTIR (KBr 1%, cm⁻¹) *v*: 3423, 3274, 1643, 1601, 1591, 1542, 1504, 1450, 1393, 1025, 993, 804, 750; HRESIMS (*m/z*): [M + H]⁺ calcd for C₁₈H₁₄N₃, 272.1182; found, 272.1181 (0 ppm); mp: 195–197 °C.
## Protocole ImPACell for cytotoxicity studies

**Cell culture.** Skin normal fibroblastic cells are purchased from Lonza (Basel, Switzerland), HuH-7, Caco-2, MDA-MB-231, HCT-116, PC3, MCF7 and NCI-H727 cancer cell lines were obtained from ATCC (American Type Culture Collection). Cells are grown at 37 °C, 5% CO₂ in ATCC recommended media: DMEM for HuH-7, MDA-MB-231, MDA-MB-468 and fibroblast, EMEM for MCF7 and CaCo-2, McCoy's for HCT-116 and RPMI for PC3 and NCI-H727. All culture media are supplemented by 10% of FBS, 1% of penicillin-streptomycin and 2 mM glutamine.

## Cytotoxic assays: primary screen (unique concentration) and secondary screen (IC₅₀)

Both studies have been performed following the protocols described in a previous paper, see ref. [2].

## Supporting Information

### Supporting Information File 1

Supplementary Table S1; spectral and analytical data for compounds **4b-s** as well as all copies of ¹H and ¹³C NMR spectra of compounds **4**.

[https://www.beilstein-journals.org/bjoc/content/supplementary/1860-5397-20-218-S1.pdf]

## Acknowledgements

We thank Chemveda Life Sciences for providing laboratory facility for carrying out these research experiments. This work has been performed also as part of the Indo-French "Joint Laboratory for Natural Products and Synthesis towards Affordable Health". We thank CSIR, CNRS, IICT and University of Rennes for their support. We thank CRMPO (University of Rennes) for the mass spectra analysis.

## Conflict of Interest

The authors declare no conflict of interest.

## Data Availability Statement

All data that supports the findings of this study is available in the published article and/or the supporting information to this article.

## References

1. Das, D.; Hong, J. *Eur. J. Med. Chem.* **2019**, *170*, 55–72.
doi:10.1016/j.ejmech.2019.03.004
See for a recent review.

2. Brahmaiah, D.; Kanaka Durga Bhavani, A.; Aparna, P.; Sampath Kumar, N.; Solhi, H.; Le Guevel, R.; Baratte, B.; Ruchaud, S.; Bach, S.; Singh Jadav, S.; Raji Reddy, C.; Roisnel, T.; Mosset, P.; Levoin, N.; Grée, R. *Bioorg. Med. Chem.* **2021**, *31*, 115962.
doi:10.1016/j.bmc.2020.115962

3. Brahmaiah, D.; Bhavani, A. K. D.; Aparna, P.; Kumar, N. S.; Solhi, H.; Le Guevel, R.; Baratte, B.; Robert, T.; Ruchaud, S.; Bach, S.; Jadav, S. S.; Reddy, C. R.; Mosset, P.; Gouault, N.; Levoin, N.; Grée, R. *Molecules* **2022**, *27*, 6149. doi:10.3390/molecules27196149

4. Das, N.; Roy, J.; Patra, B.; Saunders, E.; Sarkar, D.; Goon, S.; Sinha, B. P.; Roy, S.; Roy, S.; Sarif, J.; Bandopadhyay, P.; Barik, S.; Mukherjee, S.; McNamara, N.; Varghese, S.; Simpson, K.; Baell, J.; McConville, M.; Ganguly, D.; Talukdar, A. *Eur. J. Med. Chem.* **2024**, *269*, 116256. doi:10.1016/j.ejmech.2024.116256

5. de Souza Gama, F. H.; Dutra, L. A.; Hawgood, M.; Vinícius dos Reis, C.; Serafim, R. A. M.; Ferreira, M. A., Jr.; Teodoro, B. V. M.; Takarada, J. E.; Santiago, A. S.; Balourdas, D.-I.; Nilsson, A.-S.; Urien, B.; Almeida, V. M.; Gileadi, C.; Ramos, P. Z.; Salmazo, A.; Vasconcelos, S. N. S.; Cunha, M. R.; Mueller, S.; Knapp, S.; Massirer, K. B.; Elkins, J. M.; Gileadi, O.; Mascarello, A.; Lemmens, B. B. L. G.; Guimarães, C. R. W.; Azevedo, H.; Counago, R. M. *J. Med. Chem.* **2024**, *67*, 8609–8629.
doi:10.1021/acs.jmedchem.3c02250

6. Alagarsamy, V.; Chitra, K.; Saravanan, G.; Solomon, V. R.; Sulthana, M. T.; Narendhar, B. *Eur. J. Med. Chem.* **2018**, *151*, 628–685. doi:10.1016/j.ejmech.2018.03.076

7. Collet, J. W.; van der Nol, E. A.; Roosevelt, T. R.; Maes, B. U. W.; Ruijter, E.; Orru, R. V. A. *J. Org. Chem.* **2020**, *85*, 7378–7385.
doi:10.1021/acs.joc.0c00771

8. Dong, Y.; Zhang, J.; Yang, J.; Yan, C.; Wu, Y. *New J. Chem.* **2021**, *45*, 15344–15349. doi:10.1039/d1nj03179a

9. Sengupta, S. K.; Chatterjee, S.; Protopapa, H. K.; Modest, E. J. *J. Org. Chem.* **1972**, *37*, 1323–1328. doi:10.1021/jo00974a010

10. Rosowsky, A.; Papathanasopoulos, N. *J. Org. Chem.* **1974**, *39*, 3293–3295. doi:10.1021/jo00936a033

11. Khan, I.; Ibrar, A.; Abbas, N.; Saeed, A. *Eur. J. Med. Chem.* **2014**, *76*, 193–244. doi:10.1016/j.ejmech.2014.02.005

12. Malinowski, Z.; Fornal, E.; Warpas, A.; Nowak, M. *Monatsh. Chem.* **2018**, *149*, 1999–2011. doi:10.1007/s00706-018-2268-x

13. Leroux, F.; Mangano, G.; Schlosser, M. *Eur. J. Org. Chem.* **2005**, 5049–5054. doi:10.1002/ejoc.200500514

14. Paul, F.; Patt, J.; Hartwig, J. F. *J. Am. Chem. Soc.* **1994**, *116*, 5969–5970. doi:10.1021/ja00092a058

15. Guram, A. S.; Buchwald, S. L. *J. Am. Chem. Soc.* **1994**, *116*, 7901–7902. doi:10.1021/ja00096a059

16. Guram, A. S.; Rennels, R. A.; Buchwald, S. L. *Angew. Chem., Int. Ed. Engl.* **1995**, *34*, 1348–1350.
doi:10.1002/anie.199513481

17. Louie, J.; Hartwig, J. F. *Tetrahedron Lett.* **1995**, *36*, 3609–3612.
doi:10.1016/0040-4039(95)00605-c

18. Xiang, J.; Wang, Y.; Wang, W.; Yu, J.; Zheng, L.; Hong, Y.; Shi, L.; Zhang, C.; Chen, N.; Xu, J.; Gong, X.; Zhang, Z.; Cui, H.; Zhou, Q.; Zhang, D.; Liu, Y.; Ke, Y.; Shen, J.; Xia, G.; Bai, X. *Bioorg. Chem.* **2023**, *140*, 106765. doi:10.1016/j.bioorg.2023.106765
License and Terms

This is an open access article licensed under the terms of
the Beilstein-Institut Open Access License Agreement
([https://www.beilstein-journals.org/bjoc/terms](https://www.beilstein-journals.org/bjoc/terms)), which is
identical to the Creative Commons Attribution 4.0
International License
([https://creativecommons.org/licenses/by/4.0](https://creativecommons.org/licenses/by/4.0)). The reuse of
material under this license requires that the author(s),
source and license are credited. Third-party material in this
article could be subject to other licenses (typically indicated
in the credit line), and in this case, users are required to
obtain permission from the license holder to reuse the
material.

The definitive version of this article is the electronic one
which can be found at:
[https://doi.org/10.3762/bjoc.20.218](https://doi.org/10.3762/bjoc.20.218)