Abstract Objective: To synthesize novel N- and O-acylated derivatives of 2-arylquinoline-4-carboxylic acids (analogues of Atophan), evaluate their anti-monoamine oxidase, antibacterial, and fungicidal activities, perform molecular docking against several biological targets (RdRp of SARS-CoV-2, EGFR, MAPK14, and MAO-B), and identify lead compounds for further development. Methods: N-Acylated derivatives (amides and diamides) were obtained by reacting 2-arylquinoline-4-carbonyl chlorides with primary amines or diamines. O-Acylated derivatives (1,3-benzothiazol-2-ylmethyl and naphthyl esters) were synthesized by heating the corresponding alcohols (1,3-benzothiazol-2-ylmethanol or naphthols) with acid chlorides in anhydrous benzene. The structures were confirmed by 1H, 13C NMR, and IR spectroscopy. Anti-monoamine oxidase activity was studied on a rat brain homogenate model in vitro using serotonin (5-OT) as a substrate. Antibacterial and antifungal activities were assessed against E. coli, S. aureus, and C. albicans using the agar diffusion method. Molecular docking was performed to calculate the Gibbs free energy (ΔG°) of binding to RdRp (pdb 7btf), EGFR (pdb 3w32), MAPK14 (pdb 6zqs), and MAO-B (pdb 4a7a). Results and Discussion: A series of N-substituted 2-arylquinoline-4-carboxamides (9–21), diamides (22, 23), 1,3-benzothiazol-2-ylmethyl esters (24, 25), and naphthyl esters (26–28) were synthesized. Amides 10 and 17 activated MAO-A by 19 and 10%, respectively (1·10–6 mol/mL), while esters 25 and 28 exhibited potent anti-MAO activity (92 ± 6.3 and 91 ± 5.0% inhibition of serotonin deamination), outperforming the reference drug indopan (86 ± 6.0%). Compounds 14 and 19 showed high antibacterial activity against all tested strains. Compound 19 also demonstrated pronounced antifungal activity comparable to fluconazole (28 mm inhibition zone vs. 30 mm for fluconazole). Docking studies revealed that compounds 23 and 27 have the highest affinity for MAPK14 (ΔG° = –12.027 and –12.580 kcal/mol), while all tested compounds interacted weakly with MAO-B (ΔG° = –7 to –9 kcal/mol) and RdRp (ΔG° = –7 to –8 kcal/mol). Compounds 24 and 26 showed no significant biological activity in the assays used. Conclusions: Derivatives 25, 28, 14, 19, 23, and 27 are promising lead compounds for further development as antidepressants, antibacterial, antifungal, and anticancer agents. The study confirms that the Atophan scaffold is a valuable basis for designing multitarget bioactive molecules.

Synthesis, Docking, and Biological Properties of N- and O-Acyl Derivatives of 2-Aryl-substituted Quinolinecarboxylic Acids

期刊论文
发表日期：

2026年6月18日

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N. Z. Hakobyan,
A. S. Grigoryan,
R. A. Madoyan,
A. G. Sukiasyan,
T. A. Ambartsumyan,
M. Yu. Danghyan,
A. A. Hambardzumyan,
A. A. Harutyunyan

摘要

Abstract

Objective: To synthesize novel N- and O-acylated derivatives of 2-arylquinoline-4-carboxylic acids (analogues of Atophan), evaluate their anti-monoamine oxidase, antibacterial, and fungicidal activities, perform molecular docking against several biological targets (RdRp of SARS-CoV-2, EGFR, MAPK14, and MAO-B), and identify lead compounds for further development. Methods: N-Acylated derivatives (amides and diamides) were obtained by reacting 2-arylquinoline-4-carbonyl chlorides with primary amines or diamines. O-Acylated derivatives (1,3-benzothiazol-2-ylmethyl and naphthyl esters) were synthesized by heating the corresponding alcohols (1,3-benzothiazol-2-ylmethanol or naphthols) with acid chlorides in anhydrous benzene. The structures were confirmed by ¹H, ¹³C NMR, and IR spectroscopy. Anti-monoamine oxidase activity was studied on a rat brain homogenate model in vitro using serotonin (5-OT) as a substrate. Antibacterial and antifungal activities were assessed against E. coli, S. aureus, and C. albicans using the agar diffusion method. Molecular docking was performed to calculate the Gibbs free energy (ΔG°) of binding to RdRp (pdb 7btf), EGFR (pdb 3w32), MAPK14 (pdb 6zqs), and MAO-B (pdb 4a7a). Results and Discussion: A series of N-substituted 2-arylquinoline-4-carboxamides (9–21), diamides (22, 23), 1,3-benzothiazol-2-ylmethyl esters (24, 25), and naphthyl esters (26–28) were synthesized. Amides 10 and 17 activated MAO-A by 19 and 10%, respectively (1·10^–6 mol/mL), while esters 25 and 28 exhibited potent anti-MAO activity (92 ± 6.3 and 91 ± 5.0% inhibition of serotonin deamination), outperforming the reference drug indopan (86 ± 6.0%). Compounds 14 and 19 showed high antibacterial activity against all tested strains. Compound 19 also demonstrated pronounced antifungal activity comparable to fluconazole (28 mm inhibition zone vs. 30 mm for fluconazole). Docking studies revealed that compounds 23 and 27 have the highest affinity for MAPK14 (ΔG° = –12.027 and –12.580 kcal/mol), while all tested compounds interacted weakly with MAO-B (ΔG° = –7 to –9 kcal/mol) and RdRp (ΔG° = –7 to –8 kcal/mol). Compounds 24 and 26 showed no significant biological activity in the assays used. Conclusions: Derivatives 25, 28, 14, 19, 23, and 27 are promising lead compounds for further development as antidepressants, antibacterial, antifungal, and anticancer agents. The study confirms that the Atophan scaffold is a valuable basis for designing multitarget bioactive molecules.