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Synthesis, cytotoxicity, Pan-HDAC inhibitory activity and docking study of new N-(2-aminophenyl)-2-methylquinoline-4-carboxamide and (E)-N-(2-aminophenyl)-2-styrylquinoline-4-carboxamide derivatives as anticancer agents

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Abstract

In this study, new cytotoxic agents based on 2-aminobenzamide scaffold were designed, synthesized and evaluated against A549, HCT116 and HT-29 cancer cell lines (inhib%) in doses of 5 μM and 20 μM that displayed moderate to good effects. The synthesized compounds were evaluated for their inhibitory activity (inhib%) against Pan-HDAC on HCT116 and HT-29 cell lines which displayed inhibitory activity (%) of 0–67.34% on HT-29 and 5.67–50.18% on HCT116 cell line at concentrations of 100 μM. Generally, Pan-HDAC inhibitory activity (inhib%) in (E)-N-(2-aminophenyl)-2-styrylquinoline-4-carboxamide series was better than N-(2-aminophenyl)-2-methylquinoline-4-carboxamide series. The most potent compounds 7h, 7i, 8b, 8c, 8l and 8j were selected to determine IC50 values. Interestingly, the most cytotoxicity was calculated for small size molecules of 7h and 7i from N-(2-aminophenyl)-2-methylquinoline-4-carboxamide series, 2.4 μM (HCT116) and 6.4 μM (HT-29) for compound 7h and 5.2 μM (HCT116) and 10.65 μM (HT-29) for compound 7i. Compound 8j (5.8 μM) and compound 8l (8.5 μM) from (E)-N-(2-aminophenyl)-2-styrylquinoline-4-carboxamide series displayed the most cytotoxicity on HCT116 cell line. Docking study of selected compounds 7h, 7i, 8b, 8c, 8l, and 8j was performed on HDAC isoforms that exhibited the best docking scores on sirtuins. Generally, predicted ADME properties for synthesized compounds with the pkCSM web-tool were appropriate. Based on Molinspiration Calculations, the synthesized compounds displayed the best scores as Kinase inhibitor range from 0.06 to 0.24 and then as Enzyme inhibitor range from -0.01 to 0.19.

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Authors and Affiliations

  1. Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran

    Negar Omidkhah, Farzin Hadizadeh & Razieh Ghodsi

  2. Department of Medicinal Chemistry, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran

    Negar Omidkhah, Farzin Hadizadeh & Razieh Ghodsi

  3. Department of Pharmaceutical Chemistry, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran

    Afshin Zarghi

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Omidkhah, N., Hadizadeh, F., Zarghi, A. et al. Synthesis, cytotoxicity, Pan-HDAC inhibitory activity and docking study of new N-(2-aminophenyl)-2-methylquinoline-4-carboxamide and (E)-N-(2-aminophenyl)-2-styrylquinoline-4-carboxamide derivatives as anticancer agents. Med Chem Res 32, 506–524 (2023). https://doi.org/10.1007/s00044-023-03018-w

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