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Design, Synthesis, In Vitro Cytotoxicity, ADME Prediction, and Molecular Docking Study of Benzimidazole-Linked Pyrrolone and N-Benzylpyrrolone Derivatives

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Abstract

A series of benzimidazole-tethered pyrrolones and N-benzylpyrrolones were synthesized, charac­terized, and explored for their in vitro anti-proliferative activities. The cytotoxicity of the synthesized com­pounds was evaluated against three cancer cell lines, A549, MCF7, and DU145. (E)-5-(1H-Benzimidazol-2-yl)-3-(3,4,5-trimethoxbenzylidene)-1H-pyrrol-2(3H)-one having three methoxy groups at 3,4,5-positions exhibited excellent activity against A549, MCF7, and DU145 cancer cell lines with IC50 values of 8.3±0.53, 7.2±1.42, and 7.7±0.13 µM, respectively. Another pyrrolone derivative with one hydroxy and one methoxy substituents, (E)-5-(1H-benzimidazol-2-yl)-3-(4-hydroxy-3-methoxybenzylidene)-1H-pyrrol-2(3H)-one, also displayed very good activity against A549, MCF7, and DU145 cell lines with IC50 values of 9.6±0.12, 7.3±0.24, and 8.7± 0.24 µM, respectively. Molecular docking study revealed that all compounds fit into the pocket of VEGFR-2 within the key amino acid residues Glu885, Cys919, and Asp1046. The docking scores and binding energies were very consistent with the experimental anticancer activity. Pharmacokinetic (ADME) parameters of the potent derivatives were also found to be within an acceptable range. It could be concluded that benzimidazole-linked pyrrolones are more potent than their benzylpyrrolone analogs, and therefore this class of compounds could be explored further for the development of potent anticancer agents.

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ACKNOWLEDGMENTS

S. Parveen is grateful to Jamia Hamdard for “JH Silver Jubilee Post-Doctoral Fellowship-2016.”

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Authors and Affiliations

  1. Department of Pharmaceutical Chemistry, School of Pharmaceutical Education and Research, Jamia Hamdard, 110062, New Delhi, India

    A. Husain, M. Bhutani & M. A. Iqbal

  2. Chemistry Department, Faculty of Science, Taibah University, Yanbu Branch, 46423, Yanbu, Saudi Arabia

    S. Parveen

  3. Department of Chemistry, School of Chemical and Life Sciences, Jamia Hamdard, 110062, New Delhi, India

    S. Parveen

  4. College of Pharmacy, National University of Science and Technology, 130, Muscat, Sultanate of Oman

    S. A. Khan

  5. Health Information Technology Department, Faculty of Applied Studies, King Abdulaziz University, 21589, Jeddah, Saudi Arabia

    A. Ahmad

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  1. A. Husain
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Contributions

Conceptualization: A. Husain; methodology: A. Husain, M. Bhutani, S.A. Khan; formal analysis and investigation: S. Parveen, M. Bhutani, A. Iqbal, A. Ahmad; original draft preparation: S. Parveen, A. Husain; review and editing: S.A. Khan, A. Ahmad; resources: A. Husain; supervision: A. Husain.

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Correspondence to S. Parveen.

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Husain, A., Bhutani, M., Parveen, S. et al. Design, Synthesis, In Vitro Cytotoxicity, ADME Prediction, and Molecular Docking Study of Benzimidazole-Linked Pyrrolone and N-Benzylpyrrolone Derivatives. Russ J Org Chem 58, 1438–1450 (2022). https://doi.org/10.1134/S1070428022100098

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