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  3. Benzimidazole derivatives as tubulin polymerization inhibitors: Design, synthesis and in vitro cytotoxicity studies

Benzimidazole derivatives as tubulin polymerization inhibitors: Design, synthesis and in vitro cytotoxicity studies

  • Bioorg Med Chem Lett. 2023 Oct 3:96:129494. doi: 10.1016/j.bmcl.2023.129494.
Kritika Laxmikeshav 1,  Ziaur Rahman 2,  Ashutosh Mahale 3,  Durgesh Gurukkala Valapil 1,  Pravesh Sharma 3,  Joel George 4,  Regur Phanindranath 4,  Manoj P Dandekar 5,  Onkar P Kulkarni 3,  Narayana Nagesh 4,  Nagula Shankaraiah 6
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500037, India.
  • 2 Department of Biological Sciences, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500037, India.
  • 3 Department of Pharmacy, Birla Institute of Technology and Science-Pilani, Hyderabad Campus, Hyderabad 500078, India.
  • 4 CSIR-Centre for Cellular and Molecular Biology, Medical Biotechnology Complex, ANNEXE II, Uppal Road, Hyderabad 500007, India.
  • 5 Department of Biological Sciences, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500037, India. Electronic address: manoj.dandekar@niperhyd.ac.in.
  • 6 Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500037, India. Electronic address: shankar@niperhyd.ac.in.
PMID: 37797804 DOI: 10.1016/j.bmcl.2023.129494
Abstract

A new class of benzimidazole derivatives as tubulin polymerization inhibitors has been designed and synthesized in this study. The in vitro Anticancer profile of the developed molecules was reconnoitred on selected human Cancer cells. The highest cytotoxicity was illustrated by compounds 7n and 7u with IC50 values ranging from 2.55 to 17.89 µM with specificity toward SK-Mel-28 cells. They displayed 5-fold less cytotoxicity towards normal rat kidney epithelial NRK52E cells, which implies that they are not harmful to normal, healthy cells. The cellular staining procedures like AO/EB, DCFDA, and DAPI were applied to comprehend the inherent mechanism of Apoptosis which displayed nuclear and morphological alterations. The Annexin V binding and JC-1 studies were executed to evaluate the extent of Apoptosis and the decline in mitochondrial transmembrane potential in SK-Mel-28 cell lines. Compound 7n dose-dependently arrested the G2/M phase of the cell cycle and the target-based outcomes proposed tubulin polymerization inhibition by 7n (IC50 of 5.05±0.13 μM). Computational studies were also conducted on the tubulin protein (PDB ID: 3E22) to investigate the stabilized binding interactions of compounds 7n and 7u with tubulin, respectively.

Keywords

Anti-cancer; Benzimidazole; Carboxamide; Structure-activity relationship (SAR); Tubulin inhibition.

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