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CC BY 4.0 · SynOpen 2023; 07(01): 17-28
DOI: 10.1055/s-0042-1751835
paper

Design, Synthesis and Biological Evaluation of Imidazole-Substituted/Fused Aryl Derivatives Targeting Tubulin Polymerization as Anticancer Agents

Kapil Kumar Goel  ∗
a   Department of Pharmaceutical Sciences, Gurukul Kangri (Deemed to be University), Haridwar-249404, India
b   Amity Institute of Pharmacy, Amity University, Sector 125, Noida, Uttar Pradesh 201301, India
,
Satyendra Kumar Rajput
a   Department of Pharmaceutical Sciences, Gurukul Kangri (Deemed to be University), Haridwar-249404, India
,
Rajeev Kharb∗
b   Amity Institute of Pharmacy, Amity University, Sector 125, Noida, Uttar Pradesh 201301, India
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Abstract

The development of new pharmacologically active molecules targeting tubulin polymerization has recently attracted great interest in research groups. In efforts to develop new potent anticancer compounds, imidazole-tethered/fused pharmacologically active aryl derivatives possessing different substitution patterns targeting tubulin polymerization have been rationally designed and synthesized. The target molecules (P1-5 and KG1-5) were synthesized by multistep syntheses involving the reaction of intermediate 2-aminophenyl-tethered imidazoles with appropriate reactants in the presence of p-TsOH under different conditions. The synthesized compounds displayed moderate to good cytotoxicity, comparable to that of colchicine, against four cancer cell lines (MCF-7, MD-MBA-231, A549, and HCT-116). Compounds P2 and P5, with an imidazoloquinoxaline moiety, emerged as potential leads with cytotoxicity profiles against these cell lines similar to colchicine. Compounds P2 and P5 arrested cell division at the G2/M phase and prevented cancerous cell growth through induced apoptosis. These results favored the hypothesis that the compounds might act by binding to the colchicine binding site, which was further confirmed with the help of a tubulin polymerization inhibition assay. The results encourage the further exploration of imidazoloquinoxalines as promising leads that deserve advanced clinical investigation.

Key words

imidazoloquinoxalines - anticancer agents - tubulin - imidazoles - cytotoxicity - cell division - drug design

Supporting Information

    Supporting information for this article is available online at https://doi.org/10.1055/s-0042-1751835.
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Publication History

Received: 18 October 2022

Accepted after revision: 14 December 2022

Article published online:
26 January 2023

© 2023. This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by/4.0/)

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