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Design and Synthesis of Imidazo[2,1‐ b ]thiazole–Chalcone Conjugates: Microtubule‐Destabilizing Agents
Author(s) -
Kamal Ahmed,
Balakrishna Moku,
Nayak V. Lakshma,
Shaik Thokhir Basha,
Faazil Shaikh,
Nimbarte Vijaykumar D.
Publication year - 2014
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201402310
Subject(s) - conjugate , chalcone , hela , chemistry , thiazole , tubulin , annexin , apoptosis , a549 cell , microtubule , cell cycle , cell culture , microtubule polymerization , mtt assay , cytotoxic t cell , stereochemistry , biochemistry , cell , biology , microbiology and biotechnology , in vitro , genetics , mathematics , mathematical analysis
A series of chalcone conjugates featuring the imidazo[2,1‐ b ]thiazole scaffold was designed, synthesized, and evaluated for their cytotoxic activity against five human cancer cell lines (MCF‐7, A549, HeLa, DU‐145 and HT‐29). These new hybrid molecules have shown promising cytotoxic activity with IC 50 values ranging from 0.64 to 30.9 μ M . Among them, ( E )‐3‐(6‐(4‐fluorophenyl)‐2,3‐bis(4‐methoxyphenyl)imidazo[2,1‐ b ]thiazol‐5‐yl)‐1‐(pyridin‐2‐yl)prop‐2‐en‐1‐one ( 11 x ) showed potent antiproliferative activity with IC 50 values ranging from 0.64 to 1.44 μ M in all tested cell lines. To investigate the mechanism of action, the detailed biological aspects of this promising conjugate ( 11 x ) were carried out on the A549 lung cancer cell line. The tubulin polymerization assay and immunofluoresence analysis results suggest that this conjugate effectively inhibits microtubule assembly in A549 cells. Flow cytometric analysis revealed that this conjugate induces cell‐cycle arrest in the G2/M phase and leads to apoptotic cell death. This was further confirmed by Hoechst staining, activation of caspase‐3, DNA fragmentation analysis, and Annexin V–FITC assay. Moreover, molecular docking studies indicated that this conjugate ( 11 x) interacts and binds efficiently with the tubulin protein.