Novel chromenyl-based 2-iminothiazolidin-4-one derivatives as tubulin polymerization inhibitors: Design, synthesis, biological evaluation and molecular modelling studies

Here-in, we present molecular design, chemical synthesis and evaluation of novel chromenyl-based 2-iminothiazolidin-4-one derivatives as tubulin polymerization inhibitors. The newly synthesized compounds were evaluated for their in vitro cytotoxicities against A549 (lung cancer), MDA-MB-231 and BT-471 (breast cancer), HepG2 (liver cancer) and HCT-116 (colon cancer) cell lines by MTT assay. Among the synthesized compounds, compound 12b showed excellent anticancer activity on MDA-MB-231 cell line with IC50 value of 0.95 +/- 1.88 mu M and was verified to be safe in normal human bronchial epithelial cells (Beas-2B). Apoptosis induced by the lead 12b was observed using morphological observations, AO/EB and DAPI staining procedures. Further, dose-dependent increase in the depolarization of mitochondrial membrane was also observed through JC-1 staining. Annexin V-FITC/PI assay confirmed that 12b induced early apoptosis. Additionally, cell cycle analysis indicated that the MDA-MB-231 cells were arrested at sub-G2/M phase and also inhibited tubulin polymerization with IC50 value of 3.54 +/- 0.2 mM. Molecular docking simulations were employed to identify the important binding modes responsible for the tubulin inhibitory activity, thus supporting their effective anticancer potential. (c) 2020 Published by Elsevier B.V.

Automated summary

The newly synthesized compound 12b exhibited excellent anticancer activity on MDA-MB-231 breast cancer cell line and was found to be safe for normal human bronchial epithelial cells. It induced apoptosis, depolarized mitochondrial membrane, arrested cells at sub-G2/M phase, and inhibited tubulin polymerization, supporting its effective anticancer potential.