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

Abstract

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 μM 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 μM. Molecular docking simulations were employed to identify the important binding modes responsible for the tubulin inhibitory activity, thus supporting their effective anticancer potential.