Synthesis, anticancer evaluation and molecular docking of new benzothiazole scaffolds targeting FGFR-1

Abstract

This work deals with the design and synthesis of a series of new substituted 2-arylbenzothiazole compounds attached to 4-oxothiazolidin-2-ylidene ring 2-12 and chain elongation with different amino acids and their corresponding ester derivatives 13-18. All prepared derivatives were screened for their in vitro cytotoxicity activities against two cancer cell lines (HepG-2 and MCF-7) in comparison with doxorubicin; in addition to their safety towards thenormal cell line. Furthermore, all compounds 2-18 were evaluated as FGFR-1 inhibitors using AZD4547 as a reference. The 4-oxothiazolidin-2-ylidene derivatives 3 and 8 exhibited the highest cytotoxic activity (IC_{50 HepG-2} = 2.06, 2.21 µM and IC_{50 MCF-7} = 0.73, 0.77 µM, respectively) through their promising FGFR-1 suppression effects (IC₅₀ = 16.31 and 18.08 nM, respectively) in comparison to AZD4547 (IC₅₀ = 21.45 nM). Cell cycle and apoptosis analysis indicated that compounds 3 and 8 induce pronounced increase in the cell percentages at pre-G₁ and G₂/M phase compared to the untreated MCF-7 cancer cells, in addition to their up regulation of caspase-3/7/9. The molecular docking simulation was created to elucidate the binding modes of benzothiazole derivatives 1-18 bearing various scaffolds within the ATP-binding pocket of FGFR-1 enzyme compared with AZD4547.

Keywords: Apoptosis; Benzothiazole; Caspase-3/7/9; FGFR-1; HepG-2; MCF-7.