Novel benzothiazole-indole acetamides as potential anticancer agents: synthesis, biological evaluation, and in silico studies

Abstract

A series of novel benzothiazole-indole acetamides (9a–n) was designed and synthesized as potential anticancer agents, and their antiproliferative activities were evaluated against three cancer cell lines: A549 (human lung cancer), SW480 (human colon cancer), and HepG2 (human liver cancer). The most potent derivative identified was 2-(3-(benzo[d]thiazol-2-yl)-1H-indol-1-yl)-N-(2,4-dimethoxyphenyl)acetamide (9d) which demonstrated IC₅₀ values of 7.9 ± 1.6, 16.1 ± 0.5, and 9.3 ± 2.2 µM against A549, SW480, and HepG2 cells, respectively, comparable or even superior to those of cisplatin (IC₅₀s were 5.7 ± 1.6, 15.2 ± 0.3, and 14.3 ± 1.9 µM for A549, SW480, and HepG2 cells, respectively). Notably, compound 9d showed remarkably less toxicity on the normal MRC-5 than cisplatin. Cell cycle progression and apoptosis induction analyses revealed that 9d arrested the cell cycle at G2/M phase and induced apoptosis in A549. In silico predictions regarding drug-likeness, pharmacokinetics, and toxicological characteristics suggest that the promising derivative 9d could be proposed as a potential anticancer drug for further preclinical studies. Molecular docking studies revealed that 9d was well accommodated within the endothelial growth factor receptor (EGFR) active site.