Design, synthesis, in silico studies, and antiproliferative activity of a novel series of thiazole/1,2,3-triazole hybrids as apoptosis inducers and multi-kinase inhibitors endowed with anti-breast cancer activity

Abstract

A novel series of thiazole/1,2,3-triazole hybrids has been developed and evaluated for their in vitro anticancer efficacy. Compounds 10c, 10e, 10k, 10m, 10n, and 10o exhibited superior anticancer efficacy against the evaluated cancer cell lines, demonstrating a favorable safety profile, particularly against MCF-7 breast cancer, compared to erlotinib. The in vitro anti-breast cancer assay of compounds 10e and 10k demonstrated potent antiproliferative activity against the MCF-7 breast cancer cell line, with IC₅₀ values of 24 nM and 21 nM, respectively, relative to the reference erlotinib, which exhibited an IC₅₀ value of 40 nM. To elucidate their antiproliferative mechanism, tests for EGFR, HER-2, VEGFR-2, and BRAF^V600E kinases were performed. Compounds 10e and 10k exhibited the highest potency as multi-EGFR/HER-2/VEGFR-2 kinase inhibitors, with IC₅₀ values of 73 ± 4 nM (EGFR), 31 ± 2 nM (HER-2), and 20 ± 1 nM (VEGFR-2), and 69 ± 4 nM (EGFR), 29 ± 1 nM (HER-2), and 21 ± 1 nM (VEGFR-2), respectively. The BRAF^V600E inhibitory testing results indicated weak to moderate effectiveness for the evaluated compounds. Findings from assays of apoptotic markers (Bax, Bcl2, and p53) indicate that apoptosis may contribute to the antiproliferative effects of the examined compounds. Analysis revealed that the 1,2,3-triazole moiety, the para-substituted methoxy group, and the chalcone moiety are essential variables in enhancing activity. The in silico docking studies against EGFR, HER-2, and VEGFR-2 revealed the importance of the phenyl 1,2,3-triazole moiety and the chalcone side chain in anticancer activity. The most potent compounds demonstrated drug-like properties and could serve as prototypes for future optimization. Compounds 10e and 10k may serve as examples of multi-targeting anticancer agents that function by blocking the EGFR, HER-2, and VEGFR-2 kinases.