Design and synthesis of tetrazole tethered quinazoline derivatives via azide-isocyanide cross-coupling reaction: Exploring the utility as anticancer agents via the SRC kinase inhibition in breast cancer

Kinases, particularly non-receptor tyrosine kinases (nRTK), are vital growth factors that determine the fate of numerous cancers, including breast cancer (BC). One such nRTK is c-Src, which plays a profound role in BC, is associated with BC development and metastasis, and induces resistance to cancer therapeutics. Considering the critical role of c-Src in BC outcome, we herein rationally designed and developed the tetrazole tethered quinazoline derivatives, considering the pharmacophoric feature of the catalytic domain of c-Src. The synthesis via the azide-isocyanide cross-coupling reaction led to the development of 11 compounds (3a-3 k) in good to high yields. Biological analysis revealed that all the compounds possessed anticancer potential against BC cells. Among them, Compounds 3e and 3 g showed nanomolar range activity in the employed cells, that is, MDAMB-231 (IC₅₀: 0.826 and 0.812 nM), T47D (IC₅₀: 0.973 and 1003 nM), and MCF-7 (IC₅₀:0.654 and 0.568 nM), in comparison to the positive control. These compounds were found to be nontoxic to normal cells. The target delineation studies on cSrc revealed the potent and dose-dependent inhibition of the kinase activity by the selected compounds 3e (IC₅₀: 410 nM) and 3 g (IC₅₀: 302 nM) compared to the employed positive control bosutinib (IC₅₀: 446 nM). The analysis was rationally corroborated by the in-silico analysis, particularly the molecular docking and dynamics. Besides this, the secondary anticancer mechanisms revealed that the compounds 3e and 3 g could upsurge the ROS levels in the cancer cells, alter the mitochondrial membrane (depolarization), induce cell death primarily via apoptosis, and halt the cancer cell cycle beyond the G1 phase.