Development of di-arylated 1,2,4-triazole-based derivatives as therapeutic agents against breast cancer: synthesis and biological evaluation†

The synthesis, anticancer activity, and metabolic stability of di-arylated 1,2,4-triazole molecules have been reported. Utilizing an efficient programmed arylation technique which starts from commercially available 3-bromo-1H-1,2,4-triazole, a series of therapeutic agents have been synthesized and screened against three human breast cancer cell lines, MDA-MB-231, MCF-7, and ZR-75-1, via an in vitro growth inhibition assay. At 10 μM concentration, 4k, 4m, 4q, and 4t have displayed good anticancer potency in the MCF-7 cell line, among which 4q has shown the best efficacy (IC₅₀ = 4.8 μM). Mechanistic investigations of 4q have indicated the elevation of the pro-apoptotic BAX protein in the malignant cells along with mitochondrial outer membrane permeabilization which are hallmarks of apoptosis. Further metabolic stability studies in diverse liver microsomes have provided insights into the favorable pharmacokinetic properties of 4q in humans, establishing it as a promising lead compound of this series that deserves further investigation.