Design, synthesis, molecular docking and biological evaluation of 1,2,4 triazole derivatives possessing a hydrazone moiety as anti-breast cancer agents

Compounds containing 1,2,4-triazoles and hydrazone structural frameworks have been widely studied and demonstrated to exhibit a wide range of pharmacological properties. In this work, a descriptive series of new hybrid compounds with a 1,2,4-triazole ring and a hydrazone moiety were designed and synthesized by oxidative cyclization of thiourea derivatives using molecular iodine under mild conditions. The structure of synthesized compounds was characterized by employing different spectral techniques including FTIR, 1H NMR, 13C NMR, HRMS, and X-ray analysis. Furthermore, the proposed structure of BIH2 was resolved using single-crystal X-ray analysis. The compounds were evaluated for their in vitro anti-breast cancer activity and the most promising compound BIH4 with a methyl group substituted to a benzene ring exhibited significant dose-dependent cytotoxicity with selectivity to MDA-MB-231 cells in a Resazurin assay. The investigation of cell cycle progression analysis of the most active compound using a flow cytometer displayed a cell cycle arrest in the sub G1 phase. Furthermore, molecular modeling studies for the synthesized compounds were performed to predict their binding affinities toward the active site of BCL-2. The findings of the molecular modeling investigations were highly consistent with those of the cytotoxicity results.