Diacetoxy iodobenzene mediated regioselective synthesis and characterization of novel [1,2,4]triazolo[4,3-a]pyrimidines: apoptosis inducer, antiproliferative activities and molecular docking studies

Abstract

Prompt and regioselective synthesis of eleven novel [1,2,4]triazolo[4,3-a]pyrimidines <b>2a-2k</b>, <i>via</i> intramolecular oxidative-cyclization of 2-(2-arylidenehydrazinyl)-4-methyl-6-phenylpyrimidine derivatives <b>1a-1k</b> has been demonstrated here using diacetoxy iodobenzene (DIB) as inexpensive and ecofriendly hypervalent iodine(III) reagent in CH₂Cl₂ at room temperature. Regiochemistry of final product has been established by developing single crystal and studied X-ray crystallographic data for two derivatives <b>2c</b> and <b>2h</b> without any ambiguity. These prominent [1,2,4]triazolo[4,3-a]pyrimidines were evaluated for human osteosarcoma bone cancer (MG-63) and breast cancer (MCF-7) cell lines using MTT assay to find potent antiproliferative agent and also on testicular germ cells to find potent apoptotic inducing activities. All compounds show significant cytotoxicity, particularly 3-(2,4-dichlorophenyl)-5-methyl-7-phenyl-[1,2,4]triazolo[4,3-a]pyrimidine (<b>2g</b>) was found significant apoptotic inducing molecule, as well as the most potent cytotoxic agent against bone cancer (MG-63) and breast cancer (MCF-7) cell lines with GI₅₀ value 148.96 µM and 114.3 µM respectively. Molecular docking studies has been carried out to see the molecular interactions of synthesized compounds with the protein thymidylate synthase (PBD ID: 2G8D).Communicated by Ramaswamy H. Sarma.