Novel Antimicrobial and Antitumor Agents Bearing Pyridine-1,2,4-triazole-3-thione-hydrazone Scaffold: Synthesis, Biological Evaluation, and Molecular Docking Investigation.

A series of target 4-substituted-5-(2-(pyridine-2-ylamino)ethyl)-2,4-dihydro-3-1,2,4-triazole-3-thiones and their chloro analogs - were synthesized in a reaction of the selected aldehydes with the corresponding 4-amino-1,2,4-triazole-3-thiones and , which were obtained from 3-(pyridin-2-ylamino)propanoic acid () or 3-((5-chloropyridin-2-yl)amino)propanoic acid (), respectively, with thioacetohydrazide. The antibacterial and antifungal activities of the synthesized hydrazones were screened against the bacteria , , and and the fungi and by agar diffusion and serial dilution methods. 4-Amino-5-(2-((5-chloropyridin-2-yl)amino)ethyl)-2,4-dihydro-3-1,2,4-triazole-3-thione () and 4-(benzylideneamino)-5-(2-(pyridin-2-ylamino)ethyl)-2,4-dihydro-3-1,2,4-triazole-3-thione () were identified as exceptionally active (MIC 0.9 µg/mL) against the fungus 5-Chloropyridine derivatives bearing 4-benzylidene , 2-nitrobenzylidene , pyridinylmethylene , and 4-methylthiobenzylidene moieties showed very high antibacterial activity (MIC 3.9 µg/mL) against the strain. The cell viability screening of the synthesized compounds using triple-negative breast cancer MDA-MB-231 and glioblastoma U-87 cell lines by MTT assay identified three active hydrazones, of which 5-(2-(pyridin-2-ylamino)ethyl)-4-((pyridin-3-ylmethylene)amino)-2,4-dihydro-3-1,2,4-triazole-3-thione () had the highest effect on the viability of cells (IC value 39.2 ± 1.7 μM against MDA-MD-231). The in silico molecular modeling results suggested that these three most active hydrazones might have influenced the mitogen-activated protein kinase pathway through the inhibition of BRAF and MEK serine-threonine protein kinases. 5-(2-((5-Chloropyridin-2-yl)amino)ethyl)-4-((4-(methylthio)benzylidene)amino)-2,4-dihydro-3-1,2,4-triazole-3-thione () demonstrated the highest affinity among them.