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-3H-1,2,4-triazole-3-thiones and their chloro analogs 7-21 were synthesized in a reaction of the selected aldehydes with the corresponding 4-amino-1,2,4-triazole-3-thiones 5 and 6, which were obtained from 3-(pyridin-2-ylamino)propanoic acid (3) or 3-((5-chloropyridin-2-yl)amino)propanoic acid (4), respectively, with thioacetohydrazide. The antibacterial and antifungal activities of the synthesized hydrazones were screened against the bacteria Escherichia coli, Staphylococcus aureus, and Mycobacterium luteum and the fungi Candida tenuis and Aspergillus niger by agar diffusion and serial dilution methods. 4-Amino-5-(2-((5-chloropyridin-2-yl)amino)ethyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione (6) and 4-(benzylideneamino)-5-(2-(pyridin-2-ylamino)ethyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione (7) were identified as exceptionally active (MIC 0.9 µg/mL) against the fungus C. tenuis. 5-Chloropyridine derivatives bearing 4-benzylidene 8, 2-nitrobenzylidene 10, pyridinylmethylene 16, and 4-methylthiobenzylidene 21 moieties showed very high antibacterial activity (MIC 3.9 µg/mL) against the M. luteum 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-3H-1,2,4-triazole-3-thione (15) had the highest effect on the viability of cells (IC50 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-3H-1,2,4-triazole-3-thione (21) demonstrated the highest affinity among them.