Synthesis, characterization, molecular structures, antimicrobial and anti-proliferative activities of thiophene-linked 1,2,4-triazoles and condensed triazoles

Series of 1,2,4-triazole and condensed triazole derivatives carrying thiophene moieties have synthesized. The compounds were characterized using 1H NMR, 13C NMR and ESI-MS spectrometry. The synthesized compounds were tested for inhibitory activity against a panel of pathogenic Gram-positive and Gram-negative bacteria, as well as pathogenic fungal strains. Additionally, the anti-proliferative activity was evaluated against four human cancer cell lines. The 7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine analogue 6c and the [1,2,4]triazolo[3,4-b] [1,3,4]thiadiazole 5c were found to possess most potent anti-proliferative and antibacterial activities, respectively. The crystal structures of three representative compounds 4b, 4c and 5e was studied by single crystal X ray diffraction. Compounds 4b and 4c crystallized in the monoclinic system (P21/c) with two molecules in the asymmetric unit, and both showed similar crystal packing. However, differences were obtained in their intermolecular interactions and molecular dimers. The crystal structure of 4b is stabilized by N-H & sdot;& sdot;& sdot;N, C-H & sdot;& sdot;& sdot;N/S/pi and pi-stacking interactions. In contrast, 4c exhibits similar stabilizing interactions but also includes two sigma-hole interactions such as S & sdot;& sdot;& sdot;N chalcogen bond and type II Cl & sdot;& sdot;& sdot;Cl halogen bond. Compound 5e also crystallized in the monoclinic system but in the C2/c space group with two crystallographically independent molecules, and its structure is stabilized by intermolecular C-H & sdot;& sdot;& sdot;N/S/pi and pi-stacking interactions, along with C-H & sdot;& sdot;& sdot;Cl interaction and two sigma-hole (S & sdot;& sdot;& sdot;N chalcogen and N & sdot;& sdot;& sdot;N pnictogen bonds) interactions. Hirshfeld surface analysis was performed to examine the nature of intermolecular interactions and their contributions to the crystal packing in 4b, 4c and 5e. The most potent antibacterial compound 6c was subjected to molecular docking with the DNA gyrase of S. aureus, while the most effective anti-proliferative agent 5c was docked with the human CDK2 target. The molecular docking results showed that these compounds can bind to their respective targets and interact with key active site residues.