Synthesis, molecular modelling, and antimicrobial activity of new triazole-thiophene compounds

• A series of new triazolyl-thiophene compounds 3, 4 , and 5 were synthesized and characterized by IR, NMR , and MS tools. • The DFT molecular modelling of the studied triazolyl-thiophene compounds suggested non-planar structures. • They have coincided configuration of their FMO's , except for the nitrophenyl derivatives. • The triazolyl-thiophene compound 4b displayed robust activity against DNA gyrase inhibition. • Compounds 3a-b, 4a-b , and 5a were satisfactory absorbed by the GI tract but then didn't pass through the BBB . A series of nine triazole-linked thiophene ring systems 3, 4 , and 5 were synthesized by thiocarbamolyation of 4-acetyl-1-aryl-triazoles 1a-c with phenyl isothiocyanate and in situ heterocyclization of thioamide compounds 2a-c with ethyl chloroacetate, chloroacetone, and/or chloroacetonitrile. The DFT analysis of the synthesized compounds revealed a twisted configuration. In addition, the FMO's exploration indicated that the studied compounds revealed coincided configuration of their HOMO and LUMO, except for the nitrophenyl derivatives, in which the phenylaminothiophene and nitrophenyltriazole moieties acted as the donor and acceptor groups, respectively. Moreover, derivative 5c was identified as the most effective, exhibiting the lowest MIC values across various bacterial and fungal strains, including (24.5 µg/mL) for both Escherichia coli and S. aureus in addition (98.0 µg/mL) against Salmonella typhimurium . Temporarily, derivative 5a also exhibited substantial potency, mainly against Gram-positive bacteria. Meanwhile, the DNA gyrase inhibitory activity of synthesized compounds presented hybrid 4b with the strongest inhibitory action (IC 50 = 4.84±0.29 µM), followed by 4a (5.22±0.13 µM). These findings indicate that some of the produced compounds exhibit strong DNA gyrase inhibition, suggesting that they are intriguing candidates for future development as antibacterial compounds. Molecular docking of the synthesized triazole-thiophene compounds was applied to understand their binding with PDB: 3TTZ amino acids. The results revealed that compounds 4a and 4b exhibited the highest binding affinities between the synthesized derivatives, primarily interacting with amino acid residues through π-H interactions. In addition, the pharmacokinetic properties of the synthesized compounds were found to comply with Lipinski's rule of five through SwissADME analysis, suggesting that they are favorable drugs. Compounds 3a-b, 4a-b , and 5a were well absorbed by the gastrointestinal tract (GI) but did not pass through the blood-brain barrier (BBB) or bind to P-glycoprotein (Pgp). These findings indicate that they have the potential for oral administration and minimal adverse effects on the central nervous system (CNS).