Quinolone Tethered 1,2,3-triazole Conjugates: Design, Synthesis, and Computational Docking Studies on New Heterocycles as Potent Antimicrobial Targets

The synthesis and biological properties of molecules simultaneously comprising various heterocycles, such as fused 2-quinolones and 1,2,3-triazoles, have been evaluated as a part of our ongoing research in medicinal and organic chemistry. We were successful in developing a synthetic procedure for 1,2,3-triazole substituted quinolone derivatives. Infrared, proton, and carbon nuclear magnetic resonance, mass spectroscopy and elemental analysis were used to characterise the structures of the recently synthesised triazole derivatives. From screening results, all the compounds demonstrated increased antibacterial action against both Gram-positive and Gram-negative bacteria. Moreover, 1,2,3-triazoles linked to tert-butyl benzyl (3a), trifluoromethyl benzyl (3b), 3-chlorobenzyl (3c), 4- hydroxy-3-nitrobenzyl (6b), 4-hydroxy-4-trifluoromethylbenzyl (6d), and 4-hydroxy-2,4- difluorobenzyl (6e) compounds showed promising antibacterial and antifungal activities with MICs values of 1.07-4.33 μg/mL. The prepared ligand 4-hydroxy-2,4-difluoro benzyl-1,2,3-triazole (6e) exhibited the highest docking score of -6.34 kcal/mol and showed interacting amino acid residues ArgB:¹¹²², MetB:¹¹²¹, AspB:¹⁰⁸³, TryB:¹⁰⁸⁷, AlaB:¹¹¹⁸, AlaB:¹¹²⁰, GluB:¹⁰⁸⁸, GlyB:¹¹¹⁷, SerB:¹⁰⁸⁴, and AlaB:¹¹¹⁹ within the active site of 2XCT. Final scaffolds were further evaluated for their ADMET and physicochemical properties by using ADMETlab2.0 and SwissADME web servers as good oral bioavailability drugs.