Novel Etodolac-Based 1,2,4-Triazole Derivatives as Antimicrobial Agents: Synthesis, Biological Evaluation, and Molecular Docking Study

Abstract

A series of novel 1,2,4-triazole nonsteroidal anti-inflammatory drugs (NSAIDs) derived from etodolac were designed and synthesized. The synthesized compounds were identified using ¹H and ¹³C NMR, IR, and mass spectra and elemental analyses and evaluated for their in vitro antibacterial activity against Gram-positive microorganisms like Streptococcus pneumoniae and Klebsiella pneumoniae and Gram-negative strains such as Pseudomonas aeruginosa and Enterobacter cloacae with pefloxacin as a reference drug. Some compounds showed a potent activity at a concentration 50 mg/mL with inhibition zones of 30 to 36 mm against S. pneumoniae. Etodolac-derived N-isobutyl- and N-ethyl-1,2,4-triazoles containing 4-methoxybenzylsulfanyl and 3-nitrobenzylsulfanyl groups were active against P. aeruginosa with inhibition zones of 25–29 mm at a concentration of 50 mg/mL. All compounds showed excellent antioxidant activity with IC₅₀ values ranging from 72.39±0.25 µg/mL to 16.39±0.65 µg/mL in comparison with ascorbic acid (IC₅₀ 16.81±0.18 µg/mL). Molecular docking studies revealed strong hydrogen bonding, π–π, and π–σ interactions of 3-nitro-, 4-methoxy-, and 4-methylbenzyl moieties with Ser421, Val120, Tyr124, Phe319, Ala44, and Val120 amino acid residues of the active site of glycogen synthase kinase-3 (GSK-3) protein.