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.

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Fig. 1.

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ACKNOWLEDGMENTS

A. Shaik thanks our Research Supervisor Pilli V.V.N. Kishore for providing us required facilities and motivation for completion of the research work. We also extend our gratitude toward Department of Sciences and Humanities, VFSTR University.

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Correspondence to P. V. V. N. Kishore.

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Shaik, A., Rao, A.T., Venkatarao, D.V. et al. Novel Etodolac-Based 1,2,4-Triazole Derivatives as Antimicrobial Agents: Synthesis, Biological Evaluation, and Molecular Docking Study. Russ J Org Chem 56, 2179–2187 (2020). https://doi.org/10.1134/S1070428020120210

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Keywords:

  • nonsteroidal anti-inflammatory drugs
  • antioxidant activity
  • antibacterial activity
  • docking studies
  • 1,2,4-triazoles
  • GSK-3