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Design, synthesis, and evaluation of metronidazole-1,2,3-triazole derivatives as potent urease inhibitors


A new series of metronidazole-1,2,3-triazole derivatives 6a–o was synthesized and evaluated as Helicobacter pylori urease inhibitors. All the synthesized compounds were more potent than standard inhibitor thiourea against urease. Among the synthesized compounds, compound 6f (IC50 = 1.975 ± 0.25 µM) with inhibitory activity around 11-fols more than thiourea (IC50 = 22.00 ± 0.14 µM) was the most potent compound. Kinetic study of this compound revealed that compound 6f inhibited urease in an uncompetitive mode. Based on molecular modeling study, compound 6f pointed toward the bi-nickel center and stabilized by H-bond and T-shape π–π hydrophobic interactions with the critical residues His492 and Asp633. Moreover, it anchored to the helix-turn-helix motif in the active site cavity through interaction with His593 and Arg609. Consequently, it proposed that compound 6f through stabilization of active site flap inhibited urease activity.

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Correspondence to Mahmood Biglar or Mohammad Mahdavi.

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Rezaei, E.B., Abedinifar, F., Azizian, H. et al. Design, synthesis, and evaluation of metronidazole-1,2,3-triazole derivatives as potent urease inhibitors. Chem. Pap. 75, 4217–4226 (2021).

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  • Urease inhibitors
  • 1,2,3-Triazole
  • Metronidazole
  • Kinetic study
  • Molecular modeling