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Design, Synthesis, and Evaluation of Metronidazole-1,2,3-Triazole Derivatives As Potent Urease Inhibitors Publisher



Rezaei EB1 ; Abedinifar F1 ; Azizian H2 ; Montazer MN3 ; Asadi M3 ; Hosseini S4 ; Sepehri S5 ; Mohammadikhanaposhtani M6 ; Biglar M1 ; Larijani B1 ; Amanlou M3 ; Mahdavi M1
Authors
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Authors Affiliations
  1. 1. Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
  2. 2. Department of Medicinal Chemistry, School of Pharmacy-International Campus, Iran University of Medical Sciences, Tehran, Iran
  3. 3. Department of Medicinal Chemistry, Faculty of Pharmacy and Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Tehran, Iran
  4. 4. Department of Pharmaceutical Chemistry, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran
  5. 5. Department of Medicinal Chemistry, School of Pharmacy, Ardabil University of Medical Sciences, Ardabil, Iran
  6. 6. Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran

Source: Chemical Papers Published:2021


Abstract

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. © 2021, Institute of Chemistry, Slovak Academy of Sciences.
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