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

Rezaei, Elham Babazadeh; Abedinifar, Fahimeh; Azizian, Homa; Montazer, Mohammad Nazari; Asadi, Mehdi; Hosseini, Samanesadat; Sepehri, Saghi; Mohammadi-Khanaposhtani, Maryam; Biglar, Mahmood; Larijani, Bagher; Amanlou, Massoud; Mahdavi, Mohammad

doi:10.1007/s11696-021-01653-4

Original Paper
Published: 20 April 2021

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

Elham Babazadeh Rezaei¹,
Fahimeh Abedinifar¹,
Homa Azizian²,
Mohammad Nazari Montazer³,
Mehdi Asadi³,
Samanesadat Hosseini⁴,
Saghi Sepehri⁵,
Maryam Mohammadi-Khanaposhtani⁶,
Mahmood Biglar¹,
Bagher Larijani¹,
Massoud Amanlou³ &
Mohammad Mahdavi¹

Chemical Papers volume 75, pages 4217–4226 (2021)Cite this article

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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.

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Authors and Affiliations

Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
Elham Babazadeh Rezaei, Fahimeh Abedinifar, Mahmood Biglar, Bagher Larijani & Mohammad Mahdavi
Department of Medicinal Chemistry, School of Pharmacy-International Campus, Iran University of Medical Sciences, Tehran, Iran
Homa Azizian
Department of Medicinal Chemistry, Faculty of Pharmacy and Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Tehran, Iran
Mohammad Nazari Montazer, Mehdi Asadi & Massoud Amanlou
Department of Pharmaceutical Chemistry, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran
Samanesadat Hosseini
Department of Medicinal Chemistry, School of Pharmacy, Ardabil University of Medical Sciences, Ardabil, Iran
Saghi Sepehri
Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran
Maryam Mohammadi-Khanaposhtani

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Elham Babazadeh Rezaei
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Fahimeh Abedinifar
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Homa Azizian
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Mohammad Nazari Montazer
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Mehdi Asadi
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Samanesadat Hosseini
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Saghi Sepehri
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Maryam Mohammadi-Khanaposhtani
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Mahmood Biglar
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Bagher Larijani
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Massoud Amanlou
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Mohammad Mahdavi
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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). https://doi.org/10.1007/s11696-021-01653-4

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Received: 09 September 2020
Accepted: 12 April 2021
Published: 20 April 2021
Issue Date: August 2021
DOI: https://doi.org/10.1007/s11696-021-01653-4

Keywords

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