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

Cited by 15 publications

(12 citation statements)

References 31 publications

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“…This result was observed in other studies in which the most potent compounds chelated the Ni 2+ ion at the active site. [ 5,28,29 ]…”

Section: Resultsmentioning

confidence: 99%

“…This result was observed in other studies in which the most potent compounds chelated the Ni 2+ ion at the active site. [5,28,29] The validity of the docking method was confirmed through the redocking of AHA over H. pylori urease. The root mean square deviation (RMSD) was performed for AHA due to evaluate the docking prediction accuracy.…”

Section: Molecular Docking Studymentioning

confidence: 93%

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Design, synthesis, and in silico studies of tetrahydropyrimidine analogs as urease enzyme inhibitors

Ahangarzadeh

Shakour

Rezvanpoor

et al. 2022

Archiv der Pharmazie

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The urease enzyme, a metalloenzyme having Ni 2+ ions, is recognized in some bacteria, fungi, and plants. Particularly, it is vital to the progress of infections induced by pathogenic microbes, such as Proteus mirabilis and Helicobacter pylori. Herein, we reported the synthesis of a series of tetrahydropyrimidine derivatives and evaluated their antiurease activity. Finally, quantitative and qualitative analyses of the derivatives were performed via in silico studies. Urease inhibitory activity was determined as the reaction of H. pylori urease with different concentrations of compounds, and thiourea was used as a standard compound. Docking and dynamics methodologies were applied to study the interactions of the best compounds with the amino acids in the active site. All compounds showed good to excellent antiurease activity. The potent compounds were not cytotoxic against the HUVEC normal cell line. Based on the docking study, compound 4e with the highest urease inhibitory activity (IC 50 = 6.81 ± 1.42 µM) showed chelates with both Ni 2+ ions of the urease active site. Further, compound 4f displayed a very good inhibitory activity (IC 50 = 8.45 ± 1.64 μM) in comparison to thiourea (IC 50 = 22.03 ± 1.24 μM). The molecular docking and dynamics simulation results were correlated with the in vitro assay results. Moreover, the derivatives 4a-n followed Lipinski's rule-of-five and had drug-likeness properties.

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“…This result was observed in other studies in which the most potent compounds chelated the Ni 2+ ion at the active site. [ 5,28,29 ]…”

Section: Resultsmentioning

confidence: 99%

Section: Molecular Docking Studymentioning

confidence: 93%

Design, synthesis, and in silico studies of tetrahydropyrimidine analogs as urease enzyme inhibitors

Ahangarzadeh

Shakour

Rezvanpoor

et al. 2022

Archiv der Pharmazie

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“…The nitrogen at 1 st position of 1,2,4‐triazole interacts with CME 592 and that at 2 nd position interacts with ARG 439 while the aromatic ring of triazole interacts with ALA 440 and HIS 492 amino acids at the active site ( PDB ID: 3LA4 ; Canavalia ensiformis ) [92] . There are limited reports for urease inhibition by 1,2,3‐triazoles, however, the reported data revealed that the 1,2,3‐triazole ring interacts with HIS 492 and HIS 519 amino acid residues ( PDB ID: 4H9M ; Canavalia ensiformis ) [101] (Figure 47). This review article will be useful to medicinal chemists in discovering target selective, optimized, and diverse hybrids for the inhibition of enzyme urease.…”

Section: Molecular Modelingmentioning

confidence: 99%

Urease Inhibition and Structure‐Activity Relationship Study of Thiazolidinone‐, Triazole‐, and Benzothiazole‐Based Heterocyclic Derivatives: A Focus Review

et al. 2023

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Urease has a long and distinguished history in the development of enzymology since it was the first enzyme crystallized by Sumner in 1926. The present review article is focused on the urease inhibitory potential of thiazolidinone, triazole, and benzothiazole‐based heterocyclic derivatives. The study begins with the historical developments in the discovery of urease and its substrate, urea, along with the active site architecture of ureases of different origins. The two pathways for the urease‐catalyzed hydrolysis of urea are explained in detail. The urease inhibitory potential of the aforementioned heterocyclic derivatives is reviewed and arranged systematically. Structure‐activity relationships (SARs) study provided the substituents necessary for urease inhibition and will be useful for the researchers working in the field of anti‐ulcer agents. To a step further, important binding interactions were identified with the amino acid residues at the active site of the enzyme. The information gathered is anticipated to offer logical direction and an effective method for creating innovative, potent, and efficient urease inhibitors that will have greater practical uses in the future.

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“…The observed results are nearby in agreement with the described literature on anti-urease activity. [27] According to the reported urease inhibitors, [16,27,28] current hybrids revealed a moderate to good activity.…”

Section: Evaluation Of Anti-urease Activitymentioning

confidence: 99%

“…[26,17,19,20,8] Furthermore, recently, our research group has reported 1,2,3,4-THPM derivatives A and metronidazole-1,2,3-triazole derivatives B with high inhibitory activity against urease (Figure 2). [27,28] Therefore, in our continuous effort to introduce new urease inhibitors, we attached benzyl 1,2,3-triazole moiety to 1,2,3,4-THPM derivatives to design 1,2,3-triazole-1,2,3,4-THPM hybrids 9a -g as a new urease inhibitor (Figure 2). Given this, we synthesized these hybrids with varying substituted and evaluated them for urease inhibitory activity in vitro.…”

Section: Introductionmentioning

confidence: 99%

Synthesis, Biological Activity Evaluation, Docking and Molecular Dynamics Studies of New Triazole‐Tetrahydropyrimidinone(thione) Hybrid Scaffolds as Urease Inhibitors

Rezvanpoor

Shakour

Ahangarzadeh

et al. 2023

Chemistry & Biodiversity

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New series of triazole-tetrahydropyrimidinone(thione) hybrids (9a -g) were synthesized. FT-IR, 1 H-NMR, 13 C-NMR, elemental analysis and mass spectroscopic studies characterized the structures of the synthesized compounds. Then, the synthesized compounds were screened to determine the urease inhibitory activity. Methyl 4-(4-((1-(2-chlorobenzyl)-1H-1,2,3-triazol-4-yl)methoxy)phenyl)-6-methyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5carboxylate (9c) exhibited the highest urease inhibitory activity (IC 50 = 25.02 μM) among the compounds which was almost similar to thiourea as standard (IC 50 = 22.32 μM). The docking study of the screened compounds demonstrated that these compounds fit well in the urease active site. Based on the docking study, compound 9c with the highest urease inhibitory activity showed chelates with both Ni 2 + ions of the urease active site. Moreover, the molecular dynamic study of the most potent compounds showed that they created important interactions with the active site flap residues, His322, Cys321, and Met317.

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

Cited by 15 publications

References 31 publications

Design, synthesis, and in silico studies of tetrahydropyrimidine analogs as urease enzyme inhibitors

Design, synthesis, and in silico studies of tetrahydropyrimidine analogs as urease enzyme inhibitors

Urease Inhibition and Structure‐Activity Relationship Study of Thiazolidinone‐, Triazole‐, and Benzothiazole‐Based Heterocyclic Derivatives: A Focus Review

Synthesis, Biological Activity Evaluation, Docking and Molecular Dynamics Studies of New Triazole‐Tetrahydropyrimidinone(thione) Hybrid Scaffolds as Urease Inhibitors

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