Novel Coumarin-Based Acetohydrazide-1,2,3-Triazole Derivatives As Urease Enzyme Inhibitors: Synthesis, in Vitro Evaluation, and Molecular Dynamics Simulation Studies

Novel Coumarin-Based Acetohydrazide-1,2,3-Triazole Derivatives As Urease Enzyme Inhibitors: Synthesis, in Vitro Evaluation, and Molecular Dynamics Simulation Studies Publisher

Sepehrmansourie H¹ ; Azimi M² ; Ebadi A^{2, 3} ; Chehardoli G^{2, 3} ; Zolfigol MA⁴ ; Amanlou M⁵ ; Montazer MN⁵ ; Mahdavi M⁶ ; Najafi Z^{2, 3}

Show Affiliations

1. Faculty of Converging Science and Technologies, University of Qom, Qom, Iran
2. Department of Medicinal Chemistry, School of Pharmacy, Hamadan University of Medical Sciences, Hamadan, Iran
3. Medicinal Plants and Natural Products Research Center, Institute of Cancer, Avicenna Health Research Institute, Hamadan University of Medical Sciences, Hamadan, Iran
4. Department of Organic Chemistry, Faculty of Chemistry and Petroleum Sciences, Bu-Ali Sina University, Hamedan, Iran
5. Department of Medicinal Chemistry, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
6. Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran

Source: Heliyon Published:2025

Abstract

Urease enzyme inhibition is a well-established and promising strategy for preventing the harmful effects of ureolytic bacterial infections, particularly those caused by H. pylori. However, acetohydroxamic acid, the only approved urease inhibitor, has limited use due to significant side effects, including teratogenicity and psycho-neurological symptoms. To discover new inhibitors, novel coumarin-based acetohydrazide-1,2,3-triazole derivatives were synthesized and evaluated for their urease inhibitory activity. All tested compounds displayed remarkable anti-urease activity (IC50 = 1.62–16.91 μM) compared to thiourea as reference standard (IC50 = 23.11 ± 1.02 μM). The most potent derivative,(E)-N'-(4-((1-Benzyl-1H-1,2,3-triazol-4-yl)methoxy)benzylidene)-2-((4,7-dimethyl-2-oxo-2H-chromen-5-yl)oxy)acetohydrazide (13a), acted as an uncompetitive inhibitor with a Ki of 1.99 μM. The stable enzyme-inhibitor complex in molecular dynamics simulations (MD) indicated critical interactions between the ligand and the Cys592 and His593 residues, which stabilize the flap motif of the enzyme. Molecular dynamics simulations suggested that compound 13a tends to remain near the SER579-HIS593 α-helix rather than the nickel ions, stabilizing it in an open state. Thus, the MD studies confirmed the proposed mechanism of uncompetitive inhibition. Overall, these findings highlight the potential of coumarin-based acetohydrazide-1,2,3-triazole hybrids as potent and novel inhibitors for developing new therapeutics against urease-related diseases. © 2024 The Authors

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Style	Citing Format
MLA	Sepehrmansourie H, et al.. "Novel Coumarin-Based Acetohydrazide-1,2,3-Triazole Derivatives As Urease Enzyme Inhibitors: Synthesis, in Vitro Evaluation, and Molecular Dynamics Simulation Studies." Heliyon, vol. 11, no. 1, 2025, pp. -.
APA	Sepehrmansourie H, Azimi M, Ebadi A, Chehardoli G, Zolfigol MA, Amanlou M, Montazer MN, Mahdavi M, Najafi Z (2025). Novel Coumarin-Based Acetohydrazide-1,2,3-Triazole Derivatives As Urease Enzyme Inhibitors: Synthesis, in Vitro Evaluation, and Molecular Dynamics Simulation Studies. Heliyon, 11(1), -.
Chicago	Sepehrmansourie H, Azimi M, Ebadi A, Chehardoli G, Zolfigol MA, Amanlou M, Montazer MN, Mahdavi M, Najafi Z. "Novel Coumarin-Based Acetohydrazide-1,2,3-Triazole Derivatives As Urease Enzyme Inhibitors: Synthesis, in Vitro Evaluation, and Molecular Dynamics Simulation Studies." Heliyon 11, no. 1 (2025): -.
Harvard	Sepehrmansourie H et al. (2025) 'Novel Coumarin-Based Acetohydrazide-1,2,3-Triazole Derivatives As Urease Enzyme Inhibitors: Synthesis, in Vitro Evaluation, and Molecular Dynamics Simulation Studies', Heliyon, 11(1), pp. -.
Vancouver	Sepehrmansourie H, Azimi M, Ebadi A, Chehardoli G, Zolfigol MA, Amanlou M, et al.. Novel Coumarin-Based Acetohydrazide-1,2,3-Triazole Derivatives As Urease Enzyme Inhibitors: Synthesis, in Vitro Evaluation, and Molecular Dynamics Simulation Studies. Heliyon. 2025;11(1):-.
BibTex	@article{ author = {Sepehrmansourie H and Azimi M and Ebadi A and Chehardoli G and Zolfigol MA and Amanlou M and Montazer MN and Mahdavi M and Najafi Z}, title = {Novel Coumarin-Based Acetohydrazide-1,2,3-Triazole Derivatives As Urease Enzyme Inhibitors: Synthesis, in Vitro Evaluation, and Molecular Dynamics Simulation Studies}, journal = {Heliyon}, volume = {11}, number = {1}, pages = {-}, year = {2025} }
RIS	TY - JOUR AU - Sepehrmansourie H AU - Azimi M AU - Ebadi A AU - Chehardoli G AU - Zolfigol MA AU - Amanlou M AU - Montazer MN AU - Mahdavi M AU - Najafi Z TI - Novel Coumarin-Based Acetohydrazide-1,2,3-Triazole Derivatives As Urease Enzyme Inhibitors: Synthesis, in Vitro Evaluation, and Molecular Dynamics Simulation Studies JO - Heliyon VL - 11 IS - 1 SP - EP - PY - 2025 ER -

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