Novel coumarin-based acetohydrazide-1,2,3-triazole derivatives as urease enzyme inhibitors: Synthesis, in vitro evaluation, and molecular dynamics simulation studies
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, incl...
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Elsevier
2025-01-01
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| Series: | Heliyon |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2405844024173525 |
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| author | Hassan Sepehrmansourie Mohammad Azimi Ahmad Ebadi Gholamabbas Chehardoli Mohammad Ali Zolfigol Massoud Amanlou Mohammad Nazari Montazer Mohammad Mahdavi Zahra Najafi |
| author_facet | Hassan Sepehrmansourie Mohammad Azimi Ahmad Ebadi Gholamabbas Chehardoli Mohammad Ali Zolfigol Massoud Amanlou Mohammad Nazari Montazer Mohammad Mahdavi Zahra Najafi |
| author_sort | Hassan Sepehrmansourie |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-c7b6b860f0f1453d98f2777887149a8d |
| institution | Kabale University |
| issn | 2405-8440 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Heliyon |
| spelling | doaj-art-c7b6b860f0f1453d98f2777887149a8d2025-01-17T04:50:54ZengElsevierHeliyon2405-84402025-01-01111e41321Novel coumarin-based acetohydrazide-1,2,3-triazole derivatives as urease enzyme inhibitors: Synthesis, in vitro evaluation, and molecular dynamics simulation studiesHassan Sepehrmansourie0Mohammad Azimi1Ahmad Ebadi2Gholamabbas Chehardoli3Mohammad Ali Zolfigol4Massoud Amanlou5Mohammad Nazari Montazer6Mohammad Mahdavi7Zahra Najafi8Faculty of Converging Science and Technologies, University of Qom, Qom, IranDepartment of Medicinal Chemistry, School of Pharmacy, Hamadan University of Medical Sciences, Hamadan, IranDepartment of Medicinal Chemistry, School of Pharmacy, Hamadan University of Medical Sciences, Hamadan, Iran; Medicinal Plants and Natural Products Research Center, Institute of Cancer, Avicenna Health Research Institute, Hamadan University of Medical Sciences, Hamadan, IranDepartment of Medicinal Chemistry, School of Pharmacy, Hamadan University of Medical Sciences, Hamadan, Iran; Medicinal Plants and Natural Products Research Center, Institute of Cancer, Avicenna Health Research Institute, Hamadan University of Medical Sciences, Hamadan, IranDepartment of Organic Chemistry, Faculty of Chemistry and Petroleum Sciences, Bu-Ali Sina University, Hamedan, IranDepartment of Medicinal Chemistry, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, IranDepartment of Medicinal Chemistry, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, IranEndocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, IranDepartment of Medicinal Chemistry, School of Pharmacy, Hamadan University of Medical Sciences, Hamadan, Iran; Medicinal Plants and Natural Products Research Center, Institute of Cancer, Avicenna Health Research Institute, Hamadan University of Medical Sciences, Hamadan, Iran; Corresponding author. Department of Medicinal Chemistry, School of Pharmacy, Hamadan University of Medical Sciences, Hamadan, Iran.najafi.zch@gmail.comUrease 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.http://www.sciencedirect.com/science/article/pii/S2405844024173525CoumarinAcetohydrazide1,2,3-TriazoleUrease inhibitionMolecular dockingMolecular dynamics simulations |
| spellingShingle | Hassan Sepehrmansourie Mohammad Azimi Ahmad Ebadi Gholamabbas Chehardoli Mohammad Ali Zolfigol Massoud Amanlou Mohammad Nazari Montazer Mohammad Mahdavi Zahra Najafi Novel coumarin-based acetohydrazide-1,2,3-triazole derivatives as urease enzyme inhibitors: Synthesis, in vitro evaluation, and molecular dynamics simulation studies Heliyon Coumarin Acetohydrazide 1,2,3-Triazole Urease inhibition Molecular docking Molecular dynamics simulations |
| title | Novel coumarin-based acetohydrazide-1,2,3-triazole derivatives as urease enzyme inhibitors: Synthesis, in vitro evaluation, and molecular dynamics simulation studies |
| title_full | Novel coumarin-based acetohydrazide-1,2,3-triazole derivatives as urease enzyme inhibitors: Synthesis, in vitro evaluation, and molecular dynamics simulation studies |
| title_fullStr | Novel coumarin-based acetohydrazide-1,2,3-triazole derivatives as urease enzyme inhibitors: Synthesis, in vitro evaluation, and molecular dynamics simulation studies |
| title_full_unstemmed | Novel coumarin-based acetohydrazide-1,2,3-triazole derivatives as urease enzyme inhibitors: Synthesis, in vitro evaluation, and molecular dynamics simulation studies |
| title_short | Novel coumarin-based acetohydrazide-1,2,3-triazole derivatives as urease enzyme inhibitors: Synthesis, in vitro evaluation, and molecular dynamics simulation studies |
| title_sort | novel coumarin based acetohydrazide 1 2 3 triazole derivatives as urease enzyme inhibitors synthesis in vitro evaluation and molecular dynamics simulation studies |
| topic | Coumarin Acetohydrazide 1,2,3-Triazole Urease inhibition Molecular docking Molecular dynamics simulations |
| url | http://www.sciencedirect.com/science/article/pii/S2405844024173525 |
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