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Diamide-based sulfonamide derivatives as new urease inhibitors: Synthesis, biological evaluation, and computational studies.

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Τίτλος: Diamide-based sulfonamide derivatives as new urease inhibitors: Synthesis, biological evaluation, and computational studies.
Συγγραφείς: Mohammadi Oshnari A; Chemistry and Chemical Engineering Research Center of Iran (CCERCI), P.O. Box 14335-186, Tehran, Iran., Mohammadi AA; Chemistry and Chemical Engineering Research Center of Iran (CCERCI), P.O. Box 14335-186, Tehran, Iran. Electronic address: aliamohammadi@yahoo.com., Ahmad I; Division of Computer-Aided Drug Design, Department of Pharmaceutical Chemistry, R. C. Patel Institute of Pharmaceutical Education and Research, Shirpur, Maharashtra, India; Department of Pharmaceutical Chemistry, Prof. Ravindra Nikam College of Pharmacy, Gondur, Dhule, 424002, Maharashtra, India., Ekhtiari Z; Department of Medicinal Chemistry, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran., Tahmasebi E; Department of Medicinal Chemistry, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran., Mohammadi-Khanaposhtani M; Pharmaceutical Sciences Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran., Amanlou M; Department of Medicinal Chemistry, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran., Mahdavi M; Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran.
Πηγή: Bioorganic chemistry [Bioorg Chem] 2026 Sep 15; Vol. 180, pp. 110240. Date of Electronic Publication: 2026 Jul 10.
Τύπος έκδοσης: Journal Article
Γλώσσα: English
Στοιχεία περιοδικού: Publisher: Elsevier Country of Publication: United States NLM ID: 1303703 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1090-2120 (Electronic) Linking ISSN: 00452068 NLM ISO Abbreviation: Bioorg Chem Subsets: MEDLINE
Imprint Name(s): Publication: Amsterdam : Elsevier
Original Publication: New York, London, Academic Press.
Ιατρικοί όροι (MeSH): Urease*/antagonists & inhibitors , Urease*/metabolism , Sulfonamides*/chemistry , Sulfonamides*/pharmacology , Sulfonamides*/chemical synthesis , Enzyme Inhibitors*/chemical synthesis , Enzyme Inhibitors*/pharmacology , Enzyme Inhibitors*/chemistry, Structure-Activity Relationship ; Molecular Docking Simulation ; Molecular Structure ; Molecular Dynamics Simulation ; Dose-Response Relationship, Drug
Περίληψη: Sulfonamide is a well-recognized bioactive functional group in medicinal chemistry that has gained significant attention owing to its broad application potential in this field. In this work, a new series of diamide-based sulfonamide derivatives, compounds 10a-g and 11a-e, was specifically designed as urease inhibitors and synthesized via the reaction of azlactone derivatives with 4-aminobenzenesulfonamide. The structures of the synthesized compounds were confirmed using 1H and 13C NMR spectroscopy, FT-IR spectroscopy, CHN elemental analysis, and LC-MS. Interestingly, all synthesized derivatives displayed outstanding urease inhibitory activity, with IC50 values in the low micromolar range (IC50 values ≤0.71 μM), demonstrating potency far superior to that of the reference inhibitor thiourea (IC50 value = 21.34 μM). To elucidate the binding mechanism, molecular docking and molecular dynamics (MD) simulations were performed on the most potent compound (10a), which further confirmed stable and favorable interactions with the enzyme's active site, particularly with the catalytic nickel center and key residues. Additionally, in silico pharmacokinetic profiling predicted promising drug-like characteristics for the most active compound. Density functional theory (DFT) calculations provided insights into the electronic structures and reactivity descriptors of these compounds. The combined experimental and computational data firmly establish this novel sulfonamide series as a highly potent and promising class for the development of anti-urease agents in future.
(Copyright © 2026. Published by Elsevier Inc.)
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Contributed Indexing: Keywords: Alum; Azlactone; Diamide; Sulfonamide; Urease
Substance Nomenclature: EC 3.5.1.5 (Urease)
0 (Sulfonamides)
0 (Enzyme Inhibitors)
Entry Date(s): Date Created: 20260714 Date Completed: 20260725 Latest Revision: 20260725
Update Code: 20260725
DOI: 10.1016/j.bioorg.2026.110240
PMID: 42447748
Βάση Δεδομένων: MEDLINE
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  Data: Diamide-based sulfonamide derivatives as new urease inhibitors: Synthesis, biological evaluation, and computational studies.
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  Data: <searchLink fieldCode="AU" term="%22Mohammadi+Oshnari+A%22">Mohammadi Oshnari A</searchLink>; Chemistry and Chemical Engineering Research Center of Iran (CCERCI), P.O. Box 14335-186, Tehran, Iran.<br /><searchLink fieldCode="AU" term="%22Mohammadi+AA%22">Mohammadi AA</searchLink>; Chemistry and Chemical Engineering Research Center of Iran (CCERCI), P.O. Box 14335-186, Tehran, Iran. Electronic address: aliamohammadi@yahoo.com.<br /><searchLink fieldCode="AU" term="%22Ahmad+I%22">Ahmad I</searchLink>; Division of Computer-Aided Drug Design, Department of Pharmaceutical Chemistry, R. C. Patel Institute of Pharmaceutical Education and Research, Shirpur, Maharashtra, India; Department of Pharmaceutical Chemistry, Prof. Ravindra Nikam College of Pharmacy, Gondur, Dhule, 424002, Maharashtra, India.<br /><searchLink fieldCode="AU" term="%22Ekhtiari+Z%22">Ekhtiari Z</searchLink>; Department of Medicinal Chemistry, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.<br /><searchLink fieldCode="AU" term="%22Tahmasebi+E%22">Tahmasebi E</searchLink>; Department of Medicinal Chemistry, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.<br /><searchLink fieldCode="AU" term="%22Mohammadi-Khanaposhtani+M%22">Mohammadi-Khanaposhtani M</searchLink>; Pharmaceutical Sciences Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran.<br /><searchLink fieldCode="AU" term="%22Amanlou+M%22">Amanlou M</searchLink>; Department of Medicinal Chemistry, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.<br /><searchLink fieldCode="AU" term="%22Mahdavi+M%22">Mahdavi M</searchLink>; Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran.
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  Data: <searchLink fieldCode="JN" term="%221303703%22">Bioorganic chemistry</searchLink> [Bioorg Chem] 2026 Sep 15; Vol. 180, pp. 110240. <i>Date of Electronic Publication: </i>2026 Jul 10.
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  Data: Sulfonamide is a well-recognized bioactive functional group in medicinal chemistry that has gained significant attention owing to its broad application potential in this field. In this work, a new series of diamide-based sulfonamide derivatives, compounds 10a-g and 11a-e, was specifically designed as urease inhibitors and synthesized via the reaction of azlactone derivatives with 4-aminobenzenesulfonamide. The structures of the synthesized compounds were confirmed using <superscript>1</superscript>H and <superscript>13</superscript>C NMR spectroscopy, FT-IR spectroscopy, CHN elemental analysis, and LC-MS. Interestingly, all synthesized derivatives displayed outstanding urease inhibitory activity, with IC<subscript>50</subscript> values in the low micromolar range (IC<subscript>50</subscript> values ≤0.71 μM), demonstrating potency far superior to that of the reference inhibitor thiourea (IC<subscript>50</subscript> value = 21.34 μM). To elucidate the binding mechanism, molecular docking and molecular dynamics (MD) simulations were performed on the most potent compound (10a), which further confirmed stable and favorable interactions with the enzyme's active site, particularly with the catalytic nickel center and key residues. Additionally, in silico pharmacokinetic profiling predicted promising drug-like characteristics for the most active compound. Density functional theory (DFT) calculations provided insights into the electronic structures and reactivity descriptors of these compounds. The combined experimental and computational data firmly establish this novel sulfonamide series as a highly potent and promising class for the development of anti-urease agents in future.<br /> (Copyright © 2026. Published by Elsevier Inc.)
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  Data: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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  Data: EC 3.5.1.5 (Urease)<br />0 (Sulfonamides)<br />0 (Enzyme Inhibitors)
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