title: Novel organophosphorus scaffolds of urease inhibitors obtained by substitution of Morita-Baylis-Hillman adducts with phosphorus nucleophiles.
abstract: The reactivity of Morita-Baylis-Hillman allyl acetates was employed to introduce phosphorus-containing functionalities to the side chain of the cinnamic acid conjugated system by nucleophilic displacement. The proximity of two acidic groups, the carboxylate and phosphonate/phosphinate groups, was necessary to form interactions in the active site of urease by recently described inhibitor frameworks. Several organophosphorus scaffolds were obtained and screened for inhibition of the bacterial urease, an enzyme that is essential for survival of urinary and gastrointestinal tract pathogens. α-Substituted phosphonomethyl- and 2-phosphonoethyl-cinnamate appeared to be the most potent and were further optimized. As a result, one of the most potent organophosphorus inhibitors of urease, α-phosphonomethyl-p-methylcinnamic acid, was identified, with Ki= 0.6 μM for Sporosarcina pasteurii urease. High complementarity to the enzyme active site was achieved with this structure, as any further modifications significantly decreased its affinity. Finally, this work describes the challenges faced in developing ligands for urease.
authors.affiliation: Laboratory of Organic Chemistry, Department of Chemistry, University of Athens, Panepistimiopolis, Zografou, 15701 Athens, Greece.
authors.forename: Vassilis
authors.initials: V
authors.lastname: Ntatsopoulos
authors.affiliation: Laboratory of Organic Chemistry, Department of Chemistry, University of Athens, Panepistimiopolis, Zografou, 15701 Athens, Greece. Electronic address: svassiliou@chem.uoa.gr.
authors.forename: Stamatia
authors.initials: S
authors.lastname: Vassiliou
authors.affiliation: Department of Bioorganic Chemistry, Faculty of Chemistry, Wrocław University of Technology, Wybrzeże Wyspiańskiego 27, 50-370 Wrocław, Poland.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Macegoniuk
authors.affiliation: Department of Bioorganic Chemistry, Faculty of Chemistry, Wrocław University of Technology, Wybrzeże Wyspiańskiego 27, 50-370 Wrocław, Poland.
authors.forename: Łukasz
authors.initials: Ł
authors.lastname: Berlicki
authors.affiliation: Department of Bioorganic Chemistry, Faculty of Chemistry, Wrocław University of Technology, Wybrzeże Wyspiańskiego 27, 50-370 Wrocław, Poland. Electronic address: artur.mucha@pwr.edu.pl.
authors.forename: Artur
authors.initials: A
authors.lastname: Mucha
mesh_terms: D000085:Acetates / Q000737:chemistry / Q000494:pharmacology; D000498:Allyl Compounds / Q000737:chemistry / Q000494:pharmacology; D020134:Catalytic Domain / Q000187:drug effects; D002934:Cinnamates / Q000737:chemistry / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D062105:Molecular Docking Simulation; D063065:Organophosphonates / Q000737:chemistry* / Q000494:pharmacology*; D058644:Sporosarcina / Q000187:drug effects / Q000201:enzymology*; D014510:Urease / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000085:Acetates; D000498:Allyl Compounds; D002934:Cinnamates; D004791:Enzyme Inhibitors; D063065:Organophosphonates; C029010:cinnamic acid; C498551:allyl acetate; D014510:Urease
keywords: Binding mode; Enzyme inhibitors; Phosphonic and phosphinic acids; Structure-activity relationship; Substitution of allyl acetates