Τίτλος:
Structural exploration of cinnamate-based phosphonic acids as inhibitors of bacterial ureases
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
The conjugated system of cinnamic acid, α-substituted with a phosphonoalkyl residue, was previously validated as a scaffold that provided one of the most potent organophosphorus inhibitors of bacterial urease. Following the idea of using Morita-Baylis-Hillman adducts to introduce the terminal phosphonic side chain functionality to the α,β-unsaturated system, we currently report the synthesis and activity of an extended series of compounds. Cinnamates modified with 3-phosphonopropyl and 4-phosphonobutyl side chains were obtained in a convenient two-step procedure, which involved Pd-mediated transformations of the Morita-Baylis-Hillman bromides as the key substrates. The introduction of a terminal alkenyl fragment, which was achieved by Stille coupling with stannanes, was followed by a tandem C-P bond formation/oxidation process. A submicromolar ligand of Sporosarcina pasteurii urease (Ki = 0.509 μM) was identified among the active molecules. In addition, inhibitors of Proteus mirabilis urease affected bacterial growth at the micromolar level. Based on the structure-activity relationship and the mechanism of inhibition, we suggest a nontypical mixed mode of action for the slow binding compounds. We presume that the molecular distance between the phosphonic group and the backbone double bond allows a dual activity: complexation of the acidic group with nickel ions and Michael addition of a cysteine forming the active site lid. © 2018 Elsevier Masson SAS
Συγγραφείς:
Ntatsopoulos, V.
Macegoniuk, K.
Mucha, A.
Vassiliou, S.
Berlicki, Ł.
Περιοδικό:
European Journal of Medicinal Chemistry
Εκδότης:
Elsevier Masson s.r.l.
Λέξεις-κλειδιά:
3 (4 chlorophenyl) 2 (3 phosphonopropyl)propenoic acid; 3 (4 chlorophenyl) 2 (4 phosphonobutyl)propenoic acid; 3 (4 fluorophenyl) 2 (3 phosphonopropyl)propenoic acid; 3 (4 fluorophenyl) 2 (4 phosphonobutyl)propenoic acid; 3 (4 methoxyphenyl) 2 (3 phosphonopropyl)propenoic acid; 3 (4 methoxyphenyl) 2 (4 phosphonobutyl)propenoic acid; 3 (4 methylphenyl) 2 (3 phosphonopropyl)propenoic acid; 3 (4 methylphenyl) 2 (4 phosphonobutyl)propenoic acid; 3 phenyl 2 (3 phosphonopropyl)propenoic acid; 3 phenyl 2 (4 phosphonobutyl)propenoic acid; antibiotic agent; cinnamic acid derivative; cysteine; methyl 3 (4 chlorophenyl) 2 (3 phosphonopropyl)propenoate; methyl 3 (4 chlorophenyl) 2 (4 phosphonobutyl)propenoate; methyl 3 (4 fluorophenyl) 2 (3 phosphonopropyl)propenoate; methyl 3 (4 fluorophenyl) 2 (4 phosphonobutyl)propenoate; methyl 3 (4 methoxyphenyl) 2 (3 phosphonopropyl)propenoate; methyl 3 (4 methoxyphenyl) 2 (4 phosphonobutyl)propenoate; methyl 3 (4 methylphenyl) 2 (3 phosphonopropyl)propenoate; methyl 3 (4 methylphenyl) 2 (4 phosphonobutyl)propenoate; methyl 3 phenyl 2 (3 phosphonopropyl)propenoate; methyl 3 phenyl 2 (4 phosphonobutyl)propenoate; phosphonic acid derivative; unclassified drug; urease; urease inhibitor; cinnamic acid derivative; enzyme inhibitor; phosphorous acid, antibacterial activity; Article; bacterial growth; chemical bond; complex formation; drug synthesis; enzyme active site; Michael addition; nonhuman; oxidation; Proteus mirabilis; Sporosarcina pasteurii; Stille reaction; structure activity relation; antagonists and inhibitors; chemical structure; chemistry; dose response; drug effect; enzymology; growth, development and aging; metabolism; microbial sensitivity test; Sporosarcina; structure activity relation; synthesis, Cinnamates; Dose-Response Relationship, Drug; Enzyme Inhibitors; Microbial Sensitivity Tests; Molecular Structure; Phosphorous Acids; Proteus mirabilis; Sporosarcina; Structure-Activity Relationship; Urease
DOI:
10.1016/j.ejmech.2018.09.074
