title: Designing analogs of ticlopidine, a wall teichoic acid inhibitor, to avoid formation of its oxidative metabolites.
abstract: The thienopyridine antiplatelet agent, ticlopidine and its analog, clopidogrel, have been shown to potentiate the action of β-lactam antibiotics, reversing the methicillin-resistance phenotype of methicillin-resistant Staphylococcus aureus (MRSA), in vitro. Interestingly, these thienopyridines inhibit the action of TarO, the first enzyme in the synthesis of wall teichoic acid, an important cell wall polymer in Gram-positive bacteria. In the human body, both ticlopidine and clopidogrel undergo a rapid P450-dependent oxidation into their respective antiplatelet-active metabolites, resulting in very low plasma concentrations of intact drug. Herein, a series of analogs of ticlopidine and clopidogrel that would avoid oxidative metabolism were designed, prepared and evaluated as inhibitors of TarO. Specifically, we replaced the P450-labile thiophene ring of ticlopidine and clopidogrel to a more stable phenyl group to generate 2-(2-chlorobenzyl)-1,2,3,4-tetrahydro-isoquinoline) (6) and (2-chloro-phenyl)-(3,4-dihydro-1H-isoquinolin-2-yl)-acetic acid methyl ester (22), respectively. The latter molecules displayed inhibitory activity against TarO and formed the basis of a library of analogs. Most synthesized compounds exhibited comparable efficacy to ticlopidine and clopidogrel. So far, it was introduction of a trifluoromethyl group to compound 6, to generate 2-(2-trifluoromethyl-benzyl)-1,2,3,4-tetrahydro-isoquinoline (13) that exhibited enhanced activity against TarO. Compound 13 represents a novel stable inhibitor of TarO with synergistic impact on β-lactam antibiotics against MRSA and low potential for P-450 metabolism.
authors.affiliation: M.G. DeGroote Institute for Infectious Disease Research and Department of Biochemistry and Biomedical Sciences, McMaster University, 1200 Main St. W., Hamilton, Ontario L8N 3Z5, Canada.
authors.forename: Maya A
authors.initials: MA
authors.lastname: Farha
authors.affiliation: M.G. DeGroote Institute for Infectious Disease Research and Department of Biochemistry and Biomedical Sciences, McMaster University, 1200 Main St. W., Hamilton, Ontario L8N 3Z5, Canada.
authors.forename: Kalinka
authors.initials: K
authors.lastname: Koteva
authors.affiliation: M.G. DeGroote Institute for Infectious Disease Research and Department of Biochemistry and Biomedical Sciences, McMaster University, 1200 Main St. W., Hamilton, Ontario L8N 3Z5, Canada.
authors.forename: Robert T
authors.initials: RT
authors.lastname: Gale
authors.affiliation: M.G. DeGroote Institute for Infectious Disease Research and Department of Biochemistry and Biomedical Sciences, McMaster University, 1200 Main St. W., Hamilton, Ontario L8N 3Z5, Canada.
authors.forename: Edward W
authors.initials: EW
authors.lastname: Sewell
authors.affiliation: M.G. DeGroote Institute for Infectious Disease Research and Department of Biochemistry and Biomedical Sciences, McMaster University, 1200 Main St. W., Hamilton, Ontario L8N 3Z5, Canada. Electronic address: wrightge@mcmaster.ca.
authors.forename: Gerard D
authors.initials: GD
authors.lastname: Wright
authors.affiliation: M.G. DeGroote Institute for Infectious Disease Research and Department of Biochemistry and Biomedical Sciences, McMaster University, 1200 Main St. W., Hamilton, Ontario L8N 3Z5, Canada. Electronic address: ebrown@mcmaster.ca.
authors.forename: Eric D
authors.initials: ED
authors.lastname: Brown
mesh_terms: D000077144:Clopidogrel; D015195:Drug Design; D020128:Inhibitory Concentration 50; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects; D015394:Molecular Structure; D010084:Oxidation-Reduction / Q000187:drug effects; D013682:Teichoic Acids / Q000037:antagonists & inhibitors* / Q000737:chemistry; D013988:Ticlopidine / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D013682:Teichoic Acids; D000077144:Clopidogrel; D013988:Ticlopidine
keywords: Clopidogrel; MRSA; Structure–activity relationship; Ticlopidine; Wall teichoic acids