title: Synthesis and antituberculosis activity of C-phosphonate analogues of decaprenolphosphoarabinose, a key intermediate in the biosynthesis of mycobacterial arabinogalactan and lipoarabinomannan.
abstract: The cell wall complex in mycobacteria, including the human pathogen Mycobacterium tuberculosis, is comprised in large part of two polysaccharides that contain a significant number of arabinofuranose residues. Both polysaccharides are assembled by a family of arabinosyltransferases that use decaprenolphosphoarabinose (3) as the donor species. In this paper, we describe the synthesis of a panel of C-phosphonate analogues of 3, which were designed to inhibit these arabinosyltransferases and thus block the biosynthesis of mycobacterial cell wall polysaccharides. A number of routes were explored for the preparation of the targets. The successful approach involved the synthesis of a protected C-phosphonate allyl ester 16, which was then coupled to an alkene via an olefin cross metathesis reaction. Subsequent reduction of the alkene with diimide and deprotection afforded the targets. Screening of these compounds in vitro against Mycobacterium tuberculosis revealed that one of the compounds, 15f, possessed antituberculosis activity, with an MIC value of 3.13 microg/mL.
authors.affiliation: Department of Chemistry, The Ohio State University, 100 West 18th Avenue, Columbus 43210, USA.
authors.forename: Charla A
authors.initials: CA
authors.lastname: Centrone
authors.forename: Todd L
authors.initials: TL
authors.lastname: Lowary
mesh_terms: D000995:Antitubercular Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D002240:Carbohydrate Sequence; D002384:Catalysis; D003500:Cyclization; D005685:Galactans / Q000378:metabolism; D008070:Lipopolysaccharides / Q000378:metabolism; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D009169:Mycobacterium tuberculosis / Q000378:metabolism*; D063065:Organophosphonates / Q000138:chemical synthesis* / Q000494:pharmacology*; D010430:Pentosyltransferases / Q000378:metabolism
chemical_list: D000995:Antitubercular Agents; D005685:Galactans; D008070:Lipopolysaccharides; D063065:Organophosphonates; C050016:lipoarabinomannan; D010430:Pentosyltransferases; C101967:arabinosyltransferase; C005653:arabinogalactan