title: Design, synthesis, biochemical evaluation and antimycobacterial action of phosphonate inhibitors of antigen 85C, a crucial enzyme involved in biosynthesis of the mycobacterial cell wall.
abstract: Phosphonate inhibitors of antigen 85C were prepared. The inhibitors, comprising a phosphonate moiety, mycolic acid mimetic and a trehalose surrogate, contain substituted benzyl alcohols, N-(omega-hydroxyalky)phthalimide, 2-phenylethanol or 4-(phthalimido)butanol as trehalose mimetics, and an alkyl chain of different lengths mimicking the mycolic acid side chain. The best compounds inhibited the mycolyltransferase activity of antigen 85C with IC(50) in the low micromolar range and inhibited the growth of Mycobacterium avium in culture. The best compounds in the 3-phenoxybenzyl- and omega-(phthalimido)alkoxy series, ethyl 3-phenoxybenzyl butylphosphonate (4a) and (1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl ethyl heptylphosphonate (5c) displayed IC(50) values of 2.0 and 1.3 microM, respectively, in a mycolyltransferase inhibition assay. In a M. avium growth inhibition assay MIC of 4a and (1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl ethyl nonylphosphonate (5d) were 248.8 and 84.5 microg/mL, respectively.
authors.affiliation: Faculty of Pharmacy, University of Ljubljana, Askerceva 7, 1000 Ljubljana, Slovenia.
authors.forename: Stanislav
authors.initials: S
authors.lastname: Gobec
authors.forename: Ivan
authors.initials: I
authors.lastname: Plantan
authors.forename: Janez
authors.initials: J
authors.lastname: Mravljak
authors.forename: Urban
authors.initials: U
authors.lastname: Svajger
authors.forename: Rosalind A
authors.initials: RA
authors.lastname: Wilson
authors.forename: Gurdyal S
authors.initials: GS
authors.lastname: Besra
authors.forename: Sousana L
authors.initials: SL
authors.lastname: Soares
authors.forename: Rui
authors.initials: R
authors.lastname: Appelberg
authors.forename: Danijel
authors.initials: D
authors.lastname: Kikelj
mesh_terms: D000217:Acyltransferases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D000942:Antigens, Bacterial / Q000737:chemistry; D000995:Antitubercular Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002473:Cell Wall / Q000378:metabolism; D015195:Drug Design; D009162:Mycobacterium avium / Q000187:drug effects / Q000378:metabolism; D063065:Organophosphonates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000942:Antigens, Bacterial; D000995:Antitubercular Agents; D063065:Organophosphonates; D000217:Acyltransferases; C119774:antigen 85C, Mycobacterium tuberculosis