Design, synthesis, biochemical evaluation and antimycobacterial action of phosphonate inhibitors of antigen 85C, a crucial enzyme involved in biosynthesis of the mycobacterial cell wall

S Gobec, I Plantan, J Mravljak, U Svajger, RA Wilson, Gurdyal Besra, S Soares, R Appelberg, D Kikelj

Research output: Contribution to journalArticle

38 Citations (Scopus)

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.
Original languageEnglish
Pages (from-to)54-63
Number of pages10
JournalEuropean Journal of Medicinal Chemistry
Volume42
Issue number1
DOIs
Publication statusPublished - 1 Jan 2007

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