Design, synthesis, biochemical evaluation and antimycobacterial action of phosphonate inhibitors of antigen 85C, a crucial enzyme involved in biosynthesis of the mycobacterial cell wall
| Autor: | Urban Švajger, Rosalind A. Wilson, Danijel Kikelj, Stanislav Gobec, Sousana L. Soares, Gurdyal S. Besra, Rui Appelberg, Janez Mravljak, Ivan Plantan |
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| Přispěvatelé: | Instituto de Ciências Biomédicas Abel Salazar |
| Rok vydání: | 2007 |
| Předmět: |
medicine.drug_class
Stereochemistry Antitubercular Agents Organophosphonates Antimycobacterial Chemical synthesis Mycolic acid Phthalimide Structure-Activity Relationship chemistry.chemical_compound Health sciences Basic medicine Cell Wall Basic medicine [Medical and Health sciences] Drug Discovery medicine Antibacterial agent Pharmacology chemistry.chemical_classification Antigens Bacterial biology Organic Chemistry Medicina básica [Ciências médicas e da saúde] General Medicine Phosphonate Trehalose chemistry Biochemistry Enzyme inhibitor Drug Design biology.protein Ciências da Saúde Medicina básica Acyltransferases Mycobacterium avium |
| Zdroj: | Repositório Científico de Acesso Aberto de Portugal Repositório Científico de Acesso Aberto de Portugal (RCAAP) instacron:RCAAP |
| ISSN: | 0223-5234 |
| DOI: | 10.1016/j.ejmech.2006.08.007 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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