Design, synthesis, biochemical evaluation and antimycobacterial action of phosphonate inhibitors of antigen 85C, a crucial enzyme involved in biosynthesis of the mycobacterial cell wall
Design, synthesis, biochemical evaluation and antimycobacterial action of phosphonate inhibitors of antigen 85C, a crucial enzyme involved in biosynthesis of the mycobacterial cell wall
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DOI：
10.1016/j.ejmech.2006.08.007
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发表时间：
2007-01-01
影响因子：
6.7
通讯作者：
Kikelj, Danijel
中科院分区：
文献类型：
--
作者：
Gobec, Stanislav;Plantan, Ivan;Kikelj, Danijel
制备了抗原85C的磷酸盐抑制剂。所述抑制剂包括膦酸段、模拟霉菌酸和海藻糖替代物，含有取代苯甲醇、N-（ω -羟基）邻苯酰亚胺、2-苯乙醇或4-（邻苯酰亚胺）丁醇作为模拟海藻糖，以及模拟霉菌酸侧链的不同长度的烷基链。最佳化合物对抗原85C真菌转移酶活性的抑制作用在低微摩尔范围内，抑制了鸟分枝杆菌的生长。3-phenoxybenzyl-和omega-（邻苯二胺）烷氧基系列中，3-phenoxybenzyl- butylphosphonate乙酯（4a）和（1,3-dioxo-1,3-dihydro- 2h -isoindol-2-yl） methyl ethyl heptylphosphonate （5c）的IC50值分别为2.0和1.3 μ M。在M. avium生长抑制实验中，4a和（1,3-二氧基-1,3-二氢- 2h -异吲哚-2-基）壬基膦酸甲酯（5d）的MIC分别为248.8和84.5 μ g/mL。(c) 2006 Elsevier Masson SAS。版权所有。
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 IC50 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 IC50 values of 2.0 and 1.3 mu M, 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 mu g/mL, respectively. (c) 2006 Elsevier Masson SAS. All rights reserved.