Antimycobacterial agents. Novel diarylpyrrole derivatives of BM212 endowed with high activity toward mycobacterium tuberculosis and low cytotoxicity
Antimycobacterial agents. Novel diarylpyrrole derivatives of BM212 endowed with high activity toward mycobacterium tuberculosis and low cytotoxicity
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DOI：
10.1021/jm0602662
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发表时间：
2006-08-10
影响因子：
7.3
通讯作者：
Botta, Maurizio
中科院分区：
文献类型：
--
作者：
Biava, Mariangela;Cesare Porretta, Giulio;Botta, Maurizio
根据抗结核药物药效模型或我们先前描述的许多吡咯的构效关系分析，我们在这里设计和合成了1,5-（4-氯苯基）-2-甲基-3-（4-甲基哌嗪-1-基）甲基- 1h -吡咯（BM212）的新类似物。在吡咯核的第1位和第5位添加不同取代基，评价其对结核分枝杆菌（MTB）和非典型分枝杆菌活性的影响。生物学数据显示，虽然发现一些非结核分枝杆菌菌株对MTB敏感，但MIC值高于MTB。最佳化合物（1-（4-氟苯基）-2-甲基-3-（噻吩啉-4-基）-甲基-5-（4-甲基苯基）- 1h -吡咯，5）的MIC为0.4 μ g/mL（优于BM212和链霉素），保护指数为160，优于BM212、异烟肼和链霉素（分别为6、128和128）。最后，进行了分子模拟研究，以使新化合物的活性在抗结核化合物的药效模型上的叠加性和它们的疏水性方面合理化。
On the basis of suggestions derived either from a pharmacophoric model for antitubercular agents or from a structure-activity relationship analysis of many pyrroles previously described by us, we report here the design and synthesis of new analogues of 1,5-(4-chlorophenyl)-2-methyl-3-(4-methylpiperazin-1-yl)methyl-1H- pyrrole (BM212). Various substituents with different substitution patterns were added to both positions 1 and 5 of the pyrrole nucleus to evaluate their influence on the activity toward Mycobacterium tuberculosis (MTB) and atypical mycobacteria. Biological data showed that, although some nontuberculosis mycobacterial strains were found to be sensitive, MIC values were higher than those found toward MTB. The best compound (1-(4-fluorophenyl)-2-methyl-3-(thiomorpholin-4-yl)methyl-5-(4-methylphenyl)-1H-pyrrole, 5) possessed a MIC of 0.4 mu g/mL (better than BM212 and streptomycin) and a very high protection index (160), better than BM212, isoniazid, and streptomycin ( 6, 128, and 128, respectively). Finally, molecular modeling studies were performed to rationalize the activity of the new compounds in terms of both superposition onto a pharmacophoric model for antitubercular compounds and their hydrophobic character.