Combinatorial lead optimization of [1,2]-diamines based on ethambutol as potential antituberculosis preclinical candidates
Combinatorial lead optimization of [1,2]-diamines based on ethambutol as potential antituberculosis preclinical candidates
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DOI：
10.1021/cc020071p
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发表时间：
2003-03-01
影响因子：
--
通讯作者：
Barry, CE
中科院分区：
文献类型：
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作者：
Lee, RE;Protopopova, M;Barry, CE
尽管药效相对较弱，乙胺丁醇（EMB, (S，S)-[N，N-二-2-氨基-1-丁醇]乙二胺）仍是当代治疗结核病的主要化疗药物。我们开发了一种固相合成的1,2-二胺EMB类似物，使用一种新的酰化还原序列，与高通量96孔格式化学兼容。使用该方法，我们在10个适合测试的池中合成了63 238个二胺类似物。使用MIC和基于靶标的报告试验对这些混合物中的2796个化合物进行直接反卷积，并以毫克为单位重新合成69个最有效的分子以进行命中确认。对这些活性二胺类似物进行纯化，鉴定出活性等于或大于EMB的26种化合物。活性化合物中最常出现的胺包括许多具有大疏水基团的胺，这表明优化可能是对EMB的阿拉伯糖基转移酶靶点的类异戊二烯结合位点的选择。n -香叶基- n '-(2-adamantyl)乙烷-1,2-二胺（109）是这些二胺中最具活性的，与EMB相比，在体外对结核分枝杆菌的活性提高了14-35倍。
Despite relatively modest potency, ethambutol (EMB, (S,S)-[N,N-di-2-amino-1-butanol]ethylenediamine) is a mainstay of contemporary chemotherapy for the treatment of tuberculosis. We have developed a solid-phase synthesis of 1,2-diamine analogues of EMB using a novel acylation-reduction sequence that is compatible with high-throughput 96-well format chemistry. Using this procedure, we have synthesized 63 238 diamine analogues in pools of 10 that are suitable for testing. MIC and a target-based reporter assay were used to direct deconvolution of 2796 individual compounds from these mixtures, and the 69 most potent molecules were resynthesized in milligram quantities for hit confirmation. Purification of these individual active diamine analogues allowed the identification of 26 compounds with activity equal to or greater than EMB. Amines which occurred most frequently in active compounds included many with large hydrophobic moieties, suggesting that optimization was perhaps selecting for the isoprenoid binding site of the arabinosyltransferase target of EMB. N-Geranyl-N'-(2-adamantyl)ethane-1,2-diamine (109), the most active of these diamines, displayed a 14-35-fold improvement in activity in vitro against Mycobacterium tuberculosis, as compared to EMB.