Pyrrolidine bis-cyclic guanidines with antimicrobial activity against drug-resistant Gram-positive pathogens identified from a mixture-based combinatorial library
Pyrrolidine bis-cyclic guanidines with antimicrobial activity against drug-resistant Gram-positive pathogens identified from a mixture-based combinatorial library
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DOI：
10.1016/j.bmcl.2006.07.037
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发表时间：
2006-10-01
影响因子：
2.7
通讯作者：
Nefzi, Adel
中科院分区：
文献类型：
--
作者：
Hensler, Mary E.;Bernstein, Gregory;Nefzi, Adel
耐药性革兰氏阳性细菌感染的迅速增加促使我们探索新的策略的发展，用于合成适合高通量筛选抗微生物活性的大型化学文库。在这里，我们报告了738，192个成员的吡咯烷双环胍化学库的固相合成，其中26个不同的氨基酸在三个位置的多样性和42个羧酸在第四个位置。该合成组合文库被开发用于位置扫描，并针对重要的人类病原体耐甲氧西林金黄色葡萄球菌（MRSA）筛选抑菌和杀菌活性。使用对MRSA具有杀菌活性（10 μ g/mL）的八种化合物混合物来指导36种单独化合物的合成，然后筛选这些化合物对MRSA、耐万古霉素粪肠球菌（VRE）和两种革兰氏阴性菌的活性。细菌物种。至少有20种化合物对MRSA具有杀菌作用，
The rapid rise in antibiotic-resistant Gram-positive bacterial infections prompted us to explore the development of novel strategies for synthesis of large chemical libraries amenable to high-throughput screening for antimicrobial activities. Here we report the solid-phase synthesis of a 738,192 member pyrrolidine bis-cyclic guanidine chemical library with 26 different amino acids at three positions of diversity and 42 carboxylic acids at the fourth position. This synthetic combinatorial library was developed for positional scanning and screened for bacteriostatic and bactericidal activities against the important human pathogen methicillin-resistant Staphylococcus aureus (MRSA). The eight compound mixtures exhibiting bactericidal activity (10 mu g/mL) against MRSA were used to direct the synthesis of 36 individual compounds that were then screened for activity against MRSA, vancomycin-resistant Enterococcus faecalis (VRE), and two Gram-negative bacterial species. At least 20 individual compounds were bactericidal for MRSA at