The synthesis and SAR study of phenylalanine-derived (Z)-5-arylmethylidene rhodanines as anti-methicillin-resistant Staphylococcus aureus (MRSA) compounds
The synthesis and SAR study of phenylalanine-derived (Z)-5-arylmethylidene rhodanines as anti-methicillin-resistant Staphylococcus aureus (MRSA) compounds
复制标题
DOI：
10.1016/j.bmcl.2013.08.059
复制
发表时间：
2013-10-15
影响因子：
2.7
通讯作者：
Talele, Tanaji T.
中科院分区：
文献类型：
--
作者：
Patel, Bhargav A.;Ashby, Charles R., Jr.;Talele, Tanaji T.
合成了一个在 C5 位含有新型取代基的罗丹宁化合物集中文库，并针对一组临床相关的 MRSA 菌株进行了体外测试。目前的 SAR 研究基于我们的先导化合物 1 (MIC = 1.95 mu g/mL)，重点是确定最佳的 C5-亚芳基取代基。为了实现这一目标，我们将几种独特的芳香醛与苯丙氨酸衍生的绕丹宁中间体缩合，以获得C5取代的目标绕丹宁化合物，用于评估抗MRSA化合物。这些努力产生了三种具有显着疗效的化合物：23、32和44，与参考抗生素青霉素G（MIC=15.60-250.0μg/mL）和环丙沙星（MIC=7.80-62.50μg/mL）相比，对所有测试的MRSA菌株的MIC值范围为0.98至1.95μg/mL，并且与万古霉素相当（MIC = 0.48 微克/毫升）。此外，化合物24、28、37、41、46和48（MIC=1.95-3.90μg/mL）对所有MRSA菌株均有效。大多数合成的化合物在浓度仅比其 MIC 高两到四倍时就具有杀菌活性。总体而言，结果表明化合物23、32和44可能具有治疗MRSA感染的潜在用途。 (C) 2013 Elsevier Ltd. 保留所有权利。
A focused library of rhodanine compounds containing novel substituents at the C5-position was synthesized and tested in vitro against a panel of clinically relevant MRSA strains. The present SAR study was based on our lead compound 1 (MIC = 1.95 mu g/mL), with a focus on identifying optimal C5-arylidene substituents. In order to obtain this objective, we condensed several unique aromatic aldehydes with phenylalanine-derived rhodanine intermediates to obtain C5-substituted target rhodanine compounds for evaluation as anti-MRSA compounds. These efforts produced three compounds with significant efficacy: 23, 32 and 44, with MIC values ranging from 0.98 to 1.95 mu g/mL against all tested MRSA strains as compared to the reference antibiotics penicillin G (MIC = 15.60-250.0 mu g/mL) and ciprofloxacin (MIC = 7.80-62.50 mu g/mL) and comparable to that of vancomycin (MIC = 0.48 mu g/mL). In addition, compounds 24, 28, 37, 41, 46 and 48 (MIC = 1.95-3.90 mu g/mL) were efficacious against all MRSA strains. The majority of the synthesized compounds had bactericidal activity at concentrations only two to fourfold higher than their MIC. Overall, the results suggest that compounds 23, 32 and 44 may be of potential use in the treatment of MRSA infections. (C) 2013 Elsevier Ltd. All rights reserved.