Department of Organic Chemistry, College of Pharmacy, Al-Azhar University , Cairo 11884, Egypt.
Department of Comparative Pathobiology, College of Veterinary Medicine, Purdue University , West Lafayette, Indiana 47907, United States.
J Med Chem. 2017 May 11;60(9):4074-4085. doi: 10.1021/acs.jmedchem.7b00392. Epub 2017 May 1.
Phenylthiazoles were reported previously as a new scaffold with antibacterial activity against an array of multidrug-resistant staphylococci. However, their promising antibacterial activity was hampered in large part by their short half-life due to excessive hepatic clearance. Close inspection of the structure-activity-relationships (SARs) of the phenylthiazoles revealed two important structural features necessary for antibacterial activity (a nitrogenous and a lipophilic component). Incorporating the nitrogenous part within a pyrimidine ring resulted in analogues with a prolonged half-life, while the biphenyl moiety revealed the most potent analogue 1b. In this study, advantageous moieties have been combined to generate a new hybrid scaffold of 5-pyrimidinylbiphenylthiazole with the objective of enhancing both anti-MRSA activity and drug-like properties. Among the 37 tested biphenylthiazoles, piperazinyl-containing derivatives 10, 30, and 36 were the most potent analogues with MIC values as low as 0.39 μg/mL. Additionally, 36 exhibited significant improvement in stability to hepatic metabolism.
苯并噻唑类化合物曾被报道具有抗多种耐药性葡萄球菌的抗菌活性，是一种新的结构骨架。然而，由于其在肝脏中的清除率过高，导致半衰期过短，从而在很大程度上限制了它们的应用。对苯并噻唑类化合物的结构-活性关系（SAR）进行仔细研究发现，其具有抗菌活性的两个重要结构特征（含氮部分和脂溶性部分）。将含氮部分纳入嘧啶环中可得到半衰期延长的类似物，而联苯部分则揭示了最有效的类似物 1b。在这项研究中，将有利的部分结合起来，生成了一种新的 5-嘧啶基联苯并噻唑的杂合骨架，旨在提高抗耐甲氧西林金黄色葡萄球菌（MRSA）活性和类药性。在所测试的 37 个联苯并噻唑中，含哌嗪基的衍生物 10、30 和 36 是最有效的类似物，其 MIC 值低至 0.39μg/mL。此外，36 对肝代谢的稳定性有显著提高。
