Phenylthiazoles with nitrogenous side chain: An approach to overcome molecular obesity
Phenylthiazoles with nitrogenous side chain: An approach to overcome molecular obesity
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DOI：
10.1016/j.ejmech.2019.111593
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发表时间：
2019-11-15
影响因子：
6.7
通讯作者：
Mayhoub, Abdelrahman S.
中科院分区：
文献类型：
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作者：
Elsebaei, Mohamed M.;Abutaleb, Nader S.;Mayhoub, Abdelrahman S.
制备了一系列在苯基 4 位带有环胺的新型苯基噻唑，其目的是降低亲脂性并改善化合物的整体理化性质和药代动力学特征。简而言之，当针对 16 种多重耐药临床分离株进行测试时，哌啶环（化合物 10 和 12）在抗菌活性方面提供了最佳环尺寸。这两种化合物在消除受感染巨噬细胞内的耐甲氧西林金黄色葡萄球菌 (MRSA) 和破坏成熟 MRSA 生物膜的能力方面均优于万古霉素。此外，化合物 10 和 12 在体外表现出快速杀菌作用。此外，新衍生物的水溶性比之前的先导化合物 1b 高 160 倍。因此，化合物 10 具有口服生物利用度，在体内具有高度可接受的药代动力学特征，半衰期为 4 小时，并达到了超过所有测试细菌分离株的最小抑制浓度 (MIC) 值的最大血浆浓度。 (C) 2019 Elsevier Masson SAS。版权所有。
A novel series of phenylthiazoles bearing cyclic amines at the phenyl-4 position was prepared with the objective of decreasing lipophilicity and improving the overall physicochemical properties and pharmacokinetic profile of the compounds. Briefly, the piperidine ring (compounds 10 and 12) provided the best ring size in terms of antibacterial activity when tested against 16 multidrug-resistant clinical isolates. Both compounds were superior to vancomycin in the ability to eliminate methicillin-resistant Staphylococcus aureus (MRSA), residing within infected macrophages and to disrupt mature MRSA biofilm. Additionally, compounds 10 and 12 exhibited a fast-bactericidal mode of action in vitro. Furthermore, the new derivatives were 160-times more soluble in water than the previous lead compound 1b. Consequently, compound 10 was orally bioavailable with a highly-acceptable pharmacokinetic profile in vivo that exhibited a half-life of 4 h and achieved a maximum plasma concentration that exceeded the minimum inhibitory concentration (MIC) values against all tested bacterial isolates. (C) 2019 Elsevier Masson SAS. All rights reserved.