Laboratory of Microbiology, Parasitology and Hygiene (LMPH), S7, Faculty of Pharmaceutical, Biomedical and Veterinary Sciences, University of Antwerp, Universiteitsplein 1, B-2610 Wilrijk, Belgium.
Faculty of Technology, Tomas Bata University, Vavrečkova 275, CZ-760 01 Zlín, Czech Republic.
Eur J Med Chem. 2017 Sep 29;138:491-500. doi: 10.1016/j.ejmech.2017.06.061. Epub 2017 Jun 29.
In this study, a 50-membered library of substituted 4-hydroxyquinolin-2(1H)-ones and two closely related analogues was designed, scored in-silico for drug likeness and subsequently synthesized. Thirteen derivatives, all sharing a common 3-phenyl substituent showed minimal inhibitory concentrations against Mycobacterium tuberculosis H37Ra below 10 μM and against Mycobacterium bovis AN5A below 15 μM but were inactive against faster growing mycobacterial species. None of these selected derivatives showed significant acute toxicity against MRC-5 cells or early signs of genotoxicity in the Vitotox™ assay at the active concentration range. The structure activity study relation provided some insight in the further favourable substitution pattern at the 4-hydroxyquinolin-2(1H)-one scaffold and finally 6-fluoro-4-hydroxy-3-phenylquinolin-2(1H)-one (38) was selected as the most promising member of the library with a MIC of 3.2 μM and a CC against MRC-5 of 67.4 μM.
在这项研究中，设计了一个由 50 个取代的 4-羟基喹啉-2(1H)-酮和两个密切相关的类似物组成的库，通过计算机进行药物相似性评分，随后进行合成。13 种衍生物均具有共同的 3-苯基取代基，对结核分枝杆菌 H37Ra 的最小抑菌浓度（MIC）低于 10 μM，对牛分枝杆菌 AN5A 的 MIC 低于 15 μM，但对生长较快的分枝杆菌种无活性。在活性浓度范围内，这些选定的衍生物中没有一种对 MRC-5 细胞表现出显著的急性毒性，也没有在 Vitotox™测定中表现出遗传毒性的早期迹象。结构活性研究关系为在 4-羟基喹啉-2(1H)-酮支架上进一步有利的取代模式提供了一些见解，最终选择 6-氟-4-羟基-3-苯基喹啉-2(1H)-酮（38）作为该文库中最有前途的成员，其 MIC 为 3.2 μM，对 MRC-5 的 CC 为 67.4 μM。
