Department of Pharmaceutical Chemistry, Centre of Excellence for Pharmaceutical Sciences, North-West University, Potchefstroom, South Africa.
SAMRC/NHLS/UCT Molecular Mycobacteriology Research Unit, Department of Pathology, University of Cape Town, Observatory, South Africa.
Arch Pharm (Weinheim). 2022 Oct;355(10):e2200172. doi: 10.1002/ardp.202200172. Epub 2022 Jun 8.
A recent study identified quinolone-based thiosemicarbazone with an MIC value of 2 µM against Mycobacterium tuberculosis (Mtb). Herein, we report further optimization of the previous hit, which led to the discovery of quinolone-tethered aminoguanidine molecules with generally good antitubercular activity. Compounds 7f and 8e emerged as the hits of the series with submicromolar antitubercular activity, exhibiting MIC values of 0.49/0.90 and 0.49/0.60 µM, respectively, in the 7H9 CAS GLU Tx medium. This shows a fivefold increase in antitubercular activity compared to the previous study. Target compounds were also screened against ESKAPE (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) pathogens. However, the series generally exhibited poor antibacterial activities, with only compounds 8d and 8e demonstrating >50% growth inhibition of Staphylococcus aureus and Pseudomonas aeruginosa at 32 µg/ml. The compounds displayed selective antitubercular activity as they showed no cytotoxicity effects against two noncancerous human cell lines. In silico studies predict 7f to have good solubility, no inhibitory effect on cytochrome P450 isoenzymes, and to be a non-pan-assay interfering compound.
最近的一项研究发现，一种对结核分枝杆菌（Mtb）具有 2μM 的 MIC 值的基于喹诺酮的硫代缩氨基脲。在此，我们报告了对先前的命中化合物的进一步优化，这导致了发现具有一般良好抗结核活性的喹诺酮连接的氨基胍分子。化合物 7f 和 8e 作为该系列的命中化合物出现，具有亚微摩尔抗结核活性，在 7H9 CAS GLU Tx 培养基中的 MIC 值分别为 0.49/0.90 和 0.49/0.60μM。这表明与之前的研究相比，抗结核活性增加了五倍。目标化合物也针对 ESKAPE（粪肠球菌、金黄色葡萄球菌、肺炎克雷伯菌、鲍曼不动杆菌、铜绿假单胞菌和肠杆菌属）病原体进行了筛选。然而，该系列通常表现出较差的抗菌活性，只有化合物 8d 和 8e 在 32μg/ml 时对金黄色葡萄球菌和铜绿假单胞菌的生长抑制率超过 50%。这些化合物表现出选择性的抗结核活性，因为它们对两种非癌细胞系没有细胞毒性作用。计算机研究预测 7f 具有良好的溶解度、对细胞色素 P450 同工酶没有抑制作用、并且是非全分析干扰化合物。
