Alsayed Shahinda S R, Lun Shichun, Luna Giuseppe, Beh Chau Chun, Payne Alan D, Foster Neil, Bishai William R, Gunosewoyo Hendra
School of Pharmacy and Biomedical Sciences, Faculty of Health Sciences, Curtin University, Bentley, Perth, WA 6102, Australia. Email:
Center for Tuberculosis Research, Department of Medicine, Division of Infectious Disease, Johns Hopkins School of Medicine, 1550, Orleans Street, Baltimore, Maryland 21231-1044, USA. Email:
RSC Adv. 2020 Feb 23;10(13):7523-7540. doi: 10.1039/c9ra10663d. Epub 2020 Feb 19.
Our group has previously reported several indolecarboxamides exhibiting potent antitubercular activity. Herein, we rationally designed several arylcarboxamides based on our previously reported homology model and the recently published crystal structure of the mycobacterial membrane protein large 3 (MmpL3). Many analogues showed considerable anti-TB activity against drug-sensitive (DS) () strain. Naphthamide derivatives and were the most active compounds in our study (MIC: 6.55, 7.11 μM, respectively), showing comparable potency to the first line anti-tuberculosis (anti-TB) drug ethambutol (MIC: 4.89 μM). In addition to the naphthamide derivatives, we also identified the quinolone-2-carboxamides and 4-arylthiazole-2-carboxamides as potential MmpL3 inhibitors in which compounds and had MIC values of 9.97 and 9.82 μM, respectively. All four compounds retained their high activity against multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains. It is worth noting that the two most active compounds and also exhibited the highest selective activity towards DS, MDR and XDR strains over mammalian cells [IC (Vero cells) ≥ 227 μM], indicating their potential lack of cytotoxicity. The four compounds were docked into the MmpL3 active site and were studied for their drug-likeness using Lipinski's rule of five.
我们小组之前报道过几种具有强效抗结核活性的吲哚甲酰胺。在此，我们基于之前报道的同源模型和最近发表的分枝杆菌膜蛋白大3（MmpL3）晶体结构，合理设计了几种芳基甲酰胺。许多类似物对药物敏感（DS）（）菌株显示出相当大的抗结核活性。萘甲酰胺衍生物和是我们研究中活性最高的化合物（MIC分别为6.55、7.11 μM），其效力与一线抗结核药物乙胺丁醇（MIC为4.89 μM）相当。除了萘甲酰胺衍生物，我们还确定喹啉-2-甲酰胺和4-芳基噻唑-2-甲酰胺为潜在的MmpL3抑制剂，其中化合物和的MIC值分别为9.97和9.82 μM。所有这四种化合物对耐多药（MDR）和广泛耐药（XDR）（）菌株均保持高活性。值得注意的是，两种活性最高的化合物和对DS、MDR和XDR（）菌株相对于哺乳动物细胞也表现出最高的选择性活性[IC（Vero细胞）≥227 μM]，表明它们可能没有细胞毒性。这四种化合物被对接至MmpL3活性位点，并根据Lipinski的五规则研究了它们的类药性。
