Department of Organic and Bioorganic Chemistry, Faculty of Pharmacy in Hradec Králové, Charles University, Akademika Heyrovského 1203, 500 05, Hradec Králové, Czech Republic.
Department of Biological and Medical Sciences, Faculty of Pharmacy in Hradec Králové, Charles University, Akademika Heyrovského 1203, 500 05, Hradec Králové, Czech Republic.
Eur J Med Chem. 2019 Nov 1;181:111578. doi: 10.1016/j.ejmech.2019.111578. Epub 2019 Aug 1.
The research of novel antimycobacterial drugs represents a cutting-edge topic. Thirty phenolic N-monosubstituted carbamates, derivatives of salicylanilides and 4-chlorophenol, were investigated against Mycobacterium tuberculosis HRa, HRv including multidrug- and extensively drug-resistant strains, Mycobacterium avium, Mycobacterium kansasii, Mycobacterium aurum and Mycobacterium smegmatis as representatives of nontuberculous mycobacteria (NTM) and for their cytotoxic and cytostatic properties in HepG2 cells. Since salicylanilides are multi-targeting compounds, we determined also inhibition of mycobacterial isocitrate lyase, an enzyme involved in the maintenance of persistent tuberculous infection. The minimum inhibitory concentrations were from ≤0.5 μM for both drug-susceptible and resistant M. tuberculosis and from ≤0.79 μM for NTM with no cross-resistance to established drugs. The presence of halogenated salicylanilide scaffold results into an improved activity. We have verified that isocitrate lyase is not a key target, presented carbamates showed only moderate inhibitory activity (up to 18% at a concentration of 10 μM). Most of the compounds showed no cytotoxicity for HepG2 cells and some of them were without cytostatic activity. Cytotoxicity-based selectivity indexes of several carbamates for M. tuberculosis, including resistant strains, were higher than 125, thus favouring some derivatives as promising features for future development.
新型抗分枝杆菌药物的研究代表了一个前沿课题。本文以结核分枝杆菌 HRa、HRv（包括耐多药和广泛耐药菌株）、鸟分枝杆菌、堪萨斯分枝杆菌、金黄分枝杆菌和耻垢分枝杆菌（非结核分枝杆菌的代表）为研究对象，对 30 种新型酚类 N-单取代氨基甲酸酯（水杨酰苯胺和 4-氯苯酚的衍生物）进行了抗分枝杆菌活性和细胞毒性评价。鉴于水杨酰苯胺类化合物具有多靶点特性，本文还测定了其对分枝杆菌异柠檬酸裂解酶（一种参与持续性结核感染的酶）的抑制作用。结果表明，这些化合物对药物敏感和耐药的结核分枝杆菌的最低抑菌浓度均≤0.5 μM，对非结核分枝杆菌的最低抑菌浓度均≤0.79 μM，与现有药物之间无交叉耐药性。含卤素的水杨酰苯胺骨架的存在可提高其活性。此外，本文还验证了异柠檬酸裂解酶不是关键靶标，所研究的氨基甲酸酯类化合物仅表现出中等抑制活性（在 10 μM 浓度下，最高抑制率为 18%）。大多数化合物对 HepG2 细胞无细胞毒性，其中一些化合物无细胞生长抑制活性。基于细胞毒性的几种氨基甲酸酯类化合物对结核分枝杆菌（包括耐药菌株）的选择性指数均高于 125，这表明它们具有一定的开发潜力。
