Department of Organic and Bioorganic Chemistry, Faculty of Pharmacy in Hradec Králové, Charles University, Akademika Heyrovského 1203, 500 05 Hradec Králové, Czechia.
Department of Biochemical Sciences, Faculty of Pharmacy in Hradec Králové, Charles University, Akademika Heyrovského 1203, 500 05 Hradec Králové, Czechia.
Eur J Pharm Sci. 2022 Sep 1;176:106252. doi: 10.1016/j.ejps.2022.106252. Epub 2022 Jul 3.
Novel antimycobacterial drugs are needed, especially those with dual activity against both actively growing and non-replicating subpopulations of mycobacteria. Isocitrate lyase (ICL) is one of proposed targets and this enzyme is inhibited by itaconic acid. That is why we have designed and prepared sixteen amides of itaconic acid and various anilines and amine antimicrobial drugs to evaluate them as potential inhibitors of ICL and antimycobacterial agents. N-Phenylitaconamides were prepared from itaconic anhydride and substituted anilines (yields 57-99%). They were characterized and evaluated against mycobacterial ICL and against actively growing mycobacteria (M. tuberculosis HRv, M. avium, two strains of M. kansasii). All derivatives showed antimycobacterial efficacy with minimum inhibitory concentrations starting from 125 µM. M. kansasii was the most susceptible species. Itaconamides derived from sulfonamides or p-aminosalicylic acid were optimal for activity against extracellular mycobacteria. ICL1 was significantly inhibited by two compounds, with 2-methylene-4-[(4-nitrophenyl)amino]-4-oxobutanoic acid 1k being the most potent (36% inhibition at 10 µM), which was also more efficient than two comparators. Molecular docking revealed its mode of binding to the enzyme. Using in silico tools, physicochemical properties and structural features for drug-likeness and gastrointestinal absorption were evaluated.
需要新型抗分枝杆菌药物，特别是那些对处于生长活跃状态和非复制亚群的分枝杆菌具有双重活性的药物。异柠檬酸裂解酶（ICL）是一个潜在的作用靶点，该酶可以被衣康酸抑制。因此，我们设计并制备了十六种衣康酸酰胺及其与各种苯胺和胺类抗菌药物的衍生物，以评估它们作为潜在的 ICL 抑制剂和抗分枝杆菌药物的潜力。N-芳基衣康酰胺由衣康酸酐和取代苯胺（产率 57-99%）制备。它们的结构得到了表征，并针对分枝杆菌 ICL 和处于生长活跃状态的分枝杆菌（结核分枝杆菌 HRv、鸟分枝杆菌、两种堪萨斯分枝杆菌）进行了评估。所有衍生物均显示出抗分枝杆菌的活性，最低抑菌浓度（MIC）从 125μM 开始。堪萨斯分枝杆菌是最敏感的物种。衍生自磺胺或对氨基水杨酸的衣康酰胺对细胞外分枝杆菌的活性最佳。两种化合物可显著抑制 ICL1，其中 2-亚甲基-4-[(4-硝基苯基)氨基]-4-氧代丁酸 1k 的抑制作用最强（在 10μM 时抑制率为 36%），其抑制效果也优于两种对照药物。分子对接揭示了它与酶的结合模式。使用计算机模拟工具，评估了其理化性质和结构特征，以确定其作为药物的可能性和在胃肠道中的吸收情况。
