Krátký Martin, Stolaříková Jiřina, Vinšová Jarmila
Department of Organic and Bioorganic Chemistry, Faculty of Pharmacy in Hradec Králové, Charles University, Heyrovského 1203, 50005 Hradec Králové, Czech Republic.
Laboratory for Mycobacterial Diagnostics and Tuberculosis, Regional Institute of Public Health in Ostrava, Partyzánské námĕstí 7, 70200 Ostrava, Czech Republic.
Molecules. 2017 Mar 28;22(4):535. doi: 10.3390/molecules22040535.
Infections caused by () and nontuberculous mycobacteria (NTM) are considered to be a global health problem; current therapeutic options are limited. Sulfonamides have exhibited a wide range of biological activities including those against mycobacteria. Based on the activity of 4-(3-heptylureido)--(5-methylisoxazol-3-yl)benzenesulfonamide against NTM, we designed a series of homologous sulfamethoxazole-based -alkyl ureas (C₁-C), as well as several related ureas and an oxalamide. Fifteen ureas and one oxalamide were synthesized by five synthetic procedures and characterized. They were screened for their activity against and three NTM strains (, ). All of them share antimycobacterial properties with minimum inhibitory concentration (MIC) values starting from 2 µM. The highest activity showed 4,4'-[carbonylbis(azanediyl)]bis[-(5-methylisoxazol-3-yl)benzenesulfonamide] with MIC of 2-62.5 µM (i.e., 1.07-33.28 µg/mL). Among -alkyl ureas, methyl group is optimal for the inhibition of both and NTM. Generally, longer alkyls led to increased MIC values, heptyl being an exception for NTM. Some of the novel derivatives are superior to parent sulfamethoxazole. Several urea and oxalamide derivatives are promising antimycobacterial agents with low micromolar MIC values.
由（）和非结核分枝杆菌（NTM）引起的感染被认为是一个全球健康问题；目前的治疗选择有限。磺胺类药物已表现出广泛的生物活性，包括对分枝杆菌的活性。基于4-（3-庚基脲基）-（5-甲基异恶唑-3-基）苯磺酰胺对NTM的活性，我们设计了一系列基于磺胺甲恶唑的同系物 - 烷基脲（C₁ - C），以及几种相关的脲和一种草酰胺。通过五种合成方法合成并表征了十五种脲和一种草酰胺。筛选了它们对（）和三种NTM菌株（，）的活性。它们都具有抗分枝杆菌特性，最低抑菌浓度（MIC）值从2μM开始。活性最高的是4,4'-[羰基双（氮杂二亚基）]双[ - （5-甲基异恶唑-3-基）苯磺酰胺]，MIC为2 - 62.5μM（即1.07 - 33.28μg/mL）。在 - 烷基脲中，甲基对于抑制（）和NTM都是最佳的。一般来说，较长的烷基会导致MIC值增加，庚基对NTM来说是个例外。一些新型衍生物优于母体磺胺甲恶唑。几种脲和草酰胺衍生物是有前景的抗分枝杆菌药物，MIC值在低微摩尔范围内。
