Krátký Martin, Bősze Szilvia, Baranyai Zsuzsa, Szabó Ildikó, Stolaříková Jiřina, Paraskevopoulos Georgios, Vinšová Jarmila
Department of Inorganic and Organic Chemistry, Faculty of Pharmacy, Charles University, Heyrovského 1203, 500 05 Hradec Králové, Czech Republic.
MTA-ELTE Research Group of Peptide Chemistry, Eötvös Loránd University, Pázmány Péter Sétány 1/A, Budapest, H-1117, P.O. Box 32, 1518 Budapest 112, Hungary.
Bioorg Med Chem. 2015 Feb 15;23(4):868-75. doi: 10.1016/j.bmc.2014.12.019. Epub 2014 Dec 19.
Based on the previously described antimicrobial activity of salicylanilide derivatives, we designed and synthesized novel 2-(phenylcarbamoyl)phenyl 4-substituted benzoates. The most active salicylanilides were selected for esterification by various 4-substituted benzoic acids. These compounds were evaluated in vitro against Mycobacterium tuberculosis, including multidrug-resistant strains, nontuberculous mycobacteria (Mycobacterium avium and Mycobacterium kansasii), and eight bacterial and fungal strains. We also investigated the cytostatic and cytotoxic actions of the esters. The minimum inhibitory concentrations (MICs) against mycobacteria ranged from 0.125 to 8μM. Interestingly, the drug-resistant strains exhibited the highest susceptibility without any cross-resistance with established drugs. 4-Bromo-2-[4-(trifluoromethyl)phenylcarbamoyl]phenyl 4-nitrobenzoate showed the most potent inhibition with MIC values ranging from 0.25 to 2μM. Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus, were inhibited by two derivatives with MIC values of at least 0.49μM, whereas Gram-negative bacteria and most of the tested fungi did not display any marked susceptibility. Benzoates exhibited no cytotoxicity at concentrations up to 50μM but most caused significant cytostasis with IC50 values lower than 10μM. Some cytotoxicity-based selectivity indexes for drug-susceptible and drug-resistant M. tuberculosis as well as Staphylococci were higher than 100. These values indicate that some of these derivatives are promising candidates for future research.
基于之前所描述的水杨酰苯胺衍生物的抗菌活性，我们设计并合成了新型的2-(苯基氨基甲酰基)苯基4-取代苯甲酸酯。选择活性最强的水杨酰苯胺与各种4-取代苯甲酸进行酯化反应。对这些化合物进行了体外抗结核分枝杆菌评估，包括耐多药菌株、非结核分枝杆菌（鸟分枝杆菌和堪萨斯分枝杆菌）以及8种细菌和真菌菌株。我们还研究了这些酯的细胞抑制和细胞毒性作用。对分枝杆菌的最低抑菌浓度（MIC）范围为0.125至8μM。有趣的是，耐药菌株表现出最高的敏感性，且与现有药物无交叉耐药性。4-溴-2-[4-(三氟甲基)苯基氨基甲酰基]苯基4-硝基苯甲酸酯显示出最有效的抑制作用，MIC值范围为0.25至2μM。包括耐甲氧西林金黄色葡萄球菌在内的革兰氏阳性菌被两种衍生物抑制，MIC值至少为0.49μM，而革兰氏阴性菌和大多数测试真菌未表现出明显的敏感性。苯甲酸酯在浓度高达50μM时无细胞毒性，但大多数会引起显著的细胞抑制，IC50值低于10μM。一些针对药物敏感和耐药结核分枝杆菌以及葡萄球菌的基于细胞毒性的选择性指数高于100。这些值表明其中一些衍生物是未来研究的有希望的候选物。
