Krátký Martin, Konečná Klára, Brokešová Kateřina, Maixnerová Jana, Trejtnar František, Vinšová Jarmila
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 Pharm Sci. 2021 Apr 1;159:105732. doi: 10.1016/j.ejps.2021.105732. Epub 2021 Jan 22.
An increasing resistance of human pathogenic bacteria and fungi has become a global health problem. Based on previous reports of 4-(salicylideneamino)benzoic acids, we designed, synthesised and evaluated their me-too analogues as potential antimicrobial agents. Forty imines derived from substituted salicylaldehydes and aminobenzoic acids, 4-aminobenzoic acid esters and 4-amino-N-phenylbenzamide were designed using molecular hybridization and prodrug strategies. The target compounds were synthesized with high yields and characterized by spectral methods. They were investigated against a panel of Gram-positive and Gram-negative bacteria, mycobacteria, yeasts and moulds. The most active imines were tested to determine their cytotoxicity and selectivity in HepG2 cells. Dihalogenosalicylaldehydes-based derivatives showed potent broad-spectrum antimicrobial properties, particularly against Gram-positive bacteria including methicillin-resistant Staphylococcus aureus (minimum inhibitory concentrations, MIC, from 7.81 µM) and Enterococcus faecalis (MIC of ≥15.62 µM), yeasts (MIC from 7.81 µM) and Trichophyton interdigitale mould (MIC of ≥3.90 µM). Methyl 4-[(2-hydroxy-3,5-diiodobenzylidene)amino]benzoate 4h exhibited excellent in vitro activity along with low toxicity to mammalian cells. This compound is selective for staphylococci, Candida spp. and Trichophyton interdigitale. In addition, this imine was evaluated as a potential inhibitor of Gram-positive biofilms. The successful approach used provided some promising derivatives with more advantageous properties than the parent 4-(salicylideneamino)benzoic acids.
人类致病细菌和真菌的耐药性不断增强已成为一个全球性的健康问题。基于先前关于4-（水杨醛亚氨基）苯甲酸的报道，我们设计、合成并评估了它们的类药类似物作为潜在的抗菌剂。利用分子杂交和前药策略设计了40种由取代水杨醛与氨基苯甲酸、4-氨基苯甲酸酯和4-氨基-N-苯基苯甲酰胺衍生的亚胺。目标化合物以高产率合成并通过光谱方法进行表征。它们针对一组革兰氏阳性菌和革兰氏阴性菌、分枝杆菌、酵母和霉菌进行了研究。对活性最高的亚胺进行了测试，以确定它们在HepG2细胞中的细胞毒性和选择性。基于二卤代水杨醛的衍生物表现出强大的广谱抗菌特性，特别是对革兰氏阳性菌，包括耐甲氧西林金黄色葡萄球菌（最低抑菌浓度，MIC，7.81 μM起）和粪肠球菌（MIC≥15.62 μM）、酵母（MIC 7.81 μM起）和指间毛癣菌（MIC≥3.90 μM）。4-[(2-羟基-3,5-二碘苄叉基)氨基]苯甲酸甲酯4h表现出优异的体外活性以及对哺乳动物细胞的低毒性。该化合物对葡萄球菌、念珠菌属和指间毛癣菌具有选择性。此外，该亚胺被评估为革兰氏阳性生物膜的潜在抑制剂。所采用的成功方法提供了一些比母体4-（水杨醛亚氨基）苯甲酸具有更有利性质的有前景的衍生物。
