Department of Organic Chemistry, Kaunas University of Technology, Radvilėnų Rd. 19, LT-50254 Kaunas, Lithuania.
Weill Cornell Medicine of Cornell University, 527 East 68th Street, New York, NY 10065, USA.
Molecules. 2021 Dec 23;27(1):74. doi: 10.3390/molecules27010074.
Rapidly growing antimicrobial resistance among clinically important bacterial and fungal pathogens accounts for high morbidity and mortality worldwide. Therefore, it is critical to look for new small molecules targeting multidrug-resistant pathogens. Herein, in this paper we report a synthesis, ADME properties, and in vitro antimicrobial activity characterization of novel thiazole derivatives bearing β-amino acid, azole, and aromatic moieties. The in silico ADME characterization revealed that compounds - meet at least 2 Lipinski drug-like properties while cytotoxicity studies demonstrated low cytotoxicity to Vero cells. Further in vitro antimicrobial activity characterization showed the selective and potent bactericidal activity of - against Gram-positive pathogens (MIC 1-64 µg/mL) with profound activity against (MIC 1-2 µg/mL) harboring genetically defined resistance mechanisms. Furthermore, the compounds - exhibited antifungal activity against azole resistant while only and showed antifungal activity against multidrug resistant yeasts including . Collectively, these results demonstrate that thiazole derivatives - and could be further explored as a promising scaffold for future development of antifungal and antibacterial agents targeting highly resistant pathogenic microorganisms.
临床重要细菌和真菌病原体的抗菌药物耐药性迅速增长，导致全球发病率和死亡率居高不下。因此，寻找针对多药耐药病原体的新型小分子药物至关重要。在此，本文报道了一系列新型含β-氨基酸、唑和芳基部分的噻唑衍生物的合成、ADME 性质和体外抗菌活性特征。基于计算机的 ADME 特征表明，化合物 - 至少符合 2 项 Lipinski 类药性质，而细胞毒性研究表明它们对 Vero 细胞的毒性较低。进一步的体外抗菌活性特征表明，化合物 - 对革兰氏阳性病原体具有选择性和有效的杀菌活性（MIC1-64µg/mL），对具有遗传定义的耐药机制的 （MIC1-2µg/mL）具有显著活性。此外，化合物 - 对唑类耐药的 表现出抗真菌活性，而只有 和 对包括 在内的多药耐药酵母表现出抗真菌活性。总的来说，这些结果表明噻唑衍生物 - 和 可以进一步探索作为针对高度耐药的致病微生物的新型抗真菌和抗菌药物的有前途的支架。
