Design, synthesis, antifungal activity, and ADME prediction of functional analogues of terbinafine

From the earlier quantitative structure–activity relationship (QSAR) and molecular modeling studies, a series of quinoline derivatives 5a–h mimicking terbinafine and containing different bulky aromatic rings in the side chain were designed using LeapFrog, a de novo drug design program. The designed compounds were synthesized and screened for antifungal activity in vitro against C. albicans. Of the ten compounds designed and synthesized, compounds 5c, d, f, h, and i exhibited minimum inhibitory concentration (MIC) in the range 4–25 μg/ml and were further evaluated for oral toxicity in animal model. The pharmacokinetic properties for these compounds were estimated in silico and compared with terbinafine. Compound 5h, N-methyl-N-[(2-naphthyl)methyl]-8-quinolinemethanamine, was found to be least toxic, possessing pharmacokinetic parameters close to those of terbinafine.     

全新药物设计方法与常用软件及其在抗癌药物设计中的应用

计算机辅助药物设计已普遍应用于药物研发过程,大大加快了药物开发的速度.特别是全新药物设计方法可以用于识别作用于特异性靶点的全新配体结构.全新药物设计常用软件有LUDI,LigBuilder,LeapFrog,SPROUT和SYNOPSIS等,常用方法有片段连接、片段生长、侧链替换和骨架跃迁等.全新药物设计方法在一些抗癌化合物,如纺锤体驱动蛋白抑制剂、血管内皮生长因子抑制剂、亲环蛋白A抑制剂和BRAF抑制剂等的发现方面,已经发挥了重要作用.综述全新药物设计方法与常用软件,并举例讨论其在新型抗癌药物领域中的应用.