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 mu g/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.