Quantitative structure activity relationship analysis of dicationic diphenylisoxazole as potent anti-trypanosomal agents

摘要

The chemotherapy of African trypanosomiasis currently centers on only small numbers of drugs, most of which were discovered more than forty years ago and are plagued by various problems ranging from poor oral absorption, acute toxicities, short duration of action and uncertainty about the mechanism of action. In quest of possible ways to understand the structural requirement for anti-trypanosomal activity we found that QSAR analysis can be powerful tool for the design of new novel chemical entities with enhanced inhibitory potencies against Trypanosome brucei rhodesiense. In view of this QSAR analysis was performed using TSAR 3D version 3.3 software on series of 43 dicationic 3, 5-diphenylisoxazoles derivatives. More than 200 physicochemical and topological descriptors were calculated and examined. Out of these descriptors statistically significant descriptors were selected by applying data reduction. Several statistical expressions were developed using stepwise multiple linear regression analysis (MLR) and partial least squares (PLS). The best MLR model showed good correlative and predictive ability with r=0.94, r2=0.88 and r 2cv=0.84 and a comparable PLS model with r 2cv=0.84 was obtained. The developed model was further validated by leave-one-out method of cross-validation and prediction of test set. The study indicates that the anti-trypanosomal activity is largely explained by cosmic energy, log P and total lipole descriptors. The QSAR study reported in present study provides important structural insights, related to anti-trypanosomal activity.