Several statistical expressions have been developed using stepwise multiple linear regression analysis (MLR) and partial least squares (PLS). The best MLR model showed good correlative and predictive ability as shown in following equation 84 has also been obtained. The developed model has been 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 has reported in present study provides important structural insights, related to anti-trypanosomal activity. Authors have developed a validated and highly predictive model sharing important structural requirement for effective binding of anti-trypanosomal compounds to minor groove of T. b. rhodesiense DNA. The model reported in the study should be helpful in development of new compounds with improved efficacy and oral bioavailability. In line to the developed model authors have also designed some molecules which showed good activity in silico. The further study of these compounds is in progress.