Structure–activity relationship analysis of cationic 2-phenylbenzofurans as potent anti-trypanosomal agents: a multivariate statistical approach

Abstract

As part of an effort to establish a structure–activity relationship of diamidines against African trypanosomes, a quantitative correlation between molecular structure and anti-trypanosomal activity of 2-phenylbenzofuran derivatives was attained using classical quantitative structure–activity relationship (QSAR) descriptors and 3D similarity indices. A good model was obtained on the basis of classical descriptors; however, the model derived using descriptors based on similarity indices neither complemented the classical descriptors nor were significantly predictive. The best QSAR model with chemical descriptors that showed good correlative and predictive ability with r = 0.91, r 2 = 0.82, and r cv 2 = 0.80 was developed using stepwise multiple linear regression analysis (MLR) and a comparable partial least squares analysis (PLS) model with r cv 2 = 0.79 was also obtained. The QSAR models revealed that a substituent steric descriptor (Verloop B 1 parameter) and geometrical (moment of inertia 3 length) and hydrophobic (log P) descriptors of the whole molecule have significant impact on anti-trypanosomal activity of the compounds. The best QSAR models were validated by the leave one out technique. To further confirm the predictive power of the models, an external set of molecules was used which was not part of the training set. The high agreement betwPLS as shown in Eqeen experimental and predicted inhibitory values, obtained in the validation procedure, indicates the good quality of the derived QSAR models. In addition to QSAR analysis Lipinski’s rule was also applied to the series under consideration and newly designed molecules in order to check the drugability of the compounds; no violation of this rule was found. Hence 2-phenylbenzofuran has tremendous potential to yield orally active anti-trypanosomal agents.