3D QSAR Studies on Benzyl Phenyl Ether Diamidine Derivatives with Antiprotozoal Activities

Abstract

Human African trypanosomiasis (HAT) is a neglected tropical disease, and some drugs treating HAT have been used for even more than 60 years. Currently, a series of benzyl phenyl ether diamidine derivatives are discovered, which exhibit high antiprotozoal activities and low cytotoxicity, leading to good development prospects. The comparative molecular field analysis (CoMFA) and the comparative molecular similarity indices analysis (CoMSIA) are used to study the relationship between the structure and antiprotozoal activities. The established 3D QSAR model shows not only significant statistical quality, but also satisfies predictive ability: the best CoMFA model had r2 = 0.958 and q2 = 0.766, the best CoMSIA model had r2 = 0.957 and q2 = 0.812, the predictive ability of CoMFA and CoMSIA model were further confirmed by a test set which had 11 compounds, giving the correlation coefficient Qext2 of 0.792, 0.873, respectively. The contour maps and contribution maps show important features that can improve the antiprotozoal activity: position 3 from substituent R4 should be a low electronegativity group, position 4 from substituent R4 should have higher electronegativity, substituent R2 should be selected to a low electronegativity and small bulk group. Together these results may offer some useful theoretical information in designing potential inhibitors.