Molecular modelling studies on 2-amino 6-aryl-sulphonylbenzonitriles as non-nucleoside reverse transcriptase inhibitors of HIV-1: A QSPR approach

Lipophilicity or hydrophobicity is a crucial physico-chemical property of an oral drug compound. In the present study, we have analysed the structural parameters responsible for enhancing the lipophilicity expressed in terms of Octanol–Water partition coefficient, log P, of 2-amino-6-arylsulfonylbenzonitrile (AASBN) derivatives used as NNRTIs in AIDS therapy. Connectivity based Randic (χ) and Balaban (J) and atomistic Kier–Hall electrotopological state (E-state) indices have been used to develop Quantitative Structure–Property Relationship (QSPR) and to predict the effect of substitution on the log P. Model has been developed using multiple linear regression analysis (MLR) for the training set (67 compounds) and the model was tested on a test set (7 compounds). Significant results were obtained for the training set (R 2 = 0⋅948, R^2 adj = 0⋅939, SE = 0⋅177, F-ratio = 101⋅22). The results of the test set too implicated a good fit (R^2 = 0⋅941, R^2 adj = 0⋅929, SE = 0⋅157, F-ratio = 80⋅05). Among the two connectivity based topological indices; Randic (χ) index showed better predictive ability than the Balaban (J) index. Kier–Hall E-state indices indicated that among the functional groups, methyl, bromo, chloro groups on ring A, with their positive coefficients enhanced the lipophilicity. Amino, cyano group on ring B and the bridging S, SO, SO2 with their negative coefficients showed an adverse effect on the lipophilicity parameter. Thus, Kier–Hall E-state indices along with topological indices could be well applied for deriving QSPR models and analysing substitution effects of various functional groups. The training set, correlation matrix and observed and experimental log P values are available as supplementary material for this article.