Molecular modeling and quantitative structure-activity studies of anti-HIV-1 2-heteroarylquinoline-4-amines

Three-dimensional quantitative structure-activity relationships (QSAR), based upon comparative molecular field analysis (CoMFA) and multiple linear regression (MLR) with geometric and quantum chemical descriptors, have been established for a novel class of non-nucleoside HIV-1 inhibitors. The training set consisted of 30 aryl (or heteroaryl) quinoline-4-amines. For the CoMFA model a ‘leave-one-out’ procedure yielded a cross-validated test r 2 = 0.602 consistent with the uncertainty of biological data. The MLR model was obtained using two newly derived descriptors with a conventional correlation coefficient r = 0.916. These descriptors were calculated using the results of molecular modeling and a quantum chemical AMI study. One of the descriptors represents the shape contribution of the amino substituent and the other represents the electrostatic contribution of the aryl or heteroaryl substituent. Together with the MLR model and our previous quantum chemical study, the CoMFA plots provide reasonable guidelines to delineate a pharmacophore for this series of anti-HIV agents.