3D-QSAR Study of 7,8-Dialkyl-1,3-diaminopyrrolo-3,2-f Quinazolines with Anticancer Activity as DHFR Inhibitors

A three-dimensional quantitative structure-activity relationship (3D-QSAR) study of a series of 7,8-dialkyl-1,3-diaminopyrrolo-3,2-f quinazolines with anticancer activity as dihydrofolate reductase (DHFR) inhibitors was carried out by using the comparative molecular field analysis (CoMFA), on the basis of our reported 2D-QSAR of these compounds. The established 3D-QSAR model has good quality of statistics and good prediction ability; the non cross-validation correlation coefficient and the cross-validation value of this model are 0.993 and 0.619, respectively, the F value is 193.4, and the standard deviation SD is 0.208.This model indicates that the steric field factor plays a much more important role than the electrostatic one, in satisfying agreement with the published 2D-QSAR model. However,the 3D-QSAR model offers visual images of the steric field and the electrostatic field. The 3D-QSAR study further suggests the following: to improve the activity, the substituent R’ should be selected to be a group with an adaptive bulk like Et or i-Pr, and the substituent R should be selected to be a larger alkyl. In particular, based on our present 3D-QSAR as well as the published 2D-QSAR, the experimentally-proposed hydrophobic binding mechanism on the receptor-binding site of the DHFR can be further explained in theory. Therefore, the QSAR studies help to further understand the “hydrophobic binding”action mechanism of this kind of compounds, and to direct the molecular design of new drugs with higher activity.