Three-dimensional (3D) quantitative structure–activity relationships (QSARs) of 36 apoptosis inducers, substituted 4-aryl/heteroaryl-4H-chromenes with anticancer activity against human breast cancer cell lines T47D, have been studied by using methods of comparative molecular field analysis (CoMFA) and comparative molecular similarity analysis (CoMSIA). The established 3D-QSAR models in training set show not only significant statistical quality, but also predictive ability, with high correlation coefficient (R2) values and cross-validation coefficient (q2) values: CoMFA (R2, q2: 0.944, 0.747), CoMSIA (R2, q2: 0.944, 0.704). Moreover, the predictive abilities of the CoMFA and CoMSIA models were further confirmed by a test set, giving the predictive correlation coefficients ([Formula: see text] values) of 0.845 and 0.851, respectively. Based on the CoMFA and CoMSIA contour map analyses, some key factors responsible for anticancer activity of this series of compounds have been found as follows: the steric interaction plays a decisive role in determining the anticancer activities of these compounds; bulky groups as substituent R 1 are not tolerated; in addition to a steric moderation, higher degree of electropositivity and hydrophobicity on the terminal alkyl of substituent R 2 might be favorable to the activity; the substituent R 3 should be hydrophobic; bulky and strong electron withdrawing groups for the substituent R 4 are not advantageous to the activity; simultaneously introducing large electronegative atoms as hydrogen-acceptors to the first atoms of the substituents R 5 and R 6 may increase the activity, but substituents R 5 and R 6 with a linking group – OCH 2 O – may decrease the activity. Such results can offer some useful theoretical references for understanding the action mechanism, designing more potent derivatives, and predicting their activities prior to synthesis.
