3D-QSAR analysis on benzazole derivatives as eukaryotic topoisomerase II inhibitors by using comparative molecular field analysis method

摘要

Selective topoisomerase Ⅱ inhibitors have created a great deal of interest in recent years for the design of new antitumoral compounds. 3D-QSAR analysis has been performed on a series of previously synthesized benzoxazole, benzimidazole, and oxazol-o(4,5-b)pyridine derivatives, which are screened as eukaryotic topoisomerase Ⅱ inhibitors, using comparative molecular field analysis (CoMFA) with partial least squares fit to predict the steric and electrostatic molecular field interactions for the activity. The CoMFA study was carried out using a training set of 16 compounds. The predictive ability of the model was assessed using a test set of 7 compounds. The analyzed 3D-QSAR CoMFA model has demonstrated a good fit, having r~2 value of 0.997 and cross-validated coefficient q~2 value as 0.435 for the model. The obtained model reveals that the electronegatively charged substituents such as NO_2 or COOCH_3 group on position R and/or R_1 at the heterocyclic ring system and positively charged atom and/or atom groups located between the benzazole moiety and 2-substituted phenyl ring as a bridge element improve the activity. On the other hand, a bulky substituent, such as methoxy group, attached to the ortho position of 2-phenyl-5-nitro-benzoxazole (1) enhances the activity similar to compound 13, which is both a meta and para substituent of the phenyl group attached to the 2-position of benzimidazole ring system, fit into the favored steric region to improve the activity.