Comparative quantitative structure-activity study of radical scavengers

Classic and three-dimensional (3-D) QSAR analyses of 13 radical scavengers (1-13) were performed to derive two classic, two Apex-3-D and one comparati ve field analysis (CoMFA) models. Two classical models with predictive cros s-validated r(2) (Q(2)) over 0.96 indicated that the activity was attribute d to the electronic C-OH and E-LUMO, steric molar refractivity (MR) and lip ophilic log P. Three-dimensional quantitative structure-activity relationsh ip (3-D-QSAR) studies were performed by 3-D pharmacophore generation (Apex- 3-D) and CoMFA techniques. For Apex-3-D studies, two best models with high Q(2) (0.94 and 0.97) were yielded. Structural properties contributing to th e activity were not only lipophilic but also the optimum steric property an d geometry of side-chain composition. For CoMFA studies, the sp(3) C( + 1) probe provided the best Q(2) of 0.79 with steric and electrostatic contribu tions of 42.3 acid 57.7%, respectively. The activity of four new compounds (14-17) not included in the derivation were predicted with these models. Al though the derived models were from limited data, the statistic relation wa s predictive. The linear correlations between the experimental IC50 values and the predicted values from classical and Apex-3-D models were found to b e high and significant. The predicted activity of 17 from CoMFA was much lo wer than the experimental value; this deviation occurred according to the m issing of hydrophobic field in standard CoMFA study. In vitro and ex vivo a ntilipid peroxidation in mouse brain and ESR studies of 14-17 were investig ated for the radical-scavenging ability. The difference between the in vitr o results, antilipid peroxidation and electron spin resonance (ESR) and ex vivo results in coumarin series was found. Thus, other properties for good bioavailability besides log P should also be taken into consideration. (C) 2000 Elsevier Science Ltd. All rights reserved.