A comprehensive structure-activity analysis 2?3,5-trisubstited 4,5-dihydro-4-oxo-3H-imidazo [4,5-c] pyridine derivatives as angiotensin II receptor antagonists: using 2D- and 3D-QSAR approach

摘要

The QSAR studies were performed on a series of 2,3,5-trisubstituted 4,5-dihydro-4-oxo-3#-imidazo [4,5-c] pyridine derivatives as angiotensin II AT_1 receptor antagonists activity to find out the structural features requirements for the antihypertensive activity. The QSAR study was carried out on V-life Molecular Design Suite software and the derived best QSAR model by partial least square principal component regression and multiple linear regression method showed variation in biological activity. The statistically best significant model with high-correlation coefficient (r~2 = 0.9425) was selected for further study and the resulted validation parameters of the model, cross-validated correlation coefficient (q2 = 0.7786 and pred_r~2 = 0.8562) show the model has good predictive activities. The model showed that the parameters SdssCcount, SssNHcount, and SaaaCcount and H_Donor count are highly correlated with angiotensin II AT] receptor antagonists activity of 2,3,5-trisubstituted 4,5-dihy-dro-4-oxo-3H-imidazo [4,5-c] pyridine derivatives. Partial least square (PLS) methodology coupled with various feature selection methods viz. stepwise, simulated annealing and genetic algorithm were applied to derive 3D-QSAR models which were further validated for statistical significance and predictive ability by internal and external validation. Molecular field analysis was used to construct the best 3D-QSAR model-7 using kappa-nearest neighbor (ANN) method, showing good correlative and predictive capabilities in terms of q~2 = 0.8316 and pred_r~2 = 0.8152. Both 2D-and 3D-QSAR study of such derivatives provide guidance for further lead optimization and designing of potent anti-hypertensive agents.