Structural insights for substituted acyl sulfonamides and acyl sulfamides derivatives of imidazole as angiotensin II receptor antagonists using molecular modeling approach

•Molecular modeling studies were performed imidazole derivatives.•Acidic tetrazole ring plays an important role for biological activity.•Models derived from PLS analysis were validated by external test validation methods.•The steric field with negative values indicating that less steric substituent's are preferred for enhancing the activity.•Pharmacophore model show aliphatic, aromatic, hydrogen bond acceptor, negative ionizable features.

Molecular modeling studies were carried out on a series of substituted acyl sulfonamides and acyl sulfamides derivatives of imidazole as angiotensin II AT1 receptor antagonists in order to determine the structural properties required for their antihypertensive activity. To elucidate the structural properties required for antihypertensive activity, four different molecular modeling techniques; two-dimensional (2D-QSAR), Group-Based QSAR (G-QSAR), 3D-QSAR and pharmacophore identification studies have been carried out on a series of substituted acyl sulfonamides and acyl sulfamides derivatives of imidazole. The partial least square (PLS) regression method and kNN-MFA methodology coupled with feature selection methods viz., stepwise (SW) and simulated annealing (SA) were applied to derive QSAR models which were further validated for statistical significance and predictive ability by internal and external validation. The statistically significant best 2D-QSAR model having r2 = 0.8711 and q2 = 0.8054 with pred_r2 = 0.8410 was developed by SW-PLS and best G-QSAR model having r2 = 0.8196 and q2 = 0.7299 with pred_r2 = 0.7693 was developed by SW-PLS method. The best 3D-QSAR model using SA-kNN-MFA method, showing good correlative and predictive capabilities in terms of q2 = 0.7862 and pred_r2 = 0.7119. The contour maps generated by the kNN models were used to identify the key structural requirements responsible for the biological activity. Continuing with substituted acyl sulfonamides and acyl sulfamides derivatives of imidazole, chemical feature based pharmacophore model with lowest RMSD value (0.0436 Å), consists of one AroC feature (aromatic), two AlaC features (aliphatic), one HAc (hydrogen bond acceptor), and one negative ionizable was developed. It could rationalize the antihypertensive activity profile of many compounds used in such study as well as the important structural features responsible for antihypertensive activity. The findings of these molecular modeling studies can serve as a useful guide for future rational design of potential agents with better antihypertensive activity.