Design, synthesis, pharmacological evaluation and <i>in silico</i> ADMET prediction of novel substituted benzimidazole derivatives as angiotensin II–AT<sub>1</sub> receptor antagonists based on predictive 3D QSAR models

<div><p>In this study we designed novel substituted benzimidazole derivatives and predicted their absorption, distribution, metabolism, excretion and toxicity (ADMET) properties, based on a predictive 3D QSAR study on 132 substituted benzimidazoles as AngII–AT<sub>1</sub> receptor antagonists. The two best predicted compounds were synthesized and evaluated for AngII–AT<sub>1</sub> receptor antagonism. Three different alignment tools for comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were used. The best 3D QSAR models were obtained using the rigid body (Distill) alignment method. CoMFA and CoMSIA models were found to be statistically significant with leave-one-out correlation coefficients (<i>q</i><sup><i>2</i></sup>) of 0.630 and 0.623, respectively, cross-validated coefficients (<i>r</i><sup><i>2</i></sup><sub><i>cv</i></sub>) of 0.651 and 0.630, respectively, and conventional coefficients of determination (<i>r</i><sup><i>2</i></sup>) of 0.848 and 0.843, respectively. 3D QSAR models were validated using a test set of 24 compounds, giving satisfactory predicted results (<i>r</i><sup><i>2</i></sup><sub><i>pred</i></sub>) of 0.727 and 0.689 for the CoMFA and CoMSIA models, respectively. We have identified some key features in substituted benzimidazole derivatives, such as lipophilicity and H-bonding at the 2- and 5-positions of the benzimidazole nucleus, respectively, for AT<sub>1</sub> receptor antagonistic activity. We designed 20 novel substituted benzimidazole derivatives and predicted their activity. <i>In silico</i> ADMET properties were also predicted for these designed molecules. Finally, the compounds with best predicted activity were synthesized and evaluated for <i>in vitro</i> angiotensin II–AT<sub>1</sub> receptor antagonism.</p></div>