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QSAR studies on 3-(4-biphenylmethyl) 4, 5-dihydro-4-oxo-3H-imidazo [4, 5-c] Pyridine derivatives as angiotensin II (AT1) receptor antagonist

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Abstract

QSAR studies were performed for correlating the chemical composition of 3-(4-biphenylmethyl) 4, 5-dihydro-4-oxo-3H-imidazo [4, 5-c] pyridines bearing aryl acetic acid esters and acetamides as angiotensin II AT\(_{1}\) receptor antagonist. Four different quantitative structure–property relationship (QSAR) methods namely two-dimensional (2D-QSAR), group-based QSAR, k-nearest neighbor and Pharmacophore Modeling were employed to obtain statistically significant models. The statistically significant best 2D-QSAR model having correlation coefficient \(r^{2} = 0.8940\) and cross-validated squared correlation coefficient \(q^{2}=0.7648\) with external predictive ability of pred_\(r^{2}=0.8177\), pred_\(r^{2}\)se = 0.4119 and best group-based QSAR model having \(r^{2}=0.7392\) and \(q^{2}=0.6710\) with pred_\(r^{2}=0.7503\) was developed by SA–principal component regression. The most predictive k-nearest neighbor model derived from the superposition of conformations has good cross-validated \(q^{2}=0.7637\) and satisfied predictive ability \(r^{2}\)_pred = 0.7143. Continuing with compounds of substituted 4, 5-dihydro-4-oxo-3H-imidazo [4, 5-c] pyridine derivatives chemical feature-based pharmacophore models with lowest RMSD value (0.3292 Å) consists of two Hac (Hydrogen bond acceptor), negative ionizable, and two AroC (Aromatic) features are important for the activity. The study suggested that substitution of group at R, R 1, R 2 and Ar, and position on 4, 5-dihydro-4-oxo-3H-imidazo [4, 5-c] pyridine ring with more electronegative nature and low bulkiness are favorable for the antihypertensive activity. These theoretical results may provide a useful reference for understanding the action mechanism and designing potential angiotensin II (AT1) receptor antagonist.

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Acknowledgments

The authors are thankful to Vlife Science Technologies Pvt. Ltd. (Pune India) for providing the trial version software.

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  1. Drug Design and Development Laboratory, School of Pharmacy, Devi Ahilya University, Takshila Campus, Khandwa Road, Indore, 452001, MP, India

    Mukesh C. Sharma

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Correspondence to Mukesh C. Sharma.

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Sharma, M.C. QSAR studies on 3-(4-biphenylmethyl) 4, 5-dihydro-4-oxo-3H-imidazo [4, 5-c] Pyridine derivatives as angiotensin II (AT1) receptor antagonist. Interdiscip Sci Comput Life Sci 7, 113–128 (2015). https://doi.org/10.1007/s12539-015-0005-2

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  • DOI: https://doi.org/10.1007/s12539-015-0005-2

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