QSAR Study of 2–Phenyl – and 2,3 - Diphenyl Quinoline – 4- Carboxylic Acid Derivatives as Biologically Active Compounds

Abstract

Quinoline derivatives are very important in synthetic medicinal chemistry because of their wide biological range in natural products and drugs; this importance led to consider the activity of newly designed and synthesized quinoline-4-carboxylic acid derivatives as human dihydroorotate dehydrogenase (DHODH) enzyme inhibitors. In this work set of data used to study quantitative structure activity relationship (QSAR) of quinoline-4-carboxylic acids derivatives were obtained from previous published article containing biological activity of quinoline derivatives having similar skeleton. Thus the models obtained can be used to predict the activity of newly designed derivatives against vesicular stomatitis virus (VSV) replication as dihydroorotate dehydrogenase (DHODH) enzyme inhibitor. A highly descriptive and predictive QSAR model was obtained through calculation of alignment-independent descriptors using MOE2009.10 software. The 25 quinoline derivatives of data set divided into training set and test set. A training set composed of 20 compounds and obtained by partial least squares (PLS) analysis resulted in a model displaying a squared correlation coefficient r2 of 0.913. Validation of this model was performed using leave-one-out method (LOO) giving q2 of 0.842 and r2pre of 0.873, for a test set of 5 compounds. This model was used to predict the biological activity of 180 new designed quinoline-4-carboxylic acid derivatives and brequinar as a reference. The 87 compounds showed higher predicted activity than that for brequinar. Lipinski's rule of five (RO5) was applied to select compounds from the 86 new designed derivatives for synthesis and elevated pharmacokinetic for them. Therefore 16 compounds were selected for synthesis possessing higher predicted activity and agreeing with rule of five. New quinolines were synthesized from three-component of different types of arylaldehyde, p-amino-acetophenone and phenyl pyruvic acid using Doebner- iv Miller reaction. Quinoline-4-carboxylic acids were reacted by Claisen-Schmidt condensation with aryaldehydes in the presence of sodium hydroxide in order to give the corresponding α,β-unsaturated carbonyl derivatives which were condensed with urea, thiourea, hydrazine, phenyl hydrazine, semicarbazide hydrochloride and monoethanolamide to produse good yield of 2-pyrimidinone, 2-pyrimidinethion, pyrazoline-1-phenyl, pyrazoline, pyrazoline-1-carboxamide and 1,4-oxazepines derivatives, respectively. The purity and identities of products were elucidated through thin layer chromatography (TLC), melting point and spectroscopic data (IR, 1H NMR, 13C NMR, GC-Mass). Docking study was performed by MOE2009.10 software for each data set, 16 synthesized compounds and 70 compounds having high predicted activity to evaluate their interactions with protein of (DHODH) enzyme. In this study a number of compounds showed higher interactions than this of stranded reference brequinar.