Antioxidant activity, molecular docking, and modeling pharmacokinetics study of some benzo[f]quinoline candidates

Abstract

Benzoquinolines were found in many pharmaceuticals and natural products and were utilized as templates for the synthesis of many drugs. Thus, 3-(3-chlorobenzo[f]quinolin-2-yl)-2-(4-oxo-4H-benzo[d][1,3]oxazin-2-yl)acrylonitrile was prepared as a key building substrate, using arylidene ethyl cyanoacetate derivative 3, and reacted with diverse mono- and bi-dentate nitrogen nucleophiles aiming to construct new heterocycles based on a benzo[f]quinoline core, for example quinazolinone, imidazoline, oxadiazolinone, and benzimidazole derivatives. The antioxidant activity of the synthesized compounds was evaluated, using ascorbic acid as a reference, and revealed the highest potency of benzimidazole derivative 19, which may be attributed to the aromaticity and extended conjugation. These findings were supported by in silico studies. A molecular docking simulation was performed to disclose the modes of interactions of benzimidazole 19 toward HCV NS5B polymerase. It exhibited a binding energy greater than that of co-crystallized ligand, referring to strong binding to certain key nucleobases and amino acids (CYS 366 and ASN 411) of HCV NS5B polymerase through hydrogen bonding and pi-hydrogen interactions, revealing its potential usage as an antioxidant agent. DFT simulation for the active compounds were studied to determine the molecular geometry and frontier orbitals of the potent compounds. Regarding ADME simulation, compounds 3, 9, and 17 exhibited a high GI absorption and good bioavailability score of 0.85, 0.55, and 0.55, respectively. The variance in GI absorption might depict the differences in observed antioxidant efficacy of compounds. Also, they showed gastrointestinal tract (GIT) absorption due to their being in the BOILED-EGG chart white area. The potent compounds 3, 9, 13, 17, and 19 exhibited fair TPSA and predicted to exhibit good passive oral absorption.