Design, synthesis, molecular modelling and biological evaluation of novel 3-(2-naphthyl)-1-phenyl-1H-pyrazole derivatives as potent antioxidants and 15-Lipoxygenase inhibitors

Abstract

Oxidative stress is one of the main causes of significant severe diseases. The discovery of new potent antioxidants with high efficiency and low toxicity is a great demand in the field of medicinal chemistry. Herein, we report the design, synthesis molecular modelling and biological evaluation of novel hybrids containing pyrazole, naphthalene and pyrazoline/isoxazoline moiety. Chalcones <b>2a-e</b> were synthesized efficiently and were used as starting materials for synthesis of a variety of heterocycles. A novel series of pyrazoline <b>3a-e</b>, phenylpyrazoline <b>4a-e</b>, isoxazoline <b>5a-e</b> and pyrazoline carbothioamide derivatives <b>6a-e</b> were synthesized and screened for <i>in vitro</i> antioxidant activity using 2,2-diphenyl-1-picrylhydrazyl (DPPH), nitric oxide (NO) and superoxide radical scavenging assay as well as 15-lipoxygenase (15-LOX) inhibition activity. Compounds <b>3a, 4e, 5b, 5c, 6a, 6c,</b> and <b>6e</b> showed excellent radical scavenging activity in all three methods in comparison with ascorbic acid and 15-LOX inhibition potency using quercetin as standard then were subjected to <i>in vivo</i> study. Catalase (CAT) activity, glutathione (GSH) and malondialdehyde (MDA) levels were assayed in liver of treated rats. Compounds <b>5b, 5c,</b> and <b>6e</b> showed significant <i>in vivo</i> antioxidant potentials compared to control group at dose of 100 mg/kg B.W. Molecular docking of compound <b>6a</b> endorsed its proper binding at the active site pocket of the human 15-LOX which explains its potent antioxidant activity in comparison with standard ascorbic acid.