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

• Published in: Journal of enzyme inhibition and medicinal chemistry Vol. 35; no. 1; pp. 847 - 863
• Main Authors: Ali, Sahar A., Awad, Samir Mohamed, Said, Ahmed Mohammed, Mahgoub, Shahenda, Taha, Heba, Ahmed, Naglaa Mohamed
• Format: Journal Article
• Language: English
• Published: England Taylor & Francis 01-01-2020; Taylor & Francis Ltd; Taylor & Francis Group
• Subjects: 15-lipoxygenase inhibitors; Animals; antioxidant activity; Antioxidants; Antioxidants - chemical synthesis; Antioxidants - chemistry; Antioxidants - pharmacology; Arachidonate 15-Lipoxygenase - metabolism; Ascorbic acid; Biphenyl Compounds - antagonists & inhibitors; Catalase; Dose-Response Relationship, Drug; Drug Design; Glutathione; Humans; Hybrids; Lipoxygenase; Lipoxygenase Inhibitors - chemical synthesis; Lipoxygenase Inhibitors - chemistry; Lipoxygenase Inhibitors - pharmacology; Male; Malondialdehyde; Models, Molecular; Molecular modelling; Molecular Structure; Naphthalene; Nitric oxide; Nitric Oxide - antagonists & inhibitors; Oxidative stress; Picrates - antagonists & inhibitors; Pyrazole; Pyrazoles - chemical synthesis; Pyrazoles - chemistry; Pyrazoles - pharmacology; Quercetin; Rats; Rats, Wistar; Research Paper; scavenging activity; Structure-Activity Relationship; Superoxide; Superoxides - antagonists & inhibitors; Toxicity; hybrids; scavenging activity; 15-lipoxygenase inhibitors; antioxidant activity; Pyrazole
• ISSN: 1475-6366; 1475-6374
• DOI: 10.1080/14756366.2020.1742116

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 2a-e were synthesized efficiently and were used as starting materials for synthesis of a variety of heterocycles. A novel series of pyrazoline 3a-e, phenylpyrazoline 4a-e, isoxazoline 5a-e and pyrazoline carbothioamide derivatives 6a-e were synthesized and screened for in vitro 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 3a, 4e, 5b, 5c, 6a, 6c, and 6e 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 in vivo study. Catalase (CAT) activity, glutathione (GSH) and malondialdehyde (MDA) levels were assayed in liver of treated rats. Compounds 5b, 5c, and 6e showed significant in vivo antioxidant potentials compared to control group at dose of 100 mg/kg B.W. Molecular docking of compound 6a 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.