title: Design, Synthesis, and Molecular Docking of Novel Pyrrolooxazepinediol Derivatives with Anti-Influenza Neuraminidase Activity.
abstract: A series of novel pyrrolo[2,1-b][1,3]oxazepine-8,9-diol derivatives 12-15 were synthesized starting from l-tartaric acid, which was transformed into anhydride which then reacted with allylamine in xylene to afford the imide 2. The target molecules 12-15 were achieved via ring-closing metathesis with the Grubbs catalyst, followed by reduction of the carbonyl group and deprotection of hydroxyl groups. Finally, catalytic hydrogenation of the double bond afforded the title compounds 12-15. Molecular docking study of the title compounds 12-15 was carried out against neuraminidase as the target enzyme, in an attempt to understand the mechanism of action of the tested compounds as potential neuraminidase inhibitors. Molecular docking of the target compounds showed that all tested compounds bind to the active site of neuraminidase, with moderate to high binding energy. Compounds 12-15 were examined for their antiviral activity against H5N1 virus (A/chicken/Egypt/1/2008). Oseltamivir phosphate was used as a control for antiviral activity. The results show that compound 12 (EC50= 0.016 μg/mL) exhibited potent anti-influenza (H5N1) activity, which approximately equals that of oseltamivir (EC50= 0.012 μg/mL). Also, it had a therapeutic index similar to that of oseltamivir phosphate (∼20). The data also revealed that compounds 13, 14, and 15 had slightly lower antiviral activity and lower cytotoxicity than oseltamivir phosphate, with LD50of 0.188, 0.162, and 0.176 μg/mL, respectively. However, 13, 14, and 15 had lower therapeutic indices than 12. In conclusion, we were able to synthesize cheap and potent anti-H5N1 compounds.
authors.affiliation: Department of Pharmaceutical Chemistry, College of Pharmacy, Taif University, Taif, Saudi Arabia.|Department of Chemistry of Natural and Microbial Product, National Research Center, Dokki, Cairo, Egypt.
authors.forename: Ahmed O H
authors.initials: AOH
authors.lastname: El-Nezhawy
authors.affiliation: Department of Pharmaceutical Chemistry, College of Pharmacy, Taif University, Taif, Saudi Arabia.|Department of Medicinal Chemistry, National Research Center, Dokki, Cairo, Egypt.
authors.forename: Ahmad F
authors.initials: AF
authors.lastname: Eweas
authors.affiliation: Department of Clinical Pharmacy, College of Pharmacy, Taif University, Taif, Saudi Arabia.
authors.forename: Ibrahim A
authors.initials: IA
authors.lastname: Maghrabi
authors.affiliation: Clinical Pharmacology, College of Pharmacy, Taif University, Taif, Saudi Arabia.
authors.forename: Ahmed S
authors.initials: AS
authors.lastname: Edalo
authors.affiliation: Department of Microbiology, College of Pharmacy, Taif University, Taif, Saudi Arabia.|Department of Microbiology and Immunology, Faculty of Medicine, Minia University, Minia, Egypt.
authors.forename: Sayed F
authors.initials: SF
authors.lastname: Abdelwahab
keywords: H5N1; Influenza; Neuraminidase inhibitors; Oseltamivir phosphate; Pyrrolo[2,1-b][1,3]-oxazepine-8,9-diol