tetano
Editor, Senior Moderator
Arch Pharm (Weinheim). 2015 Sep 17. doi: 10.1002/ardp.201500209. [Epub ahead of print]
[h=1]Design, Synthesis, and Molecular Docking of Novel Pyrrolooxazepinediol Derivatives with Anti-Influenza Neuraminidase Activity.[/h] El-Nezhawy AO[SUP]1,[/SUP][SUP]2[/SUP], Eweas AF[SUP]1,[/SUP][SUP]3[/SUP], Maghrabi IA[SUP]4[/SUP], Edalo AS[SUP]5[/SUP], Abdelwahab SF[SUP]6,[/SUP][SUP]7[/SUP].
[h=3]Author information[/h]
[h=3]Abstract[/h] 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 (EC[SUB]50[/SUB] = 0.016 μg/mL) exhibited potent anti-influenza (H5N1) activity, which approximately equals that of oseltamivir (EC[SUB]50[/SUB] = 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 LD[SUB]50[/SUB] of 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.
? 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
[h=4]KEYWORDS:[/h] H5N1; Influenza; Neuraminidase inhibitors; Oseltamivir phosphate; Pyrrolo[2,1-b][1,3]-oxazepine-8,9-diol
PMID: 26377573 [PubMed - as supplied by publisher]
[h=1]Design, Synthesis, and Molecular Docking of Novel Pyrrolooxazepinediol Derivatives with Anti-Influenza Neuraminidase Activity.[/h] El-Nezhawy AO[SUP]1,[/SUP][SUP]2[/SUP], Eweas AF[SUP]1,[/SUP][SUP]3[/SUP], Maghrabi IA[SUP]4[/SUP], Edalo AS[SUP]5[/SUP], Abdelwahab SF[SUP]6,[/SUP][SUP]7[/SUP].
[h=3]Author information[/h]
[h=3]Abstract[/h] 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 (EC[SUB]50[/SUB] = 0.016 μg/mL) exhibited potent anti-influenza (H5N1) activity, which approximately equals that of oseltamivir (EC[SUB]50[/SUB] = 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 LD[SUB]50[/SUB] of 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.
? 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
[h=4]KEYWORDS:[/h] H5N1; Influenza; Neuraminidase inhibitors; Oseltamivir phosphate; Pyrrolo[2,1-b][1,3]-oxazepine-8,9-diol
PMID: 26377573 [PubMed - as supplied by publisher]