tetano
Editor, Senior Moderator
Eur J Med Chem
. 2020 Dec 13;212:113097.
doi: 10.1016/j.ejmech.2020.113097. Online ahead of print.
Discovery of highly potent and selective influenza virus neuraminidase inhibitors targeting 150-cavity
Ruifang Jia[SUP] 1 [/SUP], Jian Zhang[SUP] 2 [/SUP], Chiara Bertagnin[SUP] 3 [/SUP], Srinivasulu Cherukupalli[SUP] 1 [/SUP], Wei Ai[SUP] 1 [/SUP], Xiao Ding[SUP] 1 [/SUP], Zhuo Li[SUP] 1 [/SUP], Jiwei Zhang[SUP] 1 [/SUP], Han Ju[SUP] 1 [/SUP], Xiuli Ma[SUP] 4 [/SUP], Arianna Loregian[SUP] 3 [/SUP], Bing Huang[SUP] 5 [/SUP], Peng Zhan[SUP] 6 [/SUP], Xinyong Liu[SUP] 7 [/SUP]
Affiliations
Abstract
Encouraged by our earlier discovery of N1-selective inhibitors, the 150-cavity of influenza virus neuraminidases (NAs) could be further exploited to yield more potent oseltamivir derivatives. Herein, we report the design, synthesis and biological evaluation of a series of novel oseltamivir derivatives via the structural modifications at C[SUB]5[/SUB]-NH[SUB]2[/SUB] of oseltamivir targeting 150-cavity. Among them, compound 5c bearing 4-(3-methoxybenzyloxy)benzyl group exhibited the most potent activity, which was lower or modestly improved activities than oseltamivir carboxylate (OSC) against N1 (H1N1), N1 (H5N1) and N1 (H5N1-H274Y). Specifically, there was 30-fold loss of activity against the wild-type strain H1N1. However, 5c displayed 4.85-fold more potent activity than OSC against H5N1-H274Y NA. Also, 5c demonstrated low cytotoxicity in vitro and no acute toxicity in mice. Molecular docking studies provided insights into the high potency of 5c against N1 and N1-H274Y mutant NAs. Besides, the in silico prediction of physicochemical properties and CYP enzymatic inhibitory ability of representative compounds were conducted to evaluate their drug-like properties.
Keywords: 150-Cavity; Influenza virus; Neuraminidase inhibitors; Oseltamivir derivatives.
. 2020 Dec 13;212:113097.
doi: 10.1016/j.ejmech.2020.113097. Online ahead of print.
Discovery of highly potent and selective influenza virus neuraminidase inhibitors targeting 150-cavity
Ruifang Jia[SUP] 1 [/SUP], Jian Zhang[SUP] 2 [/SUP], Chiara Bertagnin[SUP] 3 [/SUP], Srinivasulu Cherukupalli[SUP] 1 [/SUP], Wei Ai[SUP] 1 [/SUP], Xiao Ding[SUP] 1 [/SUP], Zhuo Li[SUP] 1 [/SUP], Jiwei Zhang[SUP] 1 [/SUP], Han Ju[SUP] 1 [/SUP], Xiuli Ma[SUP] 4 [/SUP], Arianna Loregian[SUP] 3 [/SUP], Bing Huang[SUP] 5 [/SUP], Peng Zhan[SUP] 6 [/SUP], Xinyong Liu[SUP] 7 [/SUP]
Affiliations
- PMID: 33385836
- DOI: 10.1016/j.ejmech.2020.113097
Abstract
Encouraged by our earlier discovery of N1-selective inhibitors, the 150-cavity of influenza virus neuraminidases (NAs) could be further exploited to yield more potent oseltamivir derivatives. Herein, we report the design, synthesis and biological evaluation of a series of novel oseltamivir derivatives via the structural modifications at C[SUB]5[/SUB]-NH[SUB]2[/SUB] of oseltamivir targeting 150-cavity. Among them, compound 5c bearing 4-(3-methoxybenzyloxy)benzyl group exhibited the most potent activity, which was lower or modestly improved activities than oseltamivir carboxylate (OSC) against N1 (H1N1), N1 (H5N1) and N1 (H5N1-H274Y). Specifically, there was 30-fold loss of activity against the wild-type strain H1N1. However, 5c displayed 4.85-fold more potent activity than OSC against H5N1-H274Y NA. Also, 5c demonstrated low cytotoxicity in vitro and no acute toxicity in mice. Molecular docking studies provided insights into the high potency of 5c against N1 and N1-H274Y mutant NAs. Besides, the in silico prediction of physicochemical properties and CYP enzymatic inhibitory ability of representative compounds were conducted to evaluate their drug-like properties.
Keywords: 150-Cavity; Influenza virus; Neuraminidase inhibitors; Oseltamivir derivatives.