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  • Title: Discovery of highly potent and selective influenza virus neuraminidase inhibitors targeting 150-cavity.
    Author: Jia R, Zhang J, Bertagnin C, Cherukupalli S, Ai W, Ding X, Li Z, Zhang J, Ju H, Ma X, Loregian A, Huang B, Zhan P, Liu X.
    Journal: Eur J Med Chem; 2021 Feb 15; 212():113097. PubMed ID: 33385836.
    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 C5-NH2 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.
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