Structure-Based Optimization of N-Substituted Oseltamivir Derivatives as Potent Anti-Influenza A Virus Agents with Significantly Improved Potency against Oseltamivir-Resistant N1-H274Y Variant

Abstract

Due to the emergence of highly pathogenic and oseltamivir-resistant influenza viruses, there is an urgent need to develop new anti-influenza agents. Herein, five sub-series of oseltamivir derivatives were designed and synthesized to improve their activity towards drug-resistant viral strains by further exploiting the 150-cavity in the neuraminidases (NAs). The bioassay results showed that compound 21h exhibited antiviral activities similar to or better than those of oseltamivir carboxylate (OSC) against H5N1, H5N2, H5N6 and H5N8. Besides, 21h was 5-to 86-fold more potent than OSC toward N1, N8, and N1-H274Y mutant NAs in the inhibitory assays. Computational studies provided a plausible rationale for the high potency of 21h against group-1 and N1-H274Y NAs. In addition, 21h demonstrated acceptable oral bioavailability, low acute toxicity and potent antiviral activity in vivo, and high metabolic stability. Overall, above excellent profiles make 21h a promising drug candidate for the treatment of influenza virus infection.

Medicinal chemistry strategies for discovering antivirals effective against drug-resistant viruses

“…11). Compounds 22 178 and 23 179 obtained by using this strategy maintained the same inhibitory activity as oseltamivir against the most common influenza virus subtypes, and were highly active against oseltamivir-resistant strains. Compound 23 was 50 times more potent than oseltamivir in assays carried out with the H5N1 strain carrying the oseltamivir resistance mutation H274Y (IC 50 values of 1630 nM and 27.9 nM for oseltamivir and compound 23, respectively).…”

Anno 2021: Which antivirals for the coming decade?

“… 37 , 38 A recently disclosed chemical modification at the 5-position of oseltamivir allowed for an additional interaction within the NA active site that produced new analogues with restored affinity for drug resistant strains. 39 , 40 Among those, 4-phenylthiobenzyl substituted compound 8 ( Fig. 2 ) exhibited potent inhibitory activity against various influenza virus subtypes comparable to oseltamivir in cell based assays, while being 86-fold more active against the predominant H5N1-H274Y mutant strain in a neuraminidase inhibitory assay (IC 50 = 32.8 nM).…”

“…2 ) exhibited potent inhibitory activity against various influenza virus subtypes comparable to oseltamivir in cell based assays, while being 86-fold more active against the predominant H5N1-H274Y mutant strain in a neuraminidase inhibitory assay (IC 50 = 32.8 nM). 39

Fig. 2 Examples of mechanistically distinct influenza virus inhibitors.

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Antivirals Targeting the Neuraminidase

“…The latter is potentially propitious because of the improved membrane permeability and oral drug absorption (Wang et al 2018). Many other oseltamivir derivatives designed through structure-activity relationship studies were also investigated (Gong and Xu 2008;Schade et al 2014;Li et al 2017;Zhang et al 2018;Ye et al 2019).…”

“…Different oseltamivir derivatives targeting the 150-cavity (e.g., modifications at C-5 NH 2 position, addition of N/O/C fragment/linker, and lipophilic side chains at C-5) were synthesized. These derivatives had significantly improved potency (Wang et al 2010;Xie et al 2014;Lin et al 2018;Zhang et al 2018). As these inhibitors target the 150-cavity and can specifically inhibit only the group 1 NAs, including the A(H1N1)pdm09, they may provide a prospective way to design selective NA inhibitors.…”