Optimization of N-Substituted Oseltamivir Derivatives as Potent Inhibitors of Group-1 and -2 Influenza A Neuraminidases, Including a Drug-Resistant Variant

Abstract

On the basis of 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. Among the synthesized compounds, 15b and 15c were exceptionally active against both group-1 and -2 NAs. Especially for 09N1, N2, N6, and N9 subtypes, they showed 6.80-12.47 and 1.20-3.94 times greater activity than oseltamivir carboxylate (OSC). They also showed greater inhibitory activity than OSC toward H274Y and E119V variant. In cellular assays, they exhibited greater potency than OSC toward H5N1, H5N2, H5N6, and H5N8 viruses. 15b demonstrated high metabolic stability, low cytotoxicity in vitro, and low acute toxicity in mice. Computational modeling and molecular dynamics studies provided insights into the role of R group of 15b in improving potency toward group-1 and -2 NAs. We believe the successful exploitation of the 150-cavity of NAs represents an important breakthrough in the development of more potent anti-influenza agents.

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

“…The initial structures for molecular docking were prepared as we previously described. 52 To understand the binding modes of 21h and OSC in the 150-cavity of the N1, N8, 09N1 and N1-H247Y (PDB ID: 3CL0) 53 structures, the X-ray crystal structures were preprocessed, including modeling of the closed-form of the 150-cavity and open-form for N8, 09N1 and N1-H247Y NAs, as previously described. 45 All modeled NA structures were energy-minimized using the FF99SB force field as implemented in Amber12.…”

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).…”