The hydrophobic side chain of oseltamivir influences type A subtype selectivity of Neuraminidase inhibitors

Abstract

Neuraminidase, which plays a critical role in the influenza virus life cycle, is a target for new therapeutic agents. The study of structure–activity relationships revealed that the C-5 position amino group of oseltamivir was pointed to 150-cavity of the neuraminidase in group-1. This cavity is important for selectivity of inhibitors against N1 versus N2 NA. A serial of influenza neuraminidase inhibitors with the oseltavimir scaffold containing lipophilic side chains at the C-5 position have been synthesized and evaluated for their influenza neuraminidase inhibitory activity and selectivity. The results indicated that compound 13o (H5N1 IC₅₀ = 0.1 ±0.04μM,H3N2 IC₅₀ = 0.26±0.18 μM) showed better inhibitory activity and selectivity against the group-1 neuraminidase. This study may provide a clue to design of better group-1 neuraminidase inhibitors.

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A series of oseltamivir derivatives were prepared. Most of them have better NA inhibitory activity and selectivity which indicated C-5 amino of oseltamivir was an important point to modify for finding novel influenza NA inhibitors

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