Abstract

Neuraminidase (NA), a glycoside hydrolase enzyme, plays pivotal roles in controlling biological functions not only of influenza viruses but also of humans. Zanamivir and oseltamivir designed to target influenza neuraminidase have become extensively used for influenza clinical treatment as its high anti-influenza efficacy. Unfortunately, side effects of these two drugs have been reported in clinical use. An aromatic benzene ring has been pursued as a core structure to derive stereo chemically simplified analogues with desired molecular properties. In our previous study, a series of 2-fluoro benzoic acids were synthesized and evaluated against all four human sialidase enzymes. Herein, we further evaluate the same set of 2-fluoro benzoic acids for inhibitory activity against viral sialidases expressed by influenza A virus. The most active compound 11 (4,5-diacetamido-2-fluoro benzoic acid) has an IC50 of 4.5 μM (N1) and 21 μM (N2) that is ∼60-140 fold more active than its non-fluoro counterpart 10 (3,4-diacetamido benzoic acid) that has an IC50 of 640 μM (N1) and 1400 μM (N2). Molecular docking and calculated binding free energies are in good agreement with the experimental data. Of greater significance was the observation of key interaction of 2-fluoro group with active site for improved activity and could be explored further for higher affinity and selectivity over viral sialidases with suitably substituted 2-fluoro benzoic acids.

Keywords: Influenza, Sialidase, Inhibitor design, Neu5Ac2en, Benzoic Acid, Docking.