Design, synthesis, inhibitory activity, and SAR studies of hydrophobic p-aminosalicylic acid derivatives as neuraminidase inhibitors

A series of hydrophobic p-aminosalicylic acid derivatives containing a lipophilic side chain at C-2 and an amino or guanidine at C-5 were synthesized and evaluated for their ability to inhibit neuraminidase (NA) of influenza A virus (H3N2). All compounds were synthesized in good yields starting from commercially available p-aminosalicylic acid (PAS) using a suitable synthetic strategy. These compounds showed potent inhibitory activity against influenza A NA. Within this series, six compounds, 11, 12, 13e, 16e, 17c, and 18e, have the good potency (IC50 = 0.032–0.049 μM), which are compared to Oseltamivir (IC50 = 0.021 μM) and could be used as lead compounds in the future.

Superposition of compound 12 bound to influenza A (H3N2) neuraminidase. Structure-based design has led to the synthesis of a series of influenza neuraminidase (NA) inhibitors containing benzoic acid. Several compounds exhibit some specific activity against influenza A (H3N2).Figure optionsDownload as PowerPoint slide