Neuraminidase (NA) plays a critical role in the life cycle of influenza vir
us and is a target for new therapeutic agents. A new benzoic acid inhibitor
(11) containing a lipophilic side chain at C-3 and a guanidine at C-5 was
synthesized. The X-ray structure of 4-(N-acetylamino)-5-guanidino-3-(3-pent
yloxy)benzoic acid in complex with NA revealed that the lipophilic side cha
in binds in a newly created hydrophobic pocket formed by the movement of Gl
u 278 to interact with Arg 226, whereas the guanidine of 11 interacts In a
negatively charged pocket created by Asp 152, Glu 120 and Glu 229. Compound
11 was highly selective for type A (H2N2) influenza NA (IC50 1 mu M) over
type B (B/Lee/40) influenza NA (IC50 500 mu M). (C) 1999 Elsevier Science L
td. All rights reserved.