Potent inhibition of influenza sialidase by a benzoic acid containing a 2-pyrrolidinone substituent.
On the basis of the lead compound 4-(N-acetylamino)-3-guanidinobenzoic acid (BANA 113), which inhibits influenza A sialidase with a Ki of 2.5 microM, several novel aromatic inhibitors of influenza sialidases were designed. In this study the N-acetyl group of BANA 113 was replaced with a 2-pyrrolidinone ring, which was designed in part to offer opportunities for introduction of spatially directed side chains that could potentially interact with the 4-, 5-, and/or 6-subsites of sialidase. While the parent structure 1-(4-carboxy-2-guanidinophenyl)pyrrolidin-2-one (8) was only a modest inhibitor of sialidase, the introduction of a hydroxymethyl or bis(hydroxymethyl) substituent at the C5' position of the 2-pyrrolidinone ring resulted in inhibitors (9 and 12, respectively) with low micromolar activity. Crystal structures of these inhibitors in complex with sialidase demonstrated that the substituents at the 5'-position of the 2-pyrrolidinone ring interact in the 4- and/or 5-subsites of the enzyme. Replacement of the guanidine in 12 with a hydrophobic 3-pentylamino group resulted in a large enhancement in binding to produce an inhibitor (14) with an IC50 of about 50 nM against influenza A sialidase, although the inhibition of influenza B sialidase was 2000-fold less. This represents the first reported example of a simple, achiral benzoic acid with potent (low nanomolar) activity as an inhibitor of influenza sialidase.
Atigadda
V R
VR
Department of Chemistry and Center for Macromolecular Crystallography, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA.
Brouillette
W J
WJ
Duarte
F
F
Ali
S M
SM
Babu
Y S
YS
Bantia
S
S
Chand
P
P
Chu
N
N
Montgomery
J A
JA
Walsh
D A
DA
Sudbeck
E A
EA
Finley
J
J
Luo
M
M
Air
G M
GM
Laver
G W
GW
D001565:Benzoates / Q000138:chemical synthesis* / Q000737:chemistry; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D009980:Influenza A virus / Q000737:chemistry; D009981:Influenza B virus / Q000737:chemistry; D008958:Models, Molecular; D009439:Neuraminidase / Q000037:antagonists & inhibitors* / Q000302:isolation & purification; D011760:Pyrrolidinones / Q000138:chemical synthesis* / Q000737:chemistry; D013050:Spectrometry, Fluorescence; D013329:Structure-Activity Relationship
D001565:Benzoates; D004791:Enzyme Inhibitors; D011760:Pyrrolidinones; D009439:Neuraminidase