Design and synthesis of benzoic acid derivatives as influenza neuraminidase inhibitors using structure-based drug design.
A series of 94 benzoic acid derivatives was synthesized and tested for its ability to inhibit influenza neuraminidase. The enzyme-inhibitor complex structure was determined by X-ray crystallographic analysis for compounds which inhibited the enzyme. The most potent compound tested in vitro, 5 (4-acetylamino)-3-guanidinobenzoic acid), had an IC50 = 2.5 x 10(-6) M against N9 neuraminidase. Compound 5 was oriented in the active site of the neuraminidase in a manner that was not predicted from the reported active site binding of GANA (4) with neuraminidase. In a mouse model of influenza, 5 did not protect the mice from weight loss due to the influenza virus when dosed intranasally.
Chand
P
P
BioCryst Pharmaceuticals, Inc., Birmingham, Alabama 35244, USA.
Babu
Y S
YS
Bantia
S
S
Chu
N
N
Cole
L B
LB
Kotian
P L
PL
Laver
W G
WG
Montgomery
J A
JA
Pathak
V P
VP
Petty
S L
SL
Shrout
D P
DP
Walsh
D A
DA
Walsh
G M
GM
D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001565:Benzoates / Q000138:chemical synthesis* / Q000494:pharmacology; D019817:Benzoic Acid; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D005260:Female; D051379:Mice; D008807:Mice, Inbred BALB C; D009439:Neuraminidase / Q000037:antagonists & inhibitors*; D009975:Orthomyxoviridae / Q000187:drug effects* / Q000201:enzymology; D013329:Structure-Activity Relationship
D000998:Antiviral Agents; D001565:Benzoates; D004791:Enzyme Inhibitors; D019817:Benzoic Acid; D009439:Neuraminidase