Pyrrolidinobenzoic acid inhibitors of influenza virus neuraminidase: modifications of essential pyrrolidinone ring substituents.
We recently reported the first benzoic acid, 1-[4-carboxy-2-(3-pentylamino)phenyl]-5,5-bis(hydroxymethyl)pyrrolidin-2-one (8), that is a potent inhibitor of avian influenza A neuraminidase (N9) and, unlike other reported potent neuraminidase inhibitors, does not contain a basic aliphatic amine or guanidine nor a simple N-acetyl grouping. However, 8 was a poor inhibitor of influenza B neuraminidase. In the present study we further evaluated 8 as an inhibitor of human influenza A NA isolates, and it was effective against N2NA but found to be 160-fold less active against N1NA. We also synthesized analogues of 8 involving moderate modifications of essential substituents on the pyrrolidinone ring. Specifically, the aminomethyl (9), hydroxyethyl (10), and aminoethyl (11) analogues were prepared. Only the most conservative change (compound 9) resulted in continued effective inhibition of influenza A, in addition to a noteworthy increase in the activity of 9 for N1NA. The effectiveness of 9 against influenza B neuraminidase was furthermore improved 10-fold relative to 8, but this activity remained 50-fold poorer than for type A NA.
Brouillette
Wayne J
WJ
Department of Chemistry, 901 14th Street South, CHEM 201, The University of Alabama at Birmingham, Birmingham, AL 35294, USA. wbrou@uab.edu
Bajpai
Saroj N
SN
Ali
Shoukath M
SM
Velu
Sadanandan E
SE
Atigadda
Venkatram R
VR
Lommer
Barbara S
BS
Finley
James B
JB
Luo
Ming
M
Air
Gillian M
GM
D001565:Benzoates / Q000138:chemical synthesis* / Q000494:pharmacology; D001665:Binding Sites; D006801:Humans; D009980:Influenza A virus / Q000187:drug effects / Q000201:enzymology*; D009981:Influenza B virus / Q000187:drug effects / Q000201:enzymology; D020128:Inhibitory Concentration 50; D009439:Neuraminidase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014779:Virus Replication / Q000187:drug effects
D001565:Benzoates; D011759:Pyrrolidines; D009439:Neuraminidase