221382-08-7Relevant academic research and scientific papers
Pyrrolidinobenzoic acid inhibitors of influenza virus neuraminidase: Modifications of essential pyrrolidinone ring substituents
Brouillette, Wayne J.,Bajpai, Saroj N.,Ali, Shoukath M.,Velu, Sadanandan E.,Atigadda, Venkatram R.,Lommer, Barbara S.,Finley, James B.,Luo, Ming,Air, Gillian M.
, p. 2739 - 2749 (2007/10/03)
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, d
Potent inhibition of influenza sialidase by a benzoic acid containing a 2-pyrrolidinone substituent
Atigadda, Venkatram R.,Brouillette, Wayne J.,Duarte, Franco,Ali, Shoukath M.,Babu, Yarlagadda S.,Bantia, Shanta,Chand, Pooran,Chu, Naiming,Montgomery, John A.,Walsh, David A.,Sudbeck, Elise A.,Finley, James,Luo, Ming,Air, Gillian M.,Laver, Graeme W.
, p. 2332 - 2343 (2007/10/03)
On the basis of the lead compound 4-(N-acetylamino)-3-guanidinobenzoic acid (BANA 113), which inhibits influenza A sialidase with a K(i) of 2.5 μM, 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.
