title: Synthesis and inhibitory activity of benzoic acid and pyridine derivatives on influenza neuraminidase.
abstract: Based upon the activity and X-ray crystallographic studies of tri-substituted benzene derivatives containing carboxylic acid, acetamido and guanidine groups, we investigated the effect of the fourth substituent to fulfill the fourth pocket of neuraminidase enzyme. The groups selected as fourth substituents were hydroxymethyl, hydroxyethyl, oxime and amino. These tetra-substituted benzene derivatives were synthesized and evaluated for neuraminidase inhibitory activity. All these compounds were found to have poorer IC(50) values than the tri-substituted compounds. Further, benzene ring was replaced by pyridine ring and di, tri and tetra-substituted pyridine derivatives were synthesized. The activity of the pyridine derivatives was comparable to benzene derivatives. The fourth substituent seems to disturb the binding of the other three substituents, so the activity is reduced as compared to tri-substituted benzene and pyridine derivatives.
authors.affiliation: BioCryst Pharmaceuticals, Inc., 2190 Parkway Lake Drive, Birmingham, AL 35244, USA. pchand@biocryst.com <pchand@biocryst.com>
authors.forename: Pooran
authors.initials: P
authors.lastname: Chand
authors.forename: Pravin L
authors.initials: PL
authors.lastname: Kotian
authors.forename: Philip E
authors.initials: PE
authors.lastname: Morris
authors.forename: Shanta
authors.initials: S
authors.lastname: Bantia
authors.forename: David A
authors.initials: DA
authors.lastname: Walsh
authors.forename: Yarlagadda S
authors.initials: YS
authors.lastname: Babu
mesh_terms: D001565:Benzoates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D008958:Models, Molecular; D008968:Molecular Conformation; D009439:Neuraminidase / Q000037:antagonists & inhibitors*; D009975:Orthomyxoviridae / Q000201:enzymology*; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D001565:Benzoates; D011725:Pyridines; D009439:Neuraminidase