title: New anti-viral drugs for the treatment of the common cold.
abstract: Human Rhinovirus (HRV) is the most important aetiologic agent of common cold in adults and children. HRV is a single-stranded, positive sense RNA virus and, despite the high level of conservation among different serotypes, sequence alignment of viral protease 3C with mammalian protease reveals no homology. Thus, protease 3C is an optimal target for the development of anti-HRV agents. In the present work we investigated the design, the synthesis and the development of new potential reversible inhibitors against HRV protease 3C. Docking studies on the crystallized structure of HRV2 protease 3C led us to the design and the synthesis of a series of 3,5 disubstituted benzamides able to act as analogues of the substrate. We also developed 1,3,5 trisubstituted benzamides where aromatic substitutions on the aryl ring led us to investigate the importance of pi-pi interaction on the stabilization of protease 3C-inhibitor complex. All structures were tested for enzymatic inhibition on HRV14 protease 3C. Results highlighted the inhibitory activity of compounds 13, 14, and 20 (91%, 81%, and 85% at 10 microM, respectively), with the latter exhibiting an ID(50) (dose that inhibits 50% of the viral cytopathic effect) on HRV-14=25 microg/ml.
authors.affiliation: Angelini Farmaceutici, A.C.R.A.F. SpA, P.le della Stazione snc, 00040 S. Palomba, Roma, Italy. c.maugeri@angelini.it
authors.forename: Caterina
authors.initials: C
authors.lastname: Maugeri
authors.forename: Maria A
authors.initials: MA
authors.lastname: Alisi
authors.forename: Claudia
authors.initials: C
authors.lastname: Apicella
authors.forename: Luciano
authors.initials: L
authors.lastname: Cellai
authors.forename: Patrizia
authors.initials: P
authors.lastname: Dragone
authors.forename: Elena
authors.initials: E
authors.lastname: Fioravanzo
authors.forename: Saverio
authors.initials: S
authors.lastname: Florio
authors.forename: Guido
authors.initials: G
authors.lastname: Furlotti
authors.forename: Giorgina
authors.initials: G
authors.lastname: Mangano
authors.forename: Rosella
authors.initials: R
authors.lastname: Ombrato
authors.forename: Renzo
authors.initials: R
authors.lastname: Luisi
authors.forename: Raffaello
authors.initials: R
authors.lastname: Pompei
authors.forename: Vito
authors.initials: V
authors.lastname: Rincicotti
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Russo
authors.forename: Marco
authors.initials: M
authors.lastname: Vitiello
authors.forename: Nicola
authors.initials: N
authors.lastname: Cazzolla
mesh_terms: D000086042:3C Viral Proteases; D000998:Antiviral Agents / Q000737:chemistry*; D001549:Benzamides / Q000737:chemistry* / Q000494:pharmacology*; D003139:Common Cold / Q000188:drug therapy*; D003546:Cysteine Endopeptidases / Q000187:drug effects*; D015853:Cysteine Proteinase Inhibitors / Q000737:chemistry*; D006801:Humans; D020128:Inhibitory Concentration 50; D012229:Rhinovirus / Q000201:enzymology*; D013329:Structure-Activity Relationship; D014764:Viral Proteins / Q000037:antagonists & inhibitors / Q000187:drug effects*
chemical_list: D000998:Antiviral Agents; D001549:Benzamides; D015853:Cysteine Proteinase Inhibitors; D014764:Viral Proteins; D003546:Cysteine Endopeptidases; D000086042:3C Viral Proteases