title: Preparation of thieno[3,2-h]cinnolinones as matrix metalloproteinase inhibitors.
abstract: A new series of thieno[3,2-h]cinnolinone analogues was synthesized which is structurally related to 2,3,4,4a,5,6-hexahydrothieno [3,2-h]cinnolin-3-one 1, a weak inhibitor of the matrix metalloproteinase MMP-8 (human neutrophil collagenase). Preliminary SAR studies have shown that while C4a-methyl, C7-acetylamino, C7 and C8-nitro substitution, and C4-C4a olefination provided no increase in activity relative to 1, C8-acetylamino substitution as in 5 and 8 was favourable. Moreover, to predict how the thieno[3,2-h]cinnolinone inhibitors might bind to MMP-8, the unsubstituted compound 9 was docked into the MMP-8 crystal structure. These studies revealed that inhibitor 9 does not seem to be able to coordinate the catalytically-active zinc ion but preferably interact with the peptide-binding region of the active site.
authors.affiliation: Dipartimento Farmaco Chimico Tossicologico, Università di Sassari, Italy.
authors.forename: G A
authors.initials: GA
authors.lastname: Pinna
authors.forename: M M
authors.initials: MM
authors.lastname: Curzu
authors.forename: G
authors.initials: G
authors.lastname: Murineddu
authors.forename: G
authors.initials: G
authors.lastname: Chelucci
authors.forename: G
authors.initials: G
authors.lastname: Cignarella
authors.forename: E
authors.initials: E
authors.lastname: Menta
authors.forename: H W
authors.initials: HW
authors.lastname: Krell
authors.forename: G
authors.initials: G
authors.lastname: Rastelli
authors.forename: A M
authors.initials: AM
authors.lastname: Ferrari
mesh_terms: D001665:Binding Sites; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D020784:Matrix Metalloproteinase 8 / Q000737:chemistry; D061965:Matrix Metalloproteinase Inhibitors; D008958:Models, Molecular; D011804:Quinolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D061965:Matrix Metalloproteinase Inhibitors; D011804:Quinolines; D020784:Matrix Metalloproteinase 8