Preparation of thieno[3,2-h]cinnolinones as matrix metalloproteinase inhibitors

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.