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.