New hydroxypyrimidinones as inhibitors of matrix metalloproteinases

Matrix metalloprotemases (MMPs) are a particular type of endopeptidases, which are known to catalyze the turnover of extra-cellular matrix components, and abnormal MMP activities are linked to the genesis and promotion of serious diseases such as cancer and arthritis. This work describes a set of results on three new matrix metalloproteinase inhibitors (MMPis) of 1-hydroxy-2(1H)-pyrimidinone type with different modifications at the heterocyclic 4-position, including aminoalkylamino and sulfamoyl-alkyl-amino groups. This paper will focus on results of solution studies, namely the acid-base properties and chelating abilities of the compounds towards Zn(II), as well as of bioassays on their enzyme inhibitory activity against several MMPs. The solution equilibrium studies revealed that the hydroxypyrimidinone is the zinc-binding group, independently of the presence of the sulfonamide moiety; the results of preliminary bioassays showed that the inhibitory activity is of micromolar order and it improves with the introduction of the aryl sulfonamide as a side chain substituent of the hydroxypyrimidinone ring, namely for the MMP-2 and MMP-9 gelatinases.