Exploring the pharmaceutical potential of highly substituted pyrazoles: from chemical design to antitumor activity

The pyrazole nucleus represents a privileged scaffold in medicinal chemistry being shared by several pharmaceutically relevant compounds with a broad range of activities. In the last years, we developed novel synthetic procedures for the synthesis of highly functionalized amino-pyrazole derivatives starting from the versatile N,S-ketene acetal frameworks. The cyclization reaction of these push-pull alkenes with the proper substituted hydrazine allowed us to isolate pyrazole intermediates I , differently functionalized on the heterocyclic core. Based on the structure-activity relationships (SARs) of the previous reported molecules, intermediates I were suitably converted into pyrazoles 1-3 through different stepwise procedures. The obtained derivatives were fully characterized and tested for their antitumor activities. More specifically, pyrazolyl thioureas 1 showed micromolar IC50 against Sirtuin 1 and Sirtuin 2, phenylamino pyrazoles 2 displayed antiangiogenetic activities by stabilizing IGFBP-4, while pyrazole carbamates 3 proved to inhibit USP7 deubiquitinating enzyme. The synthetic procedures, the characterization of the compounds as well as the biological results will be discussed during the presentation.