Diversity-oriented synthesis of highly-functionalized amino-pyrazoles as pharmaceutically relevant compounds

The pyrazole ring represents a valuable heterocycle in medicinal chemistry, being shared by several effective molecules with a broad range of activity. In particular, amino-pyrazoles constitute a versatile framework in drug discovery. By taking advantage of our expertise on the condensation of active methylene reagents and heterocumulenes, we developed new synthetic strategies for the preparation of highly-functionalized amino-pyrazoles through the formation of ketene N,S- or S,S-acetals. A One-pot synthetic procedure led to the formation of a series of pyrazole compounds endowed with promising antiproliferative activity in cell-based assay. Docking simulations carried out on the most active molecules indicated estrogen receptors as a potential target inside the cell. Alongside, a stepwise synthetic protocol was used to prepare novel antioxidant pyrazole hydrazones that efficiently inhibited reactive oxygen species (ROS) formation and platelet aggregation. The same synthetic approach allowed the preparation of amino-pyrazoles with interesting antiangiogenetic properties as assessed in wound healing and tube formation assays on human fibroblasts and endothelial cells. Furthermore, these compounds displayed good Akt phosphorylation inhibition in Western Blot analyses. Based on literature data, a set of pyrazoles was tested as antimalarial agents against D10 Chloroquine(CQ)-sensitive and W2 CQ-resistant P. falciparum strains. Selected derivatives showed micromolar IC50 values against the two considered protozoa strains and further SAR extension studies led to the identification of novel amino-pyrazole and pyrazolopyrimidine derivatives with improved antimalarial properties especially against the CQ-resistant W2 strain. Overall, the development of diversity-oriented procedures for the preparation of highly substituted pyrazoles allowed the identification of unreported hit compounds as antiproliferative, antiangiogenic, antioxidant and antimalarial agents and provide further support to the pharmaceutical potential of pyrazole nucleus and heterocyclic system thereof derived in different therapeutic areas.