STRUCTURAL FUNCTIONALIZATION OF TRI-SUBSTITUTED PYRAZOLE DERIVATIVES AND PRELIMINARY EVALUATION OF THEIR ANTIMALARIAL ACTIVITY

Description

The increasing prevalence of drug-resistant Plasmodium falciparum strains led to an urgent priority in the development of new antimalarial drugs. In this scenario, several pyrazole derivatives have been reported as antimalarial agents in the last years. Recently, novel Tri- and Tetrasubstituted pyrazole derivatives showed interesting antimalarial properties being endowed with micromolar IC50 values against Chloroquine (CQ)-sensitive D10 and CQ-resistant W2 Plasmodium strains. To further extend the structure activity relationships around these promising compounds, we designed and synthesized a new series of 3-phenyl-4-cyano pyrazoles bearing different basic chains at position 5. Briefly, the novel derivatives were prepared by sequentially reacting benzoylacetonitrile with carbon disulfide and iodomethane in the presence of sodium hydride. The so obtained thioketal A was substituted with the proper amine, leading to the formation of intermediates B, that were cyclized with hydrazine to afford the desired pyrazoles. All the newly isolated compounds were tested against D10 and W2 Plasmodium strains and their cytotoxicity was evaluated on normal fibroblast cells. Interestingly, the novel pyrazoles 2 showed micromolar IC50 values especially against CQ resistant W2 strain, resulting more effective than their analogues 1. Additionally, in preliminary tests the novel derivatives did not show any significant cytotoxicity on fibroblast cell line

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