Antiprotozoal Activity of Highly Substituted Pyrazole and Pyrimidine Derivatives

Based on previously identified antimalarial agents, a series of highly substituted pyrazole and pyrimidines derivatives has been synthesized and tested for antiplasmodial and antileishmanial activity. Selected derivatives show promising antiplasmodial effect with a predicted favorable pharmacokinetic profile.

To further extend the structure-activity relationships of previously reported antimalarial anilino-pyrazoles VI, trisubstituted pyrazoles 13–15, and pyrimidines 16 and 17 are designed and synthesized. The novel derivatives are prepared thorough a divergent, chemo-selective approach starting from N,S-acetal intermediates. Compounds 13–17 are tested for their antimalarial and antileishmanial activity and their cytotoxicity is evaluated against human fibroblast. Pyrazoles 14 d,e and pyrimidine 17e are identified as novel and effective antiplasmodial agents being able to inhibit, at micromolar concentrations, chloroquine(CQ)-sensitive and CQ-resistant Plasmodium falciparum strains, as well as Leishmania infatum and Leishmania tropica protozoa. Additionally, favorable pharmacokinetics and toxicity profiles are predicted for the compounds.

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