Discovery of new piperaquine hybrid analogs linked by triazolopyrimidine and pyrazolopyrimidine scaffolds with antiplasmodial and transmission blocking activities.

The World Health Organization (WHO) estimated that there were 247 million malaria cases in 2021 worldwide, representing an increase in 2 million cases compared to 2020. The urgent need for the development of new antimalarials is underscored by specific criteria, including the requirement of new modes of action that avoid cross-drug resistance, the ability to provide single-dose cures, and efficacy against both assexual and sexual blood stages. Motivated by the promising results obtained from our research group with [1,2,4]triazolo[1,5-a]pyrimidine and pyrazolo[1,5-a]pyrimidine derivatives, we selected these molecular scaffolds as the foundation for designing two new series of piperaquine analogs as potential antimalarial candidates.

The Development of Novel Compounds Against Malaria: Quinolines, Triazolpyridines, Pyrazolopyridines and Pyrazolopyrimidines.

Based on medicinal chemistry tools, new compounds for malaria treatment were designed. The scaffolds of the drugs used to treat malaria, such as chloroquine, primaquine, amodiaquine, mefloquine and sulfadoxine, were used as inspiration. We demonstrated the importance of quinoline and non-quinoline derivatives in vitro with activity against the W2 chloroquine-resistant (CQR) clone strain and in vivo against -infected mouse model.

New pyrazolopyrimidine derivatives as Leishmania amazonensis arginase inhibitors.

Arginase performs the first enzymatic step in polyamine biosynthesis in Leishmania and represents a promising target for drug development. Polyamines in Leishmania are involved in trypanothione synthesis, which neutralize the oxidative burst of reactive oxygen species (ROS) and nitric oxide (NO) that are produced by host macrophages to kill the parasite. In an attempt to synthesize arginase inhibitors, six 1-phenyl-1H-pyrazolo[3,4-d]pyrimidine derivatives with different substituents at the 4-position of the phenyl group were synthesized.

Current Antimalarial Therapies and Advances in the Development of Semi-Synthetic Artemisinin Derivatives.

According to the World Health Organization, malaria remains one of the biggest public health problems in the world. The development of resistance is a current concern, mainly because the number of safe drugs for this disease is limited. Artemisinin-based combination therapy is recommended by the World Health Organization to prevent or delay the onset of resistance.