Antiparasitic Behavior of Trifluoromethylated Pyrazole 2-Amino-1,3,4-thiadiazole Hybrids and Their Analogues: Synthesis and Structure-Activity Relationship

Abstract

A series of trifluoromethylated pyrazole thiosemicarbazone, trifluromethylated pyrazole isothiosemicarbazone, and trifluoromethylated pyrazole 2-amino-1,3,4-thiadiazole hybrids were synthesized and evaluated in vitro against the promastigote form of Leishmania amazonensis and the epimastigote form of Trypanosoma cruzi, the pathogens causing the neglected tropical diseases leishmaniasis and Chagas disease, respectively. The results show the potential of these compounds regarding their antiparasitic properties. Studies on the structure-activity relationship demonstrated that compounds containing a bulky group at the para position of the phenyl ring attached to the 5-position of the pyrazole core had better antiparasitic effects. Among the substituents attached at the 3-position of the pyrazole ring, the insertion of the 2-amino-1,3,4thiadiazole nucleus led to the most potent compounds compared to the thiosemicarbazone derivative.

The Current Directions of Searching for Antiparasitic Drugs

“…The therapy is based on the use of two drugs, nifurtimox and benznidazole. As a result of many serious side effects occurring after the implementation of treatment based on the administration of the above substances, there is a need to develop new, safer and effective drugs to combat Chagas disease and also leishmaniasis [ 48 ].…”

“…The conversion of thiosemicarbazone into S -methyl and 2-amino-1,3,4-thiadiazole derivatives improved the efficacy, mainly against Leishmania amazonensis and also Trypanosoma cruzi . It can be safely stated that S -methylthiosemicarbazones, such as 3a , 3d , 3f and 2-amino-1,3,4-thiadiazole-pyrazole hybrids ( 4a , 4d , 4f ) constitute the dominant structures in the context of the synthesis of potential antiparasitic drugs [ 48 ].…”

Bioactivity of Novel Pyrazole-Thiazolines Scaffolds against Trypanosoma cruzi: Computational Approaches and 3D Spheroid Model on Drug Discovery for Chagas Disease

“…Pyrazole derivatives have been highlighted for their effects on trypanosomatids [ 26 ]. Pyrazole-trifluoromethylated hybrids have potent activity against Leishmania amazonensis and T. cruzi , with the pyrazole 2-amino-1,3,4-thiadiazole hybrids considered as a relevant scaffold for optimization [ 27 ]. The in vitro biological activity of dialkyl pyrazole-3,5-dicarboxylates analogues has also been demonstrated against T. cruzi , Leishmania infantum and Leishmania braziliensis , showing a remarkable inhibition of iron superoxide dismutase (Fe-SOD) activity that is responsible for the antioxidant defense mechanism of the parasite.…”

Stable Carbenes as Structural Components of Partially Saturated Sulfur-Containing Heterocycles

“…Moreover, compounds containing the thiadiazole moiety are actively explored as prospective pharmaceutically active ingredients. Additionally, antileishmanial activity was recently demonstrated for quinoline-, thiophene-, and pyrazolo-substituted 1,3,4-thiadiazoles [ 6 , 7 , 8 ]. Therefore, the research on the preparation, structural characterization, and functional properties of sulfur-containing heterocycles is essential for medicinal chemistry.…”