Journal
MOLECULES
Volume 26, Issue 21, Pages -Publisher
MDPI
DOI: 10.3390/molecules26216742
Keywords
Trypanosoma cruzi; pyrazole derivatives; trypanocidal activity; 3D culture model
Funding
- Oswaldo Cruz Institute-Fiocruz
- Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq) [424015/2018-8]
- Fundacao de Amparo a Pesquisa do Estado do Rio de Janeiro (FAPERJ) [E26/010.101050/2018]
- FAPEMIG [CEX-RED-00010-14, CEX-APQ01014-14]
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This study focused on designing a small library of pyrazole derivatives to find new effective candidates for treating Chagas disease caused by Trypanosoma cruzi. The in vitro screening identified three promising compounds with good oral bioavailability prediction and increased potency in 3D microtissue. The structure-activity relationship analysis highlighted the importance of para-substituents in enhancing the efficacy of the compounds.
Chagas disease, a chronic and silent disease caused by Trypanosoma cruzi, is currently a global public health problem. The treatment of this neglected disease relies on benznidazole and nifurtimox, two nitroheterocyclic drugs that show limited efficacy and severe side effects. The failure of potential drug candidates in Chagas disease clinical trials highlighted the urgent need to identify new effective chemical entities and more predictive tools to improve translational success in the drug development pipeline. In this study, we designed a small library of pyrazole derivatives (44 analogs) based on a hit compound, previously identified as a T. cruzi cysteine protease inhibitor. The in vitro phenotypic screening revealed compounds 3g, 3j, and 3m as promising candidates, with IC50 values of 6.09 +/- 0.52, 2.75 +/- 0.62, and 3.58 +/- 0.25 mu M, respectively, against intracellular amastigotes. All pyrazole derivatives have good oral bioavailability prediction. The structure-activity relationship (SAR) analysis revealed increased potency of 1-aryl-1H-pyrazole-imidazoline derivatives with the Br, Cl, and methyl substituents in the para-position. The 3m compound stands out for its trypanocidal efficacy in 3D microtissue, which mimics tissue microarchitecture and physiology, and abolishment of parasite recrudescence in vitro. Our findings encourage the progression of the promising candidate for preclinical in vivo studies.
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