| Author | Lara, Leonardo da Silva | |
| Author | Lechuga, Guilherme Curty | |
| Author | Orlando, Lorraine Martins Rocha | |
| Author | Ferreira, Byanca Silva | |
| Author | Souto, Bernardo Araújo | |
| Author | Santos, Maurício Silva dos | |
| Author | Pereira, Mirian Claudia de Souza | |
| Access date | 2022-05-09T14:55:25Z | |
| Available date | 2022-05-09T14:55:25Z | |
| Document date | 2022 | |
| Citation | LARA, Leonardo da Silva et al. Bioactivity of Novel Pyrazole-Thiazolines Scaffolds against Trypanosoma cruzi: Computational Approaches and 3D Spheroid Model on Drug Discovery for Chagas Disease. Pharmaceutics, v. 24, 995, p. 1 - 22, May 2022. | pt_BR |
| ISSN | 1499-9923 | pt_BR |
| URI | https://www.arca.fiocruz.br/handle/icict/52588 | |
| Language | eng | pt_BR |
| Publisher | MDPI | pt_BR |
| Rights | open access | |
| Subject in Portuguese | Trypanosoma cruzi | pt_BR |
| Subject in Portuguese | Doença de Chagas | pt_BR |
| Subject in Portuguese | Pirazol | pt_BR |
| Subject in Portuguese | Quimioterapia | pt_BR |
| Subject in Portuguese | Tiazolina | pt_BR |
| Title | Bioactivity of Novel Pyrazole-Thiazolines Scaffolds against Trypanosoma cruzi: Computational Approaches and 3D Spheroid Model on Drug Discovery for Chagas Disease | pt_BR |
| Type | Article | |
| DOI | 10.3390/pharmaceutics14050995 | |
| Abstract | Chagas disease, a century-old disease that mainly affects the impoverished population in
Latin America, causes high morbidity and mortality in endemic countries. The available drugs, benznidazole
(Bz) and nifurtimox, have limited effectiveness and intense side effects. Drug repurposing,
and the development of new chemical entities with potent activity against Trypanosoma cruzi, are a
potential source of therapeutic options. The present study describes the biological activity of two
new series of pyrazole-thiazoline derivatives, based on optimization of a hit system 5-aminopyrazoleimidazoline
previously identified, using structure–activity relationship exploration, and computational
and phenotype-based strategies. Promising candidates, 2c, 2e, and 2i derivatives, showed
good oral bioavailability and ADMET properties, and low cytotoxicity (CC50 > 100 M) besides
potent activity against trypomastigotes (0.4–2.1 M) compared to Bz (19.6 2.3 M). Among them,
2c also stands out, with greater potency against intracellular amastigotes (pIC50 = 5.85). The selected
pyrazole-thiazoline derivatives showed good permeability and effectiveness in the 3D spheroids
system, but did not sustain parasite clearance in a washout assay. The compounds’ mechanism of
action is still unknown, since the treatment neither increased reactive oxygen species, nor reduced
cysteine protease activity. This new scaffold will be targeted to optimize in order to enhance its
biological activity to identify new drug candidates for Chagas disease therapy. | pt_BR |
| Affilliation | Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Ultraestrutura Celular. Rio de Janeiro, RJ, Brasil. | pt_BR |
| Affilliation | Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Ultraestrutura Celular. Rio de Janeiro, RJ, Brasil. | pt_BR |
| Affilliation | Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Ultraestrutura Celular. Rio de Janeiro, RJ, Brasil. | pt_BR |
| Affilliation | Universidade Federal de Itajubá. Instituto de Física e Química. Laboratório de Síntese de Sistemas Heterocíclicos. Itajubá, MG, Brasil. | pt_BR |
| Affilliation | Universidade Federal de Itajubá. Instituto de Física e Química. Laboratório de Síntese de Sistemas Heterocíclicos. Itajubá, MG, Brasil. | pt_BR |
| Affilliation | Universidade Federal de Itajubá. Instituto de Física e Química. Laboratório de Síntese de Sistemas Heterocíclicos. Itajubá, MG, Brasil. | pt_BR |
| Affilliation | Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Ultraestrutura Celular. Rio de Janeiro, RJ, Brasil. | pt_BR |
| Subject | Trypanosoma cruzi | pt_BR |
| Subject | Pyrazole | pt_BR |
| Subject | Thiazoline | pt_BR |
| Subject | Chemotherapy | pt_BR |
| Subject | Chagas disease | pt_BR |
| xmlui.metadata.dc.subject.ods | 03 Saúde e Bem-Estar | |
