Bioactivity of Novel Pyrazole-Thiazolines Scaffolds against <i>Trypanosoma cruzi</i>: Computational Approaches and 3D Spheroid Model on Drug Discovery for Chagas Disease
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 deve...
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-05-01
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| Series: | Pharmaceutics |
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| Online Access: | https://www.mdpi.com/1999-4923/14/5/995 |
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| author | Leonardo da Silva Lara Guilherme Curty Lechuga Lorraine Martins Rocha Orlando Byanca Silva Ferreira Bernardo Araújo Souto Maurício Silva dos Santos Mirian Claudia de Souza Pereira |
| author_facet | Leonardo da Silva Lara Guilherme Curty Lechuga Lorraine Martins Rocha Orlando Byanca Silva Ferreira Bernardo Araújo Souto Maurício Silva dos Santos Mirian Claudia de Souza Pereira |
| author_sort | Leonardo da Silva Lara |
| collection | DOAJ |
| description | 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 <i>Trypanosoma cruzi</i>, 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-aminopyrazole-imidazoline previously identified, using structure–activity relationship exploration, and computational and phenotype-based strategies. Promising candidates, <b>2c</b>, <b>2e</b>, and <b>2i</b> derivatives, showed good oral bioavailability and ADMET properties, and low cytotoxicity (CC<sub>50</sub> > 100 µM) besides potent activity against trypomastigotes (0.4–2.1 µM) compared to Bz (19.6 ± 2.3 µM). Among them, <b>2c</b> also stands out, with greater potency against intracellular amastigotes (pIC<sub>50</sub> = 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. |
| first_indexed | 2024-03-10T03:07:44Z |
| format | Article |
| id | doaj.art-9e3904bc717a4009ae4d12ad916c1875 |
| institution | Directory Open Access Journal |
| issn | 1999-4923 |
| language | English |
| last_indexed | 2024-03-10T03:07:44Z |
| publishDate | 2022-05-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceutics |
| spelling | doaj.art-9e3904bc717a4009ae4d12ad916c18752023-11-23T12:37:49ZengMDPI AGPharmaceutics1999-49232022-05-0114599510.3390/pharmaceutics14050995Bioactivity of Novel Pyrazole-Thiazolines Scaffolds against <i>Trypanosoma cruzi</i>: Computational Approaches and 3D Spheroid Model on Drug Discovery for Chagas DiseaseLeonardo da Silva Lara0Guilherme Curty Lechuga1Lorraine Martins Rocha Orlando2Byanca Silva Ferreira3Bernardo Araújo Souto4Maurício Silva dos Santos5Mirian Claudia de Souza Pereira6Laboratório de Ultraestrutura Celular, Instituto Oswaldo Cruz, Fiocruz, Av. Brasil 4365, Manguinhos, Rio de Janeiro 21040-900, BrazilLaboratório de Ultraestrutura Celular, Instituto Oswaldo Cruz, Fiocruz, Av. Brasil 4365, Manguinhos, Rio de Janeiro 21040-900, BrazilLaboratório de Ultraestrutura Celular, Instituto Oswaldo Cruz, Fiocruz, Av. Brasil 4365, Manguinhos, Rio de Janeiro 21040-900, BrazilLaboratório de Síntese de Sistemas Heterocíclicos (LaSSH), Instituto de Física e Química, Universidade Federal de Itajubá, Avenida BPS, 1303, Pinheirinho, Itajubá 37500-903, BrazilLaboratório de Síntese de Sistemas Heterocíclicos (LaSSH), Instituto de Física e Química, Universidade Federal de Itajubá, Avenida BPS, 1303, Pinheirinho, Itajubá 37500-903, BrazilLaboratório de Síntese de Sistemas Heterocíclicos (LaSSH), Instituto de Física e Química, Universidade Federal de Itajubá, Avenida BPS, 1303, Pinheirinho, Itajubá 37500-903, BrazilLaboratório de Ultraestrutura Celular, Instituto Oswaldo Cruz, Fiocruz, Av. Brasil 4365, Manguinhos, Rio de Janeiro 21040-900, BrazilChagas 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 <i>Trypanosoma cruzi</i>, 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-aminopyrazole-imidazoline previously identified, using structure–activity relationship exploration, and computational and phenotype-based strategies. Promising candidates, <b>2c</b>, <b>2e</b>, and <b>2i</b> derivatives, showed good oral bioavailability and ADMET properties, and low cytotoxicity (CC<sub>50</sub> > 100 µM) besides potent activity against trypomastigotes (0.4–2.1 µM) compared to Bz (19.6 ± 2.3 µM). Among them, <b>2c</b> also stands out, with greater potency against intracellular amastigotes (pIC<sub>50</sub> = 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.https://www.mdpi.com/1999-4923/14/5/995<i>Trypanosoma cruzi</i>pyrazolethiazolinechemotherapyChagas disease |
| spellingShingle | Leonardo da Silva Lara Guilherme Curty Lechuga Lorraine Martins Rocha Orlando Byanca Silva Ferreira Bernardo Araújo Souto Maurício Silva dos Santos Mirian Claudia de Souza Pereira Bioactivity of Novel Pyrazole-Thiazolines Scaffolds against <i>Trypanosoma cruzi</i>: Computational Approaches and 3D Spheroid Model on Drug Discovery for Chagas Disease Pharmaceutics <i>Trypanosoma cruzi</i> pyrazole thiazoline chemotherapy Chagas disease |
| title | Bioactivity of Novel Pyrazole-Thiazolines Scaffolds against <i>Trypanosoma cruzi</i>: Computational Approaches and 3D Spheroid Model on Drug Discovery for Chagas Disease |
| title_full | Bioactivity of Novel Pyrazole-Thiazolines Scaffolds against <i>Trypanosoma cruzi</i>: Computational Approaches and 3D Spheroid Model on Drug Discovery for Chagas Disease |
| title_fullStr | Bioactivity of Novel Pyrazole-Thiazolines Scaffolds against <i>Trypanosoma cruzi</i>: Computational Approaches and 3D Spheroid Model on Drug Discovery for Chagas Disease |
| title_full_unstemmed | Bioactivity of Novel Pyrazole-Thiazolines Scaffolds against <i>Trypanosoma cruzi</i>: Computational Approaches and 3D Spheroid Model on Drug Discovery for Chagas Disease |
| title_short | Bioactivity of Novel Pyrazole-Thiazolines Scaffolds against <i>Trypanosoma cruzi</i>: Computational Approaches and 3D Spheroid Model on Drug Discovery for Chagas Disease |
| title_sort | bioactivity of novel pyrazole thiazolines scaffolds against i trypanosoma cruzi i computational approaches and 3d spheroid model on drug discovery for chagas disease |
| topic | <i>Trypanosoma cruzi</i> pyrazole thiazoline chemotherapy Chagas disease |
| url | https://www.mdpi.com/1999-4923/14/5/995 |
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