Antitrypanosomal Activity of 1,2,3-Triazole-Based Hybrids Evaluated Using In Vitro Preclinical Translational Models
Chagas disease therapy still relies on two nitroderivatives, nifurtimox and benznidazole (Bz), which have important limitations and serious adverse effects. New therapeutic alternatives for this silent disease, which has become a worldwide public health problem, are essential for its control and elimination. In this study, 1,2,3-triazole analogues were evaluated for efficacy against T. cruzi. Three triazole derivatives, 1d (0.21 µM), 1f (1.23 µM), and 1g (2.28 µM), showed potent activity against trypomastigotes, reaching IC50 values 10 to 100 times greater than Bz (22.79 µM). Promising candidates are active against intracellular amastigotes (IC50 ≤ 6.20 µM). Treatment of 3D cardiac spheroids, a translational in vitro model, significantly reduced parasite load, indicating good drug diffusion and efficacy. Oral bioavailability was predicted for triazole derivatives. Although infection was significantly reduced without drug pressure in a washout assay, the triazole derivatives did not inhibit parasite resurgence. An isobologram analysis revealed an additive interaction when 1,2,3-triazole analogs and Bz were combined in vitro. These data indicate a strengthened potential of the triazole scaffold and encourage optimization based on an analysis of the structure-activity relationship aimed at identifying new compounds potentially active against T. cruzi.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:12 |
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| Enthalten in: |
Biology - 12(2023), 9 vom: 08. Sept. |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Orlando, Lorraine Martins Rocha [VerfasserIn] |
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| Links: |
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| Themen: |
Chagas disease |
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| Anmerkungen: |
Date Revised 03.10.2023 published: Electronic Citation Status PubMed-not-MEDLINE |
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| doi: |
10.3390/biology12091222 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM362558876 |
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| 520 | |a Chagas disease therapy still relies on two nitroderivatives, nifurtimox and benznidazole (Bz), which have important limitations and serious adverse effects. New therapeutic alternatives for this silent disease, which has become a worldwide public health problem, are essential for its control and elimination. In this study, 1,2,3-triazole analogues were evaluated for efficacy against T. cruzi. Three triazole derivatives, 1d (0.21 µM), 1f (1.23 µM), and 1g (2.28 µM), showed potent activity against trypomastigotes, reaching IC50 values 10 to 100 times greater than Bz (22.79 µM). Promising candidates are active against intracellular amastigotes (IC50 ≤ 6.20 µM). Treatment of 3D cardiac spheroids, a translational in vitro model, significantly reduced parasite load, indicating good drug diffusion and efficacy. Oral bioavailability was predicted for triazole derivatives. Although infection was significantly reduced without drug pressure in a washout assay, the triazole derivatives did not inhibit parasite resurgence. An isobologram analysis revealed an additive interaction when 1,2,3-triazole analogs and Bz were combined in vitro. These data indicate a strengthened potential of the triazole scaffold and encourage optimization based on an analysis of the structure-activity relationship aimed at identifying new compounds potentially active against T. cruzi | ||
| 650 | 4 | |a Journal Article | |
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| 650 | 4 | |a drug candidates | |
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| 700 | 1 | |a Lara, Leonardo da Silva |e verfasserin |4 aut | |
| 700 | 1 | |a Lechuga, Guilherme Curty |e verfasserin |4 aut | |
| 700 | 1 | |a Rodrigues, Giseli Capaci |e verfasserin |4 aut | |
| 700 | 1 | |a Pandoli, Omar Ginoble |e verfasserin |4 aut | |
| 700 | 1 | |a de Sá, Druval Santos |e verfasserin |4 aut | |
| 700 | 1 | |a Pereira, Mirian Claudia de Souza |e verfasserin |4 aut | |
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