Synthesis and biological evaluation of new long-chain squaramides as anti-chagasic agents in the BALB/c mouse model
| Autor: | Carlos Silva López, Manuel Sánchez-Moreno, Antonio Costa, Encarnación Medina-Carmona, Manuel Vega, Carmen Rotger, Clotilde Marín, Rubén Martín-Escolano, Álvaro Martín-Montes |
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| Rok vydání: | 2018 |
| Předmět: |
Chagas disease
Trypanosoma cruzi Clinical Biochemistry Pharmaceutical Science Pharmacology 01 natural sciences Biochemistry Superoxide dismutase In vivo parasitic diseases Drug Discovery Chlorocebus aethiops medicine Animals Chagas Disease Cytotoxicity Nifurtimox Molecular Biology Vero Cells Membrane Potential Mitochondrial Mice Inbred BALB C biology 010405 organic chemistry Chemistry Superoxide Dismutase Organic Chemistry DNA medicine.disease biology.organism_classification Trypanocidal Agents In vitro 0104 chemical sciences 010404 medicinal & biomolecular chemistry Benznidazole Splenomegaly biology.protein Molecular Medicine RNA Female Cyclobutanes medicine.drug |
| Zdroj: | Bioorganicmedicinal chemistry. 27(5) |
| ISSN: | 1464-3391 |
| Popis: | Chagas Disease is caused by infection with the insect-transmitted protozoan Trypanosoma cruzi and affects more than 10 million people. It is a paradigmatic example of a chronic disease without an effective treatment in Latin America where the current therapies, based on Benznidazole and Nifurtimox, are characterised by limited efficacy, toxic side-effects and frequent failures in the treatment. We present a series of new long-chain squaramides, identified based on their 1H and 13C NMR spectra, and their trypanocidal activity and cytotoxicity were tested in vitro through the determination of IC50 values. Compounds 4 and 7 were more active and less toxic than the reference drug Benznidazole, and these results were the basis of promoting in vivo assays, where parasitaemia levels, assignment of cure, reactivation of parasitaemia and others parameters were determined in mice treated in both the acute and chronic phases. Finally, the mechanisms of action were elucidated at metabolic and mitochondrial levels and superoxide dismutase inhibition. The experiments allowed us to select compound 7 as a promising candidate for treating Chagas Disease, where the activity, stability and low cost make long-chain squaramides appropriate molecules for the development of an affordable anti-chagasic agent versus current treatments. |
| Databáze: | OpenAIRE |
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