Aplicación de la química supramolecular para el diseño y experimentación en modelo murino de compuestos con actividad tripanocida
- Martin, Ruben
- Manuel Sánchez Moreno Director
- Clotilde Marín Sánchez Director
Defence university: Universidad de Granada
Fecha de defensa: 29 July 2020
Type: Thesis
Abstract
In summary, we identified that compounds 4 and 7 showed better trypanocidal properties in vitro than BZN, with higher activity, a larger spectrum of action and lower toxicity. With respect to in vivo activity, the treatment with compound 7 obtained promising results to fight CD, both in the acute and chronic phases, as indicated by the different assays, such as PCR or IS. Studies conducted in parallel to try to determine the mechanism of action suggest that compound 4 can carry out its effect by inhibiting the enzymes PK or PPDK of the glycosome. As for compound 7, we suggest that its trypanocidal effect is due to the significant depolarisation of the mitochondrial membrane, which causes an energetic deficit and induces T. cruzi cell death by necrosis in a mitochondrion-dependent manner, without forgetting its possible effect as an inhibitor of lipid biosynthesis of the parasite. It is worth considering higher doses and combined therapies (due to their different mechanisms of action) to obtain better efficacy, even improving the pharmacokinetics of both compounds. Therefore, we present candidate molecules for the development of an easy-to-synthesise anti-Chagas agent to be implemented in a further step within the preclinical phase.