New nitroaromatic candidats for trypanosomiasis therapeutics.

Abstract : African Trypanosomiasis is a neglected tropical disease, endemic in nearly 30 countries in sub-Saharan Africa. Trypanosoma brucei, the infectious agent responsible for the disease, is transmitted by the bite of Glossina (tsetse fly) and can affect both animals (AAT - Animal African Trypanosomiasis) and humans (HAT - Human African Trypanosomiasis). Without treatment, the disease is fatal. The current therapeutic care is complex and depends on trypanosome species, host and stage of the disease. Therefore, it is essential to find new treatments. In recent years, nitroaromatic compounds present a renewed interest as anti-infective agents like fexinidazole. Some studies show that their antiparasitic activity is based on their selective reduction by parasite nitroreductases (NTR). These NTR leading to metabolites that are cytotoxic for the protozoan. The objective of the study is to develop new nitroaromatic drugs efficient against Trypanosoma. Our collaboration between chemists and biologists allows to synthetize different molecules and test them on various biological models. Firstly, about 200 molecules belonging to the 8-nitroquinolin-2(1H)-one series and 3-nitroimidazo[1,2-a]pyridine series were synthetized. Secondly, in vitro evaluations were performed for all molecules on a HepG2 human cell line, and on a strain of T. b. brucei to evaluate the CC50 and IC50 respectively. In vitro pharmacokinetic tests and comet assays completed the data for the most promising molecules. The four best candidates were included in an in vivo test on a murine model of mice infected by T. b. brucei (strain AnTat 1.1E): briefly, the 4 molecules were tested to evaluate their ability to cross the blood brain barrier, their toxicity and their activity. At the end of the study, an anatomopathological analysis was performed to ensure the absence of damage on vital organs (brain, heart, kidney, liver). The finality of this project is to develop new drug candidates for human and animal therapeutic.
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Contributeur : Elisabeth Grelier <>
Soumis le : mardi 27 novembre 2018 - 16:26:09
Dernière modification le : vendredi 14 juin 2019 - 18:31:21

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  • HAL Id : hal-01936829, version 1

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Clotilde Boudot, Cyril Fersing, Julien Pedron, Valere Belle Mbou, Caroline Castera-Ducros, et al.. New nitroaromatic candidats for trypanosomiasis therapeutics.. Congress ICOPA (14th International Congress of Parasitology), Aug 2018, Daegu, South Korea. ⟨hal-01936829⟩

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