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L'origine des pharmacopées traditionnelles L'élaboration des pharmacopées Les médicaments du XXIe siècle Comment les connaissances des savoirs thérapeutiques se sont-elles transmises au travers des différentes cultures ? Cet ouvrage innovant, qui réunit les travaux présentés au 4e Congrès européen d'ethnopharmacologie, fait remonter à la préhistoire les sources des connaissances thérapeutiques. Si les pharmacopées écrites jalonnent l'histoire des grandes médecines savantes, d'autres modes d'accès à la connaissance semblent exister dans l'univers chamanique des sociétés de tradition orale ainsi que dans la façon dont les animaux malades se soignent par les plantes. L'évaluation des propriétés pharmaco-toxicologiques et chimiques des plantes d'usage traditionnel devrait par ailleurs favoriser le développement futur des médicaments à base de plantes, l'un des thèmes porteurs abordés dans cet ouvrage. Mais l'objectif de ce livre est aussi de susciter, partout dans le monde, de nouvelles thématiques de recherche dans le domaine de la préhistoire du médicament et de la compréhension de l'acquisition et de la transmission du savoir. Le développement du phytomédicament non toxique destiné à l'homme et à l'animal figure également parmi les enjeux majeurs de demain. The origin of traditional pharmacopoeias The development of pharmacopoeias The medicines of the XXIth century How have the traditional Therapeutical knowledges been transmited to the différent cultures? This innovating book containing the proceedings of the 4th European Congress of Ethnopharmacology return to prehistory the sources of fherapeutical knowledge and asks how the animals cure themselves with plants. If the printing pharmacopoeias ponctuate the history of learning medicines other way of accessibility to the knowledge seems exist in the world of shaman in society with oral tradition. Ethnopharmacological evaluation of traditional médicinal plant should favour the development of phytomedicine. The purpose of this publication is also to provide dues to scientists in the whole world and help them identify new avenues for research in the field of the prehistory of drugs, for a better understanding of the way knowledge is acquired and then transmitted, and for the development of non-toxic herbal medicines for administration to human and animal beings.

Continuing with the efforts to identify new active compounds against malaria and leishmaniasis, fourteen new 3-amino-1,4-di-N-oxide quinoxaline-2-carbonitrile derivatives were synthesized and evaluated for their in vitro antimalarial and antileishmanial activity against Plasmodium falciparum Colombian FCR-3 strain and Leishmania amazonensis strain MHOM/BR/76/LTB-012A. Further computational studies to analyze graphic SAR and ADME properties were undertaken. Results indicate that compounds with one halogenous group substituted in position 6 and 7 provide an efficient approach for further development of antimalarial and antileishmanial agents. In addition, interesting ADME properties were found

Piperazine and pyrrolidine derivatives were synthesized and evaluated for their capacity to inhibit the growth of Plasmodium falciparum chloroquine-resistant (FCR-3) strain in culture. The combined presence of a hydroxyl group, a propane chain and a fluor were shown to be crucial for the antiplasmodial activity. Five compounds of the aryl-alcohol series inhibited 50% of parasite growth at doses ≤ 10 µM. The most active compound 1-(4-fluoronaphthyl)-3-[4-(4-nitro-2-trifluoromethylphenyl)piperazin-1-yl]propan-1-ol was almost 20 to 40 times more active on Plasmodium falciparum (IC50: 0.5 µM) than on tumorogenic and non tumorogenic cells. Calculated physicochemical parameters showed a good potential for intestinal absorption, but due to difficulty in being solubilised prior to oral administration, it was weakly active against Plasmodium berghei infected mice (ED50: 35%). In silico molecular docking study and molecular electrostatic potential calculation revealed that this compound bound to the active site of Plasmodium plasmepsin II enzyme.

Two series of pyrazol and propenone quinoxaline derivatives were tested for parasiticidal activity (against amastigotes of Leishmania peruviana and trypomastigotes of Trypanosoma cruzi) and for toxicity against proliferative and non-proliferative cells. The pyrazol series was almost inactive against T. cruzi but, 2,6-Dimethyl-3-[5-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-1H-pyrazol-3-yl] - quinoxaline 1,4-dioxide inhibited 50% of Leishmania growth at 8.9 µM with no impact against proliferative kidney cells and low toxicity against Thp-1 and murine macrophages. The compounds of the propenone series were moderately active against T. cruzi. Among them, 2 compounds were particularly interesting: (2E)-1-(7-Fluoro-3-methyl-quinoxalin-2-yl)-3-(3,4,5-trimethoxy-phenyl)-propenone, that showed a selective activity against proliferative cells (cancer and parasites), being inactive against normal murine peritoneal macrophages and (2E)-3-(3,4,5-Trimethoxy-phenyl)-1-(3,6,7-trimethyl-quinoxalin-2-yl)-propenone that was only active against Leishmania and inactive against the other tested cells. Furthermore in silico studies were performed for ADME properties and docking studies, both series of compounds respected the Lipinski’s rules and show linear correlation between tripanosomaticidal activities and LogP. Docking studies revealed that compounds of the second series could interact with the poly (ADP-ribose) polymerase protein of Trypanosoma cruzi.