Planification, synthèse et activité tripanocide et leishmanicide de nouveaux dérivés hybrides à partir de 2-isoxazoline aza-bicyclique et 5,6,7,8-tétrahydroimidazo[1,2-a]pyrazine

Planification, synthèse et activité tripanocide et leishmanicide de nouveaux dérivés hybrides à partir de 2-isoxazoline aza-bicyclique et 5,6,7,8-tétrahydroimidazo[1,2-a]pyrazine Neglected diseases reach millions of people around the world. Among these are Chagas disease and Leishmaniasis. Chagas disease is caused by a protozoan, the Trypanosoma cruzi and its main form of transmission is through the faeces of the insect commonly known as barber. Leishmaniasis can be caused by more than 20 types of parasites of the genus Leishmania and there are 3 types of the disease, Cutaneous Leishmaniasis, Cutaneous-Mucous or Tegumentary Leishmaniasis, and Visceral Leishmaniasis. For the treatment of these diseases numerous problems exist, such as the large amount of side effects, low activity in the chronic phase of the disease, route of administration and appearance of resistant strains. The literature describes good biological results of 2-isoxazoline, imidazo[1,2-a]pyrazine, thiazolidine-2,4-dione, thiazolidinone and thiosemicarbazone nuclei with numerous important biological activities, including antiparasitic activity. In view of these results two series of novel hybrid molecules, 2-isoxazoline azabicyclic / thiazolidine-2,4-dione and the 5,6,7,8- tetrahydroimidazo[1,2-a]pyrazine / thiosemicarbazone, 5,6,7,8-tetrahydroimidazo[1,2- a]pyrazine / thiazolidinone and 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine / thiazolidine- 2,4-dione series were obtained through molecular hybridization. The central nucleus of the azabicyclic 2-isoxazoline series was synthesized from 1,3-dipolar cycloaddition between encyclic endocyclic enamides and Carboethoxiformonitrile Oxide (CEFNO). The isoxazoline esters were obtained and then reduced to the respective alcohols by NaBH4 and from these the isoxazoline aldehydes were synthesized by the Swern oxidation. In parallel, the thiazolidine-2,4-dione was synthesized, as well as its derivatives. To obtain the final hybrid molecules, Knoevenagel was condensed between the isoxazoline aldehydes and the thiazolidines-2,4-diones. The central nucleus of the 5,6,78-tetrahydroimidazo[1,2-a]pyrazine series was synthesized having the 2-aminopyrazine as the starting material. This series should model in positions 2 and 3 of the central nucleus. In a manner similar to the 2-isoxazoline series, an ester was obtained and then it was reduced to the respective alcohol which was then oxidized by MnO2 to the respective aldehyde. From these aldehydes, different reactions were performed to obtain the hybrid derivatives of the series. All the final molecules obtained were characterized by spectrophotometric methods (1H and 13C NMR, IR-ATR and masses) and had their physicochemical characteristics determined. The two series of molecules had the antiparasitic activity determined against the parasites Trypanosoma cruzi, Leishmania amazonensis, Leishmania infantum and Leishmania major, as well as, their cytotoxicity was determined in macrophages and HeLa cells. The molecules of the azabicyclic 2-isoxazoline series showed anti- Leishmania activity for both species tested, being more effective against L. major. The molecules of the series 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine were not active for any of the Leishmania species tested. Some molecules from both series showed promising results in view of the evolutionary forms of the parasite T. cruzi. The majority of the molecules being inactive or with an IC50 higher than benzinidazole in amastigote form.