Síntese e avaliação das atividades citotóxica e antiparasitárias de novos derivados híbridos isoxazolina aza-bicíclica/tiazol e derivados di-aril isoxazóis ; Synthèse et évaluation des activités anticancéreuses et antiparasitaires de nouveaux dérivés hybrides isoxazolines azabicycliques/thiazoles et dérivés diaryl-isoxazoles

Isoxazoles and derivatives are heterocyclics of great relevance in medicinal chemistry, as they have activities such as anti-inflammatory, anticancer and antiparasitic, and in commercial drugs. Another heterocycle of great interest is thiazole, which has shown important anticancer and leishmanicidal activities, and these activities are potentiated by hydrazones and hydrazides, generated in the formation of thiazole nucleus. In our Research Group (LASOF), the 2-isoxazoline aza-bicyclic nucleus was developed having been applied to obtain several derivatives, among which 2-isoxazoline/ hydrazone has shown promising antichagasic activity. Within the CAPES / COFECUB cooperation, the research group IICiMed - IRS2, from the University of Nantes, has great expertise in the synthesis of heterocyclic compounds that inhibit the enzyme LmCK1, an excellent target in the research of leishmanicidal activity. Therefore, the objective of this work was the synthesis, elucidation and evaluation of cytotoxic and antiparasitic activities of new 2-isoxazoline-aza-bicyclic/thiazole hybrids and that of the new diaryl-isoxazole heterocyclic compound. The methodology of synthesis applied to obtain the hybrids was cycloaddition 1,3 dipolar between nitrile oxides CEFNO (dipole) with different endocyclic enamides (dipolarophil) and subsequent cyclization of thiosemicarbazones to form the thiazole nucleus. For the formation of the diaryl-isoxazole nucleus, the 1,3-dipolar cycloaddition of CEFNO with acetylenes was performed, as well as the cyclization of -keto-enol with ammonium hydroxide, which enabled the formation of the final compound with modifications to the C3 ester to obtain amino derivatives. Therefore, two distinct series were synthesized in this work, new 2-isoxazoline-aza-bicycle/thiazole hybrids and the new diryl-isoxazole heterocyclic compounds were synthesized and elucidated by spectroscopy (1H and 13C NMR, FT-IR and masses) and their physicochemical characteristics were determined. In the assay of cytotoxic activity, two ...