Síntese, caracterização e avaliação da atividade leishmanicida de novas dialquilfosforilidrazonas derivadas de aldeídos piridínicos

Abstract

A series of thirty-two new dialquilfosforilidrazonas derived from pyridine aldehydes were synthesized in three steps. The first involves the synthesis of different dialkylphosphonates, which are obtained by phosphorus trichloride (PCl3) reaction with three mols of the corresponding alcohol. In the second step, the reaction of dialkylphosphonates with hydrazine, in a biphasic system, leads to the formation of dialkylphosphorylhydrazines. The last step is the condensation of these dialkylphosphorylhydrazines with different pyridine aldehydes. All the obtained compounds were characterized by 1H-NMR, 13C-NMR, 31P NMR, IR and mass spectrometry techniques and presented a yield in the range of 60%. Seven groups of these synthesized compounds (8, 10, 15, 18, 21, 26 e 31) containing different pyridine rings, were analyzed by HSQC, HMBC and NOEDIF due to the difficulty in assignment of some signals related to aromatic nucleus, as well as to check the existence of corresponding diastereoisomers. The effects of the fifteen dialkylphosphorylhydrazones were evaluated in vitro in the promastigote forms of L. braziliensis and L. amazonensis and in vivo on the species L. amazonensis, highlighting the compounds (6, 10, 20, 24 and 32) in the in vitro study, for presenting activity in both species, and low citotoxicity to macrophages at a 100 μM concentration, with caveat to the compound (32) that exhibited a toxicity around 20% to the evaluated cells. The compounds (20 e 24), through the correlations mentioned before, were evaluated in vivo demonstrating a significant reduction of the skin lesion, analogue to the drug miltefosina, however, unable to reduce the parasite load in the lymphnodes.