Síntese de inibidores potenciais de fosfofrutoquinase de Trypanosoma brucei derivados de 2,5-anidro-D-manitol

Abstract

Trypanosoma brucei is the etiologic agent of the sleeping sickness (human african trypanosomiasis), which is an endemic disease in regions of Africa, and that has limited treatment options of high toxicity and worsened by the development of resistance against the available drugs. A new target that has been studied for the treatment of T. brucei infections is the glycolytic enzyme phosphofructokinase, which possess a significant difference in relation to the human analogue and is essential to the parasite survival. There are reported phosphofructokinase inhibitors derived from 2,5-anhydro-D-mannitol that show good activity in in vitro assays against T. brucei (EC50 ranging between 30 and 35 µM). Based on these inhibitiors, a series of disymmetric analogues substituted in C-1 and C-6 with 3,4dichlorobenzamido, 3,4-dichlolobenzylamino or 4-toluenesulfonamido groups was planned and synthesized. Other asymmetric analogues substituted in C-1 with a 3,4dichlorobenzamido group and in C-6 with a 3,4-dichlorobenzylamino or cycloheptylamino group were also prepared. Among intermediates and final products, 28 substances were obtained, 10 unpublished, in mostly moderate to good yields. The compounds prepared will be used in biological assays for evaluation of their potential trypanocidal activity.