Activity of P536, a UDP-glucose analog, against Trypanosoma cruzi.

P536, a UDP-glucose analog which was previously described as an antiviral agent (M. J. Camaraza, P. Fernández Resa, M. T. García López, F. G. de las Heras, P. P. Mendez-Castrillón, B. Alarcón, and L. Carrasco, J. Med. Chem. 28:40-46, 1985), has a potent and selective activity against the intracellular and extracellular stages of Trypanosoma cruzi in vitro. It had a 50% inhibitory concentration of less than 5 micrograms/ml for T. cruzi extracellular cultured forms (epimastigote) and of 25 micrograms/ml for T. cruzi intracellular forms (amastigote) growing inside J774G8 macrophagelike cells. In contrast, the 50% inhibitory concentration was 100 micrograms/ml or greater for cultured mammalian cells and 180 micrograms/ml for the proliferation of mouse spleen lymphocytes. Furthermore, the addition of P536 (50 micrograms/ml) to T. cruzi-infected J774G8 cells cured the infected macrophages, making them able to grow and function normally. Studies on the mechanism of action of this drug indicated that it inhibited incorporation of [35S]methionine, [3H]thymidine, [3H]mannose, [14C]-N-acetylglucosamine, and [3H]uridine into macromolecules by T. cruzi epimastigotes, the last being the most sensitive.