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Specific Inhibitory Effect of 3-Deazaneplanocin a against Several Leishmania mexicana and L. braziliensis Strains

The growth inhibitory effect of 3-deazaneplanocin A (c³NpcA) was tested against some pathogenic members of the family of American Trypanosomatidae. Under our culture conditions, c³NpcA displayed a strongly and uniformly leishmanistatic effect on all 23 American Leishmania (L. mexicana and L. brasiliensis) strains in the study (mean dose producing 50% inhibition compared with control parasite growth [ID₅₀] = 96 ng/ml, 0.32 µM), but showed no inhibition against the several T. cruzi and T. rangeli strains tested with concentrations up to 10,000 ng/ml. This compound also induced a substantial expansion of the intracellular pools of both S-adenosylhomocysteine (AdoHcy) and S-adenosylmethionine (AdoMet), as well as a significant diminution of the AdoMet:AdoHcy ratio. Strong AdoHcy hydrolase activity was detected in American Leishmania promastigotes. At at a dose of 200 ng/ml, c³NpcA inhibited S-adenosyl-L-³H-methylmethionine and ³-thymidine incorporation by promastigotes after four days incubation in the presence of the drug. At a dose of 100 ng/ml, c³NpcA eliminated approximately 56% of the L. mexicana and L. brasiliensis from infected human macrophages, compared with simultaneously cultivated controls. Two schedules of 10 consecutive intraperitoneal injections of c³NpcA, with doses ranging from 0.5 to 1.5 mg/kg/day, significantly reduced development of cutaneous leishmanial infection produced in inbred BALB/c mice by L. b. guyanensis inoculation, although a few parasites remained at the inoculation site.