allopurinol-riboside and Chagas-Disease

Pyrazolopyrimidines are purine analogues. These compounds are metabolized by the pathogenic hemoflagellates and other members of the family Trypanosomatidae as though they were purines. This metabolic sequence does not exist in man or other mammals. In the hemoflagellates, the pyrazolopyrimidine base, of which allopurinol is the paradigm, undergoes ribosylphosphorylation to the ribonucleotide. This ribonucleotide may remain as such or be aminated to the amino analogue and further converted to the aminopyrazolopyrimidine ribonucleoside triphosphate. The latter is incorporated into RNA. This metabolic sequence has been demonstrated in the genera Leishmania and Trypanosoma.

Topics: Allopurinol; Animals; Antiprotozoal Agents; Aotus trivirgatus; Chagas Disease; Humans; Leishmania; Leishmaniasis, Visceral; Polyribosomes; Protein Biosynthesis; Ribonucleosides; RNA; Thionucleosides; Trypanosoma; Trypanosoma cruzi; Trypanosomiasis; Trypanosomiasis, African

Chagas disease and visceral leishmaniasis are two neglected tropical diseases responsible for numerous deaths around the world. For both, current treatments are largely inadequate, resulting in a continued need for new drug discovery. As both kinetoplastid parasites are incapable of

Topics: Animals; Chagas Disease; Drug Design; Drug Stability; Humans; Leishmania infantum; Male; Mice; Microsomes, Liver; Molecular Structure; Nucleosides; Pyrazoles; Pyrimidines; Structure-Activity Relationship; Trypanocidal Agents; Trypanosoma cruzi

The anti-Trypanosoma cruzi effect of allopurinol ribonucleoside and formycin B was examined against infections of the sensitive Y and Peru strains in inbred mice, strain DBA/1. Allopurinol ribonucleoside given in the drinking water at doses calculated to be 239, 511 and 929 mg/kg/day for 28 days, prevented the death of the mice but did not eradicate the infection. Formycin B given orally at 100 and 10 mg/kg/day X 5 days, showed a similar effect.

Topics: Allopurinol; Animals; Antibiotics, Antineoplastic; Chagas Disease; Formycins; Mice; Mice, Inbred DBA; Ribonucleosides; Trypanocidal Agents

Strains of Trypanosoma cruzi differ in their susceptibilities to and metabolism of pyrazolopyrimidines. Allopurinol riboside can control but not eliminate infections with a sensitive strain in both tissue culture and mice. Formycin B, which proved to be greater than 10-fold more effective on a weight basis, showed a similar strain specificity but could eliminate an infection with a sensitive strain from tissue culture. However, this drug, unlike allopurinol riboside, was converted to toxic analogues of adenosine mono-, di-, and triphosphate by uninfected tissue culture cells. Thiopurinol and its riboside were effective against all strains unless culture was performed in purine-defined medium. Thus formycin B and allopurinol riboside appear to be good models for the design of antitrypanosomal agents. Suitable modification of the molecule may provide an effective chemotherapeutic agent.

Topics: Adenine; Allopurinol; Animals; Antiprotozoal Agents; Chagas Disease; Drug Resistance; Formycins; Inosine; Mice; Mice, Inbred DBA; Ribonucleosides; Thionucleosides; Trypanosoma cruzi