Mechanisms of action of pyrazolopyrimidines in Leishmania donovani.
We investigated the antileishmanial actions of the pyrazolopyrimidines allopurinol (4-hydroxypyrazolo[3,4-d]pyrimidine), thiopurinol (4-thiopyrazolo[3,4-d]pyrimidine), and aminopurinol (4-aminopyrazolo[3,4-d]pyrimidine). These compounds affect several metabolic processes. The first is the inhibition of GMP reductase by the IMP analogues allopurinol ribonucleoside monophosphate and thipurinol ribonucleoside monophosphate which reduces the organism's ability to synthesize ATP from guanine. Second, interconversion of adenine nucleotides to guanine nucleotides, is curtailed by the inhibition of IMP dehydrogenase by these same IMP analogues. Third, the IMP analogues reduce intracellular UTP content. The fourth affect is increased catabolism of RNA and consequent reduction of protein synthesis. This latter effect is due to the adenine nucleotide analogues aminopurinol ribonucleoside mono-, di-, and/or triphosphates, metabolic products of both allopurinol and aminopurinol.
D000225:Adenine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000096:biosynthesis; D000493:Allopurinol / Q000031:analogs & derivatives* / Q000494:pharmacology*; D000818:Animals; D050899:GMP Reductase; D007168:IMP Dehydrogenase / Q000037:antagonists & inhibitors; D007893:Leishmania donovani / Q000187:drug effects* / Q000378:metabolism; D009247:NADH, NADPH Oxidoreductases / Q000037:antagonists & inhibitors; D014176:Protein Biosynthesis; D011685:Purine Nucleotides / Q000378:metabolism; D012313:RNA / Q000378:metabolism; D012263:Ribonucleosides / Q000494:pharmacology; D012265:Ribonucleotides / Q000494:pharmacology; D013872:Thionucleosides / Q000494:pharmacology; D013873:Thionucleotides / Q000494:pharmacology; D014544:Uridine Triphosphate / Q000378:metabolism
D011685:Purine Nucleotides; D012263:Ribonucleosides; D012265:Ribonucleotides; D013872:Thionucleosides; D013873:Thionucleotides; C004420:4-aminopyrazolo(3,4-d)pyrimidine; C041404:allopurinol riboside 5'-monophosphate; C033494:thiopurinol ribonucleoside; D012313:RNA; D000493:Allopurinol; C005832:tisopurine; C048828:thiopurinol ribonucleoside monophosphate; D000255:Adenosine Triphosphate; D007168:IMP Dehydrogenase; D009247:NADH, NADPH Oxidoreductases; D050899:GMP Reductase; D000225:Adenine; D014544:Uridine Triphosphate; C021958:allopurinol riboside