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. 1987 Mar;31(3):447–451. doi: 10.1128/aac.31.3.447

Biological activity of analogs of guanine and guanosine against American Trypanosoma and Leishmania spp.

J L Avila, T Rojas, A Avila, M A Polegre, R K Robins
PMCID: PMC174749  PMID: 3107463

Abstract

The growth inhibitory effects of six guanine and guanosine analogs, 3-deazaguanine (compound 1); 3-deazaguanosine (compound 2); 6-aminoallopurinol (compound 3); 9-beta-xylofuranosyl guanine (compound 4); a ribosylated derivative of compound 3, 6-aminopyrazolo(3,4-d)pyrimidin-4-one (compound 5); and 5-aminoformycin B (compound 6), were tested against some pathogenic members of the family of American Trypanosomatidae. Compounds 1 and 2 were highly active against Trypanosoma cruzi, Trypanosoma rangeli, and American Leishmania spp. in in vitro culture forms. Both compounds also showed antiprotozoal activity in T. cruzi-infected mice, with the optimal dose being about 30 mg/kg of body weight per day given as 10 consecutive doses. Compound 3 was the most active compound in vitro, inhibiting all of the American Trypanosomatidae culture forms tested. It was also highly inhibitory in mice that were acutely infected with T. cruzi, with the optimal dose being about 10 mg/kg of body weight per day. Ribosylation of compound 3 resulted in a derivative that showed decreased inhibitory activity on Trypanosomatidae multiplication. Compound 6 was highly inhibitory of in vitro multiplication of American Leishmania and T. rangeli but had no effect on T. cruzi epimastigotes and on mice that were acutely infected with T. cruzi. Compound 4 showed only a slight effect on T. cruzi epimastigotes.

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Selected References

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  1. Avila J. L., Avila A., Monzón H. Differences in allopurinol and 4-aminopyrazolo(3,4-d) pyrimidine metabolism in drug-sensitive and insensitive strains of Trypanosoma cruzi. Mol Biochem Parasitol. 1984 Apr;11:51–60. doi: 10.1016/0166-6851(84)90054-9. [DOI] [PubMed] [Google Scholar]
  2. Avila J. L., Avila A., Muñoz E. Effect of allopurinol on different strains of Trypanosoma cruzi. Am J Trop Med Hyg. 1981 Jul;30(4):769–774. doi: 10.4269/ajtmh.1981.30.769. [DOI] [PubMed] [Google Scholar]
  3. Avila J. L., Avila A., Muñoz E., Monzón H. Trypanosoma cruzi: 4-aminopyrazolopyrimidine in the treatment of experimental Chagas' disease. Exp Parasitol. 1983 Oct;56(2):236–240. doi: 10.1016/0014-4894(83)90067-x. [DOI] [PubMed] [Google Scholar]
  4. Avila J. L., Avila A. Trypanosoma cruzi: allopurinol in the treatment of mice with experimental acute Chagas disease. Exp Parasitol. 1981 Apr;51(2):204–208. doi: 10.1016/0014-4894(81)90109-0. [DOI] [PubMed] [Google Scholar]
  5. Avila J. L., Avila A., de Casanova M. A. Differential metabolism of allopurinol and derivatives in Trypanosoma rangeli and T. cruzi culture forms. Mol Biochem Parasitol. 1981 Dec 31;4(5-6):265–272. doi: 10.1016/0166-6851(81)90059-1. [DOI] [PubMed] [Google Scholar]
  6. Avila J. L., Bretaña A., Casanova M. A., Avila A., Rodríguez F. Trypanosoma cruzi: defined medium for continuous cultivation of virulent parasites. Exp Parasitol. 1979 Aug;48(1):27–35. doi: 10.1016/0014-4894(79)90051-1. [DOI] [PubMed] [Google Scholar]
  7. Avila J. L., Casanova M. A. Comparative effects of 4-aminopyrazolopyrimidine, its 2'-deoxyriboside derivative, and allopurinol on in vitro growth of American Leishmania species. Antimicrob Agents Chemother. 1982 Sep;22(3):380–385. doi: 10.1128/aac.22.3.380. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Avila J. L., Polegre M. A., Avila A., Robins R. K. Action of pyrazolopyrimidine derivatives on American Leishmania spp. promastigotes. Comp Biochem Physiol C. 1986;83(2):285–289. doi: 10.1016/0742-8413(86)90124-6. [DOI] [PubMed] [Google Scholar]
  9. Avila J. L., Polegre M. A., Robins R. K. Action of pyrazolopyrimidine derivatives on Trypanosoma rangeli culture forms. Comp Biochem Physiol C. 1986;83(2):291–294. doi: 10.1016/0742-8413(86)90125-8. [DOI] [PubMed] [Google Scholar]
  10. Berens R. L., Marr J. J., LaFon S. W., Nelson D. J. Purine metabolism in Trypanosoma cruzi. Mol Biochem Parasitol. 1981 Jul;3(3):187–196. doi: 10.1016/0166-6851(81)90049-9. [DOI] [PubMed] [Google Scholar]
  11. Berman J. D., Lee L. S., Robins R. K., Revankar G. R. Activity of purine analogs against Leishmania tropica within human macrophages in vitro. Antimicrob Agents Chemother. 1983 Aug;24(2):233–236. doi: 10.1128/aac.24.2.233. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Berman J. D., Webster H. K. In vitro effects of mycophenolic acid and allopurinol against Leishmania tropica in human macrophages. Antimicrob Agents Chemother. 1982 Jun;21(6):887–891. doi: 10.1128/aac.21.6.887. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Cook P. D., Rousseau R. J., Mian A. M., Dea P., Meyer R. B., Jr, Robins R. K. Synthesis of 3-deazaguanine, 3-deazaguanosine, and 3-deazaguanylic acid by a novel ring closure of imidazole precursors. J Am Chem Soc. 1976 Mar 17;98(6):1492–1498. doi: 10.1021/ja00422a036. [DOI] [PubMed] [Google Scholar]
  14. Fish W. R., Looker D. L., Marr J. J., Berens R. L. Purine metabolism in the bloodstream forms of Trypanosoma gambiense and Trypanosoma rhodesiense. Biochim Biophys Acta. 1982 Nov 24;719(2):223–231. doi: 10.1016/0304-4165(82)90092-7. [DOI] [PubMed] [Google Scholar]
  15. Hassan H. F., Coombs G. H. Leishmania mexicana: purine-metabolizing enzymes of amastigotes and promastigotes. Exp Parasitol. 1985 Apr;59(2):139–150. doi: 10.1016/0014-4894(85)90066-9. [DOI] [PubMed] [Google Scholar]
  16. Marr J. J., Berens R. L., Cohn N. K., Nelson D. J., Klein R. S. Biological action of inosine analogs in Leishmania and Trypanosoma spp. Antimicrob Agents Chemother. 1984 Feb;25(2):292–295. doi: 10.1128/aac.25.2.292. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Marr J. J., Berens R. L., Nelson D. J. Purine metabolism in Leishmania donovani and Leishmania braziliensis. Biochim Biophys Acta. 1978 Dec 1;544(2):360–371. doi: 10.1016/0304-4165(78)90104-6. [DOI] [PubMed] [Google Scholar]
  18. Marr J. J., Berens R. L. Pyrazolopyrimidine metabolism in the pathogenic trypanosomatidae. Mol Biochem Parasitol. 1983 Apr;7(4):339–356. doi: 10.1016/0166-6851(83)90016-6. [DOI] [PubMed] [Google Scholar]
  19. McCabe R. E., Remington J. S., Araujo F. G. In vitro and in vivo activities of formycin B against Trypanosoma cruzi. Antimicrob Agents Chemother. 1985 Apr;27(4):491–494. doi: 10.1128/aac.27.4.491. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Miller R. L., Sabourin C. L., Krenitsky T. A., Berens R. L., Marr J. J. Nucleoside hydrolases from Trypanosoma cruzi. J Biol Chem. 1984 Apr 25;259(8):5073–5077. [PubMed] [Google Scholar]
  21. Nelson D. J., LaFon S. W., Tuttle J. V., Miller W. H., Miller R. L., Krenitsky T. A., Elion G. B., Berens R. L., Marr J. J. Allopurinol ribonucleoside as an antileishmanial agent. Biological effects, metabolism, and enzymatic phosphorylation. J Biol Chem. 1979 Nov 25;254(22):11544–11549. [PubMed] [Google Scholar]
  22. SKIPPER H. E., ROBINS R. K., THOMSON J. R., CHENG C. C., BROCKMAN R. W., SCHABEL F. M., Jr Structure-activity relationships observed on screening a series of pyrazolopyrimidines against experimental neoplasms. Cancer Res. 1957 Jul;17(6):579–596. [PubMed] [Google Scholar]
  23. Schmidt G., Walter R. D., Königk E. A purine nucleoside hydrolase from Trypanosoma gambiense, purification and properties. Tropenmed Parasitol. 1975 Mar;26(1):19–26. [PubMed] [Google Scholar]
  24. Shoemaker J. P., Hoffman R. V., Jr Effects of 8-azaguanine on the pathogenesis of experimental Chagas' disease. J Parasitol. 1969 Jun;55(3):654–659. [PubMed] [Google Scholar]
  25. Spector T., Jones T. E. Guanosine 5'-monophosphate reductase from Leishmania donovani. A possible chemotherapeutic target. Biochem Pharmacol. 1982 Dec 1;31(23):3891–3897. doi: 10.1016/0006-2952(82)90307-0. [DOI] [PubMed] [Google Scholar]
  26. Streeter D. G., Koyama H. H. Inhibition of purine nucleotide biosynthesis by 3-deazaguanine, its nucleoside and 5'-nucleotide. Biochem Pharmacol. 1976 Nov 1;25(21):2413–2415. doi: 10.1016/0006-2952(76)90041-1. [DOI] [PubMed] [Google Scholar]

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