Effect of allopurinol on Trypanosoma cruzi: metabolism and biological activity in intracellular and bloodstream forms

Berens, Randolph L.; Marr, J. Joseph; Cruz, Fátima; Nelson, Donald J.

doi:10.1128/aac.22.4.657

Cited by 43 publications

(27 citation statements)

References 15 publications

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“…The prototype of this class of compounds is allopurinol (4-hydroxypyrazolo [3,4-d]pyrimidine), which was the first such compound shown to be active against leishmania (14,21,25) and subsequently against Trypanosoma cruzi (1,16) and the African trypanosomes (15). Further investigation demonstrated that the ribonucleosides of pyrazolopyrimidines were as active as, and in some cases more active than, the corresponding bases.…”

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confidence: 99%

Biological action of inosine analogs in Leishmania and Trypanosoma spp

Marr¹,

Berens²,

Cohn³

et al. 1984

Antimicrob Agents Chemother

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Previous investigations have suggested that inosine analogs would be good models for the development of chemotherapeutic agents active against pathogenic hemoflagellates. We have systematically modified the five-membered heterocyclic ring of six inosine analogs and tested them for their antiprotozoal activities and toxicity to a mammalian cell line. All six analogs were very active against the three protozoan pathogens Leishmania donovani, Trypanosoma cruzi, and Trypanosoma gambiense. Two of the six, 9-deazainosine and allopurinql ribonucleoside, had very little toxicity for mouse L cells and offer promise as potential chemotherapeutic agents.Purine metabolism in the pathogenic hemoflagellates is unique jn that it can be inhibited by pyrazolopyrimidine analogs. This is due, in part, to the fact that there is no de novo synthesis (2,6,10,18,31) and, more importantly, to the fact that the enzymes of the salvage pathways will accept the pyrazolopyrimidine ring as a purine. This property of the hemoflagellate enzymes does not occur in humans (7,12,22) and, for this reason, pyrazolopyrimidines offer promise as potential chemotherapeutic agents for the management of leishmaniasis and some forms of trypanosomiasis.The prototype of this class of compounds is allopurinol (4-hydroxypyrazolo[3,4-d]pyrimidine), which was the first such compound shown to be active against leishmania (14,21,25) and subsequently against Trypanosoma cruzi (1, 16) and the African trypanosomes (15). Further investigation demonstrated that the ribonucleosides of pyrazolopyrimidines were as active as, and in some cases more active than, the corresponding bases. Allopurinol ribonucleoside (4-hydroxypyrazolo[3,4-d]pyrimidine ribonucleoside) (24) and 4-thiopyrazolo pyrimidine ribonucleoside (17) were the first pyrazolopyrimidine ribonucleosides demonstrated to have antileishmanial action in vitro. Subsequently, formycin B (7-hydroxypyrazolo[4,3-d]pyrimidine ribonucleoside) was shown to have antileishmanial activity (5). Its metabolism is identical to that of allopurinol ribonucleoside (23,26).Since these compounds are inosine analogs (Fig. 1), we investigated several modifications of the inosine structure to determine which features of the molecule are important for activity against leishmania and trypanosomes yet prevent toxicity to mammalian hosts. The five-membered heterocyclic ring was chosen for modification since both the 3,4-d (allopurinol and thiopurinol ribonucleoside) and the 4,3-d (formycin B) configuration of the pyrazolopyrimidine ring were active against the hemoflagellates (Fig. 1).Organisms were grown as described previously (8,16,18) in the presence or absence of the compounds in question (10 ,ug/ml), and the results were expressed as a percentage of the control. Doses effective against 50% of the organisms were determined by triplicate counting of organisms in a Coulter * Corresponding author.ZBI counter and determining a mean value. Agents which inhibited growth to less than 50% of the control were tested further by titration from 1...

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mentioning

confidence: 99%

Biological action of inosine analogs in Leishmania and Trypanosoma spp

Marr¹,

Berens²,

Cohn³

et al. 1984

Antimicrob Agents Chemother

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“…Since the microorganism does not possess xanthine oxidase, allopurinol is incorrectly sensed as a purine substrate and is directly incorporated in the parasite DNA by hypoxanthine-guanine phosphorybosyltransferase, disrupting DNA-related processes. Previous assays showed the potential of the drug in arresting infection in cultured tissues 116 , and a later study with other purine and pyrimidine analogues confirmed this activity 117 . In an animal model, allopurinol was able to reduce parasite blood levels, but with mild cardiac inflammatory infiltrates at the heart.…”

Section: Purine Salvage Inhibitorsmentioning

confidence: 59%

Current and Future Chemotherapy for Chagas Disease

Gaspar¹,

Moraes²,

Freitas‐Junior³

et al. 2015

CMC

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American trypanosomiasis, commonly called Chagas disease, is one of the most neglected illnesses in the world and remains one of the most prevalent chronic infectious diseases of Latin America with thousands of new cases every year. The only treatments available have been introduced five decades ago. They have serious, undesirable side effects and disputed benefits in the chronic stage of the disease -a characteristic and debilitating cardiomyopathy and/or megavisceras. Several laboratories have therefore focused their efforts in finding better drugs. Although recent years have brought new clinical trials, these are few and lack diversity in terms of drug mechanism of action, thus resulting in a weak drug discovery pipeline. This fragility has been recently exposed by the failure of two candidates, posaconazole and E1224, to sterilely cure patients in phase 2 clinical trials. Such setbacks highlight the need for continuous, novel and high quality drug discovery and development efforts to discover better and safer treatments.In this article we will review past and current findings on drug discovery for Trypanosoma cruzi made by academic research groups, industry and other research organizations over the last half century. 2We will also analyze the current research landscape that is now better placed than ever to deliver alternative treatments for Chagas disease in the near future.

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“…However, in many countries like Mexico, both drugs are not available. Allopurinol has been reported as an agent with activity against blood trypomastigotes and amastigotes of Trypanosoma cruzi (Berens et al, 1982) but there are conflicting views about its effectiveness, as well as other pharmaceutical options used to treat the disease. Carignani et al, (2000) describes that under experimental conditions, allopurinol is not able to eliminate the presence of Trypanosoma cruzi in from infected triatomines.…”

Section: Discussionmentioning

confidence: 99%

<i>In Vivo</i> Activity of (8-Hydroxymethylen)-Trieicosanyl Acetate against <i>Trypanosoma cruzi</i> during Acute Phase of the Infection

Jiménez‐Coello

Acosta-Viana²,

G³

et al. 2011

Afr. J. Trad. Compl. Alt. Med.

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The antiprotozoal activity in vivo against Trypanosoma cruzi of (8-hydroxymethylen)-trieicosanyl acetate was evaluated in BALB/c mice during the acute phase of Chagas' disease (15 days after infection). Animals were treated during 15 days at doses of 16.8 and 33.6 µg/g, reduced parasitemia of 77.6 and 64.1% was observed respectively, in comparison with positive control mice (allopurinol 8.5 µg/g) which reduced only 29.7%. Also, amastigote nests in cardiac tissue were significant reduced in treated mice groups. The regression of effect induced after the suppression of the treatment with the compound was evaluated; animals were infected and simultaneously began the treatment with the compound during 20 days (16.8 and 33.6 µg/g). Mice were monitored after the end of the treatment for one more week. A good antitrypanosomal response was observed (66.1 and 68.9% less than untreated mice) during treatment, but 8 days after suspension of treatment, parasitemia level increased, reducing only 58.6 and 56.29 % respectively in treated animals compared with no treated. RésuméL'activité in vivo contre antiprotozoaires Trypanosoma cruzi de (8-hydroxymethylen)-acétate de trieicosanyl a été évaluée chez des souris BALB / c pendant la phase aiguë de la maladie de Chagas (15 jours après l'infection). Les animaux ont été traités pendant 15 jours à des doses de 16,8 et 33,6 mg / g, la parasitémie réduite de 77,6 et 64,1% a été observée, respectivement, en comparaison avec les souris de contrôle positif (allopurinol 8,5 mg / g), qui réduit que de 29,7%. En outre, les nids amastigote dans le tissu cardiaque ont été réduits dans les groupes importants chez les souris traitées. La régression de l'effet induit après la suppression du traitement avec le composé a été évalué, les animaux ont été infectés et, simultanément, a commencé le traitement avec le composé pendant 20 jours (16,8 et 33,6 mg / g). Les souris ont été suivis après la fin du traitement pour une semaine de plus. Une bonne réponse a été observée antitrypanosomal (66,1 et 68,9% de moins que les souris non traitées) en cours de traitement, mais 8 jours après la suspension du traitement, le niveau de la parasitémie a augmenté, réduisant seulement 58,6 et 56,29% respectivement chez les animaux traités par rapport à aucun traitement.

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Effect of allopurinol on Trypanosoma cruzi: metabolism and biological activity in intracellular and bloodstream forms

Cited by 43 publications

References 15 publications

Biological action of inosine analogs in Leishmania and Trypanosoma spp

Biological action of inosine analogs in Leishmania and Trypanosoma spp

Current and Future Chemotherapy for Chagas Disease

<i>In Vivo</i> Activity of (8-Hydroxymethylen)-Trieicosanyl Acetate against <i>Trypanosoma cruzi</i> during Acute Phase of the Infection

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