Biological action of pyrazolopyrimidine derivatives against Trypanosoma cruzi. studies in vitro and in vivo

Avila, JoséLuis; Polegre, María Argelia; Robins, Roland K.

doi:10.1016/0742-8413(87)90143-5

Cited by 9 publications

(14 citation statements)

References 20 publications

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“…Drug activity against T. cruzi was tested with the nifurtimox-sensitive Tulahuen CL2  galactosidase strain. 56 This strain was maintained on MRC-5SV2 (human lung fibroblast) cells in MEM medium, supplemented with 200 mM L-glutamine, 16.5 mM NaHCO3 and 5% inactivated fetal calf serum. All cultures and assays were conducted at 37°C/5% CO2.…”

Section: Trypanosoma Cruzi (Intracellular Amastigotes) -Tulahuen Cl2  Galactosidase Strainmentioning

confidence: 99%

Discovery of Novel 7-Aryl 7-Deazapurine 3′-Deoxy-ribofuranosyl Nucleosides with Potent Activity against Trypanosoma cruzi

et al. 2018

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Chagas disease, the leading cause of cardiac-related mortality in endemic Latin American countries.Trypanosoma cruzi, the disease-causing pathogen, is unable to synthesize purines de novo, necessitating salvage of pre-formed host purines. Therefore, purine and purine nucleoside analogs might constitute an attractive source to identify antitrypanosomal hits. In this study, structural elements of two purine nucleoside analogs, i.e. cordycepin and a recently discovered 7-substituted 7-deazaadenosine led to the identification of novel nucleoside analogs with potent in vitro activity. The structure-activity relationship of substituents at C7 was investigated, ultimately leading to the selection of compound 5 having a C7 para-chlorophenyl group for in vivo evaluation. This derivative showed complete suppression of T. cruzi Y-strain blood parasitemia when orally administered twice daily for 5 days at 25 mg/kg and was able to protect infected mice from parasite-induced mortality. However, sterile cure by immunosuppression could not be demonstrated. improved efficacy and safety profiles and preferentially with a new mode-of-action should be pursued. 4 Recently, several reports on new lead molecules have been published, marking a renewed hope in finding drugs to treat Chagas disease. [6][7][8][9][10] Trypanosoma cruzi, like their related T. brucei counterparts, are purine auxotrophs, i.e. they rely on the salvage of pre-formed purine analogs from the host as they are unable to synthesize the purine ring themselves. [11][12][13][14] Hence, focused purine (nucleoside) libraries are a promising source for discovering new antitrypanosomal agents. Natural antibiotics such as tubercidin, 15 Formycin A 16 and Formycin B, [17][18][19] cordycepin, [19][20][21][22][23] stylomycin aminonucleoside (also known as puromycin aminonucleoside) [24][25] as well as allopurinol [26][27] and certain other inosine analogs 20,[28][29] have been found to possess activity against T. cruzi (Figure 1). Allopurinol, although not a nucleoside analog sensu stricto (its active metabolite is generated by phosphoribosylation in the parasite 26 ), has been evaluated in clinical trials. 30 Figure 1: Examples of purine (nucleoside) analogs active against T. cruzi.Our group recently revisited the natural nucleoside antibiotic tubercidin and a series of 7-substituted analogs [in the body of the text, purine numbering will be used for nucleoside analogs; however, in the experimental section, IUPAC nomenclature and numbering of the pyrrolo[2,3-d]pyrimidine system will be applied] in search of novel hits active against T. brucei spp. parasites. 31 This study indicated that certain phenyl-substituted analogs (e.g. 2) also showed promising in vitro activity against intracellular T. cruzi amastigotes, which motivated us to explore related 7-substituted 7-deazapurine moieties with the carbohydrate group of cordycepin, i.e. a 3'-deoxy-D-ribofuranose for their activity against T. cruzi.Related sugar-modified 7-deazapurine nucleosides 32-34 have previously been assayed ...

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Section: Trypanosoma Cruzi (Intracellular Amastigotes) -Tulahuen Cl2  Galactosidase Strainmentioning

confidence: 99%

Discovery of Novel 7-Aryl 7-Deazapurine 3′-Deoxy-ribofuranosyl Nucleosides with Potent Activity against Trypanosoma cruzi

et al. 2018

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“…Whether there is a separate xanthine PRTase remains to be established. Interestingly, aUopurinol and 4-aminopyrazolopyrimidine, which are biologically active against T. cruzi [100][101][102], were readily converted to their ribonucleotides by hypoxanthine-guanine PRTase and adenine PRTase, respectively [103], and it is likely that these conversions are the basis of the selective toxicity of the drugs to T. cruzi.…”

Section: Trypanosoma Cruzimentioning

confidence: 99%

Purine and pyrimidine metabolism in parasitic protozoa

Hassan¹

1988

FEMS Microbiology Letters

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“…The in vitro antileishmanial activity of the ribonucleoside of allopurinol (2) is several times higher than allopurinol, but 2 was not further evaluated in vivo due to production difficulties and limited benefit over allopurinol. 46−48 The 6-amino congeners aminopurinol 3 and riboside derivative 4 (Figure 1a) were generally more active in vitro than allopurinol and 2, 46,49,50 which may be due to faster conversion to the same active triphosphate. However, 3 and 4 suffered from cytotoxicity and selectivity concerns.…”

Section: ■ Introductionmentioning

confidence: 99%

Revisiting Pyrazolo[3,4-d]pyrimidine Nucleosides as Anti-Trypanosoma cruzi and Antileishmanial Agents

et al. 2021

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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 de novo purine synthesis, they depend on purine salvage pathways that allow them to acquire and process purines from the host to meet their demands. Purine nucleoside analogues therefore constitute a logical source of potential antiparasitic agents. Earlier optimization efforts of the natural product tubercidin (7deazaadenosine) involving modifications to the nucleobase 7-position and the ribofuranose 3′-position led to analogues with potent anti-Trypanosoma brucei and anti-Trypanosoma cruzi activities. In this work, we report the design and synthesis of pyrazolo [3,4-d]pyrimidine nucleosides with 3′-and 7-modifications and assess their potential as anti-Trypanosoma cruzi and antileishmanial agents. One compound was selected for in vivo evaluation in an acute Chagas disease mouse model.

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Biological action of pyrazolopyrimidine derivatives against Trypanosoma cruzi. studies in vitro and in vivo

Cited by 9 publications

References 20 publications

Discovery of Novel 7-Aryl 7-Deazapurine 3′-Deoxy-ribofuranosyl Nucleosides with Potent Activity against Trypanosoma cruzi

Discovery of Novel 7-Aryl 7-Deazapurine 3′-Deoxy-ribofuranosyl Nucleosides with Potent Activity against Trypanosoma cruzi

Purine and pyrimidine metabolism in parasitic protozoa

Revisiting Pyrazolo[3,4-d]pyrimidine Nucleosides as Anti-Trypanosoma cruzi and Antileishmanial Agents

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