Synthesis and evaluation of a collection of purine-like C-nucleosides as antikinetoplastid agents

Bouton, Jakob; Maes, Louis; Karalić, Izet; Caljon, Guy; Calenbergh, Serge Van

doi:10.1016/j.ejmech.2020.113101

Cited by 17 publications

(13 citation statements)

References 64 publications

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“…They can inhibit the PSP enzymes or they can become toxic (e.g. cordycepin, tubercidin) when activated by these enzymes 2 – 5 . Several PSP enzymes (i.e.…”

Section: Introductionmentioning

confidence: 99%

Acyclic nucleoside phosphonates with adenine nucleobase inhibit Trypanosoma brucei adenine phosphoribosyltransferase in vitro

Doleželová

Klejch

Špaček

et al. 2021

Sci Rep

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All medically important unicellular protozoans cannot synthesize purines de novo and they entirely rely on the purine salvage pathway (PSP) for their nucleotide generation. Therefore, purine derivatives have been considered as a promising source of anti-parasitic compounds since they can act as inhibitors of the PSP enzymes or as toxic products upon their activation inside of the cell. Here, we characterized a Trypanosoma brucei enzyme involved in the salvage of adenine, the adenine phosphoribosyl transferase (APRT). We showed that its two isoforms (APRT1 and APRT2) localize partly in the cytosol and partly in the glycosomes of the bloodstream form (BSF) of the parasite. RNAi silencing of both APRT enzymes showed no major effect on the growth of BSF parasites unless grown in artificial medium with adenine as sole purine source. To add into the portfolio of inhibitors for various PSP enzymes, we designed three types of acyclic nucleotide analogs as potential APRT inhibitors. Out of fifteen inhibitors, four compounds inhibited the activity of the recombinant APRT1 with Ki in single µM values. The ANP phosphoramidate membrane-permeable prodrugs showed pronounced anti-trypanosomal activity in a cell-based assay, despite the fact that APRT enzymes are dispensable for T. brucei growth in vitro. While this suggests that the tested ANP prodrugs exert their toxicity by other means in T. brucei, the newly designed inhibitors can be further improved and explored to identify their actual target(s).

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“…They can inhibit the PSP enzymes or they can become toxic (e.g. cordycepin, tubercidin) when activated by these enzymes 2 – 5 . Several PSP enzymes (i.e.…”

Section: Introductionmentioning

confidence: 99%

Acyclic nucleoside phosphonates with adenine nucleobase inhibit Trypanosoma brucei adenine phosphoribosyltransferase in vitro

Doleželová

Klejch

Špaček

et al. 2021

Sci Rep

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“…cruzi activity, are inactive when evaluated against L. infantum intracellular amastigotes in PMM host cells. , The origins of this lack of permeability in PMM cells are currently unclear and require further study. Furthermore, it would be worthwhile to evaluate if certain nucleoside prodrugs could lead to improved permeability and/or improved in vivo efficacy.…”

Section: Results and Discussionmentioning

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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“…L. infantum was maintained in golden hamsters from which spleen‐derived amastigotes were collected and used for in vitro infection of peritoneal mouse macrophages (PMM) in RPMI‐1640 with 5 % FBS. Antiparasitic and cytotoxicity assays (MRC‐5 and PMM) were performed as previously described [15,16] . All animal experiments were approved by the ethical committee of the University of Antwerp (UA‐ECD‐2019‐10).…”

Section: Methodsmentioning

confidence: 99%

“…Antiparasitic and cytotoxicity assays (MRC-5 and PMM) were performed as previously described. [15,16] All animal experiments were approved by the ethical committee of the University of Antwerp (UA-ECD-2019-10). Experimental details are provided in the Supporting Information and the cited literature.…”

Section: Antiparasitic Activity Cytotoxicity and Selectivity Indexmentioning

confidence: 99%

Development of Novel Isoindolone‐Based Compounds against Trypanosoma brucei rhodesiense

et al. 2021

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This study identified the isoindolone ring as a scaffold for novel agents against Trypanosoma brucei rhodesiense and explored the structure‐activity relationships of various aromatic ring substitutions. The compounds were evaluated in an integrated in vitro screen. Eight compounds exhibited selective activity against T. b. rhodesiense (IC50<2.2 μm) with no detectable side activity against T. cruzi and Leishmania infantum. Compound 20 showed low nanomolar potency against T. b. rhodesiense (IC50=40 nm) and no toxicity against MRC‐5 and PMM cell lines and may be regarded as a new lead template for agents against T. b. rhodesiense. The isoindolone‐based compounds have the potential to progress into lead optimization in view of their highly selective in vitro potency, absence of cytotoxicity and acceptable metabolic stability. However, the solubility of the compounds represents a limiting factor that should be addressed to improve the physicochemical properties that are required to proceed further in the development of in vivo‐active derivatives.

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Synthesis and evaluation of a collection of purine-like C-nucleosides as antikinetoplastid agents

Cited by 17 publications

References 64 publications

Acyclic nucleoside phosphonates with adenine nucleobase inhibit Trypanosoma brucei adenine phosphoribosyltransferase in vitro

Acyclic nucleoside phosphonates with adenine nucleobase inhibit Trypanosoma brucei adenine phosphoribosyltransferase in vitro

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

Development of Novel Isoindolone‐Based Compounds against Trypanosoma brucei rhodesiense

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