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

Bouton, Jakob; Fiuza, Ludmila Ferreira de Almeida; Santos, C.; Mazzarella, Maria Angela; Soeiro, Maria de Nazaré Correia; Maes, Louis; Karalić, Izet; Caljon, Guy; Calenbergh, Serge Van

doi:10.1021/acs.jmedchem.1c00135

Cited by 26 publications

(35 citation statements)

References 97 publications

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“…Equally, the adenosine analogue Ara-A which is known to have moderate activity against T. gondii [ 23 ], also displayed low affinity for Tg244440. Nevertheless, much progress has recently been made in the identification of nucleoside analogues with highly promising antiprotozoal activities [ 12 ], including 7-deaza inosines [ 60 ], 3’-fluorinated 7-deazapurine nucleosides [ 61 ], 7-phenyl tubercidins [ 62 ] and pyrazolo[3,4-d]pyrimidine nucleosides [ 63 ]. Additionally, it is worth noting that 7-chloro-7-deazainosine and 7-bromo-7-deazainosine displayed high affinity for Tg244440.…”

Section: Discussionmentioning

confidence: 99%

A Toxoplasma gondii Oxopurine Transporter Binds Nucleobases and Nucleosides Using Different Binding Modes

Campagnaro

Elati

Balaska

et al. 2022

IJMS

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Toxoplasma gondii is unable to synthesize purines de novo, instead salvages them from its environment, inside the host cell, for which they need high affinity carriers. Here, we report the expression of a T. gondii Equilibrative Nucleoside Transporter, Tg244440, in a Trypanosoma brucei strain from which nucleobase transporters have been deleted. Tg244440 transported hypoxanthine and guanine with similar affinity (Km ~1 µM), while inosine and guanosine displayed Ki values of 4.05 and 3.30 µM, respectively. Low affinity was observed for adenosine, adenine, and pyrimidines, classifying Tg244440 as a high affinity oxopurine transporter. Purine analogues were used to probe the substrate-transporter binding interactions, culminating in quantitative models showing different binding modes for oxopurine bases, oxopurine nucleosides, and adenosine. Hypoxanthine and guanine interacted through protonated N1 and N9, and through unprotonated N3 and N7 of the purine ring, whereas inosine and guanosine mostly employed the ribose hydroxy groups for binding, in addition to N1H of the nucleobase. Conversely, the ribose moiety of adenosine barely made any contribution to binding. Tg244440 is the first gene identified to encode a high affinity oxopurine transporter in T. gondii and, to the best of our knowledge, the first purine transporter to employ different binding modes for nucleosides and nucleobases.

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Section: Discussionmentioning

confidence: 99%

A Toxoplasma gondii Oxopurine Transporter Binds Nucleobases and Nucleosides Using Different Binding Modes

Campagnaro

Elati

Balaska

et al. 2022

IJMS

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“… 23 Unfortunately, no sterile cure could be achieved despite its high capacity to fully suppress parasitaemia and provide 100% survival in mouse models of T. cruzi infection. 23 As observed with other purine nucleoside analogues, 22 , 47 , 48 Cpd 1 was inactive against BT despite its outstanding intracellular activity in infected CC cultures (EC 50 = 0.029 ± 0.006 μM) and L929 cell lines (EC 50 = 0.25 ± 0.17 μM). 23 At that time, the lack of in vivo sterilization by Cpd 1 was attributed at least in part to its inefficacy towards BT and/or to the short treatment period (only 5 days) adopted in the initial in vivo study.…”

Section: Discussionmentioning

confidence: 63%

7-Aryl-7-deazapurine 3′-deoxyribonucleoside derivative as a novel lead for Chagas’ disease therapy: in vitro and in vivo pharmacology

Cardoso-Santos

Fiuza

Silva

et al. 2021

JAC-Antimicrobial Resistance

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Background The protozoan Trypanosoma cruzi is auxotrophic for purines and causes Chagas’ disease (CD), a neglected illness affecting >6 million people. Combining the 3-deoxyribofuranose part of cordycepin with the modified purine ring of a nucleoside ‘hit’ led to the discovery of 4-amino-5-(4-chlorophenyl)-N7-(3′-deoxy-β-d-ribofuranosyl)-pyrrolo[2,3-d]pyrimidine (Cpd1), revealing promising anti-T. cruzi activity. Objectives To further evaluate Cpd1 in vitro and in vivo to fully assess its therapeutic potential against CD, covering cell culture sterilization through washout assays, drug combination with benznidazole and long-term administration in T. cruzi-infected mice. Results Although less susceptible to Cpd1 than amastigotes, trypomastigotes present an impaired capacity to successfully establish intracellular infection of cardiac cultures. Combination of benznidazole with Cpd1 indicated no interaction (additive effect) (FIC index = 0.72) while administration to mice at one-tenth of the optimal dose (2.5 mg/kg and 10 mg/kg for Cpd1 and benznidazole, respectively) suppressed parasitaemia but failed to avoid mortality. Long-term treatment (60 days) gave a rapid drop of the parasitaemia (>98% decline) and 100% mice survival but only 16% cure. In vitro washout experiments demonstrated that although parasite release into the supernatant of infected cardiac cultures was reduced by >94%, parasite recrudescence did occur after treatment. Conclusions Parasite recrudescence did occur after treatment corroborating the hypothesis of therapeutic failure due to subpopulations of dormant forms and/or genetic factors in persister parasites involved in natural drug resistance.

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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: Methodsmentioning

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

Cited by 26 publications

References 97 publications

A Toxoplasma gondii Oxopurine Transporter Binds Nucleobases and Nucleosides Using Different Binding Modes

A Toxoplasma gondii Oxopurine Transporter Binds Nucleobases and Nucleosides Using Different Binding Modes

7-Aryl-7-deazapurine 3′-deoxyribonucleoside derivative as a novel lead for Chagas’ disease therapy: in vitro and in vivo pharmacology

Development of Novel Isoindolone‐Based Compounds against Trypanosoma brucei rhodesiense

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