Biological Evaluation and X‐ray Co‐crystal Structures of Cyclohexylpyrrolidine Ligands for Trypanothione Reductase, an Enzyme from the Redox Metabolism of Trypanosoma

Gasparo, Raoul De; Brodbeck-Persch, Elke; Bryson, S.; Hentzen, Nina B.; Kaiser, Marcel; Pai, E.F.; Krauth‐Siegel, R. Luise; Diederich, François

doi:10.1002/cmdc.201800067

Cited by 18 publications

(38 citation statements)

References 61 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Additionally, most of the compounds inhibited the proliferation of P. falciparum with IC 50 values in the middle‐to‐low nanomolar range. This high cell‐based inhibition of the malarial parasite has already been observed previously and hints at the inhibition of additional targets, as P. falciparum does not possess TR –. Correlation of on‐target and cell‐based assay results is not straightforward, potentially being caused by these additional targets and differences in cell permeation.…”

Section: Figuresupporting

confidence: 61%

“…The crystal structure of 1 in complex with Trypanosoma ( T .) brucei TR confirmed binding of the inhibitor to the so‐called mepacrine binding site and suggested directions for further development of this ligand class (see Figure S1 in the Supporting Information).…”

Section: Figurementioning

confidence: 67%

“…We have recently reported on a known class of TR ligands providing a novel lead 1 with improved potency (competitive inhibition constant ( K ic )=6.1 μ m ) and physicochemical properties (Figure ). The crystal structure of 1 in complex with Trypanosoma ( T .)…”

Section: Figurementioning

confidence: 99%

“… Summary of the inhibitor development presented in this work from lead compound 1 to novel ligand (+)‐ 2 . The structural differences in (+)‐ 2 are highlighted in blue.…”

Section: Figurementioning

confidence: 99%

“…Ligands (+)‐ 2 – 12 were tested in enzymatic assays against T. brucei TR (see Section S3 in the Supporting Information for experimental details) . All ligands inhibited TR through a competitive mechanism (see Figure S4 in the Supporting Information for the Lineweaver–Burk plot of (+)‐ 2 ), with a largely improved affinity, compared to lead compound 1 .…”

Section: Figurementioning

confidence: 99%

See 4 more Smart Citations

Targeting a Large Active Site: Structure‐Based Design of Nanomolar Inhibitors of Trypanosoma brucei Trypanothione Reductase

Gasparo

Halgas

Harangozo

et al. 2019

Chemistry A European J

Self Cite

View full text Add to dashboard Cite

Trypanothione reductase (TR) plays a key role in the unique redox metabolism of trypanosomatids, the causative agents of human African trypanosomiasis (HAT), Chagas’ disease, and leishmaniases. Introduction of a new, lean propargylic vector to a known class of TR inhibitors resulted in the strongest reported competitive inhibitor of Trypanosoma (T.) brucei TR, with an inhibition constant Ki of 73 nm, which is fully selective against human glutathione reductase (hGR). The best ligands exhibited in vitro IC50 values (half‐maximal inhibitory concentration) against the HAT pathogen, T. brucei rhodesiense, in the mid‐nanomolar range, reaching down to 50 nm. X‐Ray co‐crystal structures confirmed the binding mode of the ligands and revealed the presence of a HEPES buffer molecule in the large active site. Extension of the propargylic vector, guided by structure‐based design, to replace the HEPES buffer molecule should give inhibitors with low nanomolar Ki and IC50 values for in vivo studies.

show abstract

Section: Figuresupporting

confidence: 61%

Section: Figurementioning

confidence: 67%

Section: Figurementioning

confidence: 99%

“… Summary of the inhibitor development presented in this work from lead compound 1 to novel ligand (+)‐ 2 . The structural differences in (+)‐ 2 are highlighted in blue.…”

Section: Figurementioning

confidence: 99%

Section: Figurementioning

confidence: 99%

See 3 more Smart Citations

Targeting a Large Active Site: Structure‐Based Design of Nanomolar Inhibitors of Trypanosoma brucei Trypanothione Reductase

Gasparo

Halgas

Harangozo

et al. 2019

Chemistry A European J

Self Cite

View full text Add to dashboard Cite

show abstract

Recent Advancement in the Search of Innovative Antiprotozoal Agents Targeting Trypanothione Metabolism

2020

View full text Add to dashboard Cite

Leishmania and Trypanosoma parasites are responsible for the challenging neglected tropical diseases leishmaniases, Chagas disease, and human African trypanosomiasis, which account for up to 40,000 deaths annually mainly in developing countries. Current chemotherapy relies on drugs with significant limitations in efficacy and safety, prompting the urgent need to explore innovative approaches to improve the drug discovery pipeline. The unique trypanothione‐based redox pathway, which is absent in human hosts, is vital for all trypanosomatids and offers valuable opportunities to guide the rational development of specific, broad‐spectrum and innovative anti‐trypanosomatid agents. Major efforts focused on the key metabolic enzymes trypanothione synthetase‐amidase and trypanothione reductase, whose inhibition should affect the entire pathway and, finally, parasite survival. Herein, we will report and comment on the most recent studies in the search for enzyme inhibitors, underlining the promising opportunities that have emerged so far to drive the exploration of future successful therapeutic approaches.

show abstract

The Importance of the Piperazine Ring for the Development of Trypanomicide Compounds

Gomes Pernichelle,

Tavares Marcelino Alves,

Massarico Serafim

et al. 2023

ChemistrySelect

View full text Add to dashboard Cite

Chagas disease (CD) is one of extremely Neglected Tropical Diseases (NTD) that have been challenging the health of billions of people in the world. Despite being a threat worldwide many of these diseases have a scarce chemotherapeutic armamentarium and the drugs currently used are not effective because of several reason, such as drug resistance, serious side‐effects, among others. Only two drugs are currently available for CD therapeutics, and they are not active in the chronic phase of the diseases. Considering the huge necessity of drugs for this parasitosis, the search for either new or better drugs than those used, many research groups have been involved in this investigation. New scaffolds can be used with this purpose and piperazine is one of them. Since it has many chemical, pharmacological and pharmacokinetics advantages, including multitarget activity, this group has been often used in CD. In this review, which the role of piperazine group in the structure‐activity of some important targets for T. cruzi, as cruzain, trypanothione reductase, Fe‐superoxide dismutase, and nitroreductase as well, is comprehended, several examples have been given to inspire researchers to optimize either hit or lead compounds against T. cruzi.

show abstract

Biological Evaluation and X‐ray Co‐crystal Structures of Cyclohexylpyrrolidine Ligands for Trypanothione Reductase, an Enzyme from the Redox Metabolism of Trypanosoma

Cited by 18 publications

References 61 publications

Targeting a Large Active Site: Structure‐Based Design of Nanomolar Inhibitors of Trypanosoma brucei Trypanothione Reductase

Targeting a Large Active Site: Structure‐Based Design of Nanomolar Inhibitors of Trypanosoma brucei Trypanothione Reductase

Recent Advancement in the Search of Innovative Antiprotozoal Agents Targeting Trypanothione Metabolism

The Importance of the Piperazine Ring for the Development of Trypanomicide Compounds

Contact Info

Product

Resources

About