Development of Selective Steroid Inhibitors for the Glucose-6-phosphate Dehydrogenase from Trypanosoma cruzi

Copyright © 2020 American Chemical Society..

Chagas disease is a parasitic infection affecting millions of people across Latin America, imposing a dramatic socioeconomic burden. Despite the availability of drugs, nifurtimox and benznidazole, lack of efficacy and incidence of side-effects prompt the identification of novel, efficient, and affordable drug candidates. To address this issue, one strategy could be probing the susceptibility of Trypanosoma parasites toward NADP-dependent enzyme inhibitors. Recently, steroids of the androstane group have been described as highly potent but nonselective inhibitors of parasitic glucose-6-phosphate dehydrogenase (G6PDH). In order to promote selectivity, we have synthesized and evaluated 26 steroid derivatives of epiandrosterone in enzymatic assays, whereby 17 compounds were shown to display moderate to high selectivity for T. cruzi over the human G6PDH. In addition, three compounds were effective in killing intracellular T. cruzi forms infecting rat cardiomyocytes. Altogether, this study provides new SAR data around G6PDH and further supports this target for treating Chagas disease.

Medienart:

E-Artikel

Erscheinungsjahr:

2020

Erschienen:

2020

Enthalten in:

Zur Gesamtaufnahme - volume:11

Enthalten in:

ACS medicinal chemistry letters - 11(2020), 6 vom: 11. Juni, Seite 1250-1256

Sprache:

Englisch

Beteiligte Personen:

Fredo Naciuk, Fabrício [VerfasserIn]
do Nascimento Faria, Jéssica [VerfasserIn]
Gonçalves Eufrásio, Amanda [VerfasserIn]
Torres Cordeiro, Artur [VerfasserIn]
Bruder, Marjorie [VerfasserIn]

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Journal Article

Anmerkungen:

Date Revised 12.06.2021

published: Electronic-eCollection

Citation Status PubMed-not-MEDLINE

doi:

10.1021/acsmedchemlett.0c00106

funding:

Förderinstitution / Projekttitel:

PPN (Katalog-ID):

NLM311297846