Discovery of Antitrypanosomal Indolylacetamides by a Deconstruction-Optimization Strategy Applied to Paullones.
ChemMedChem
; 18(10): e202300036, 2023 05 16.
Article
en En
| MEDLINE
| ID: mdl-36847711
ABSTRACT
The parasitic kinetoplastid diseases Leishmaniasis, Chagas disease and Human African Trypanosomiasis constitute serious threats for populations throughout the (sub-)tropics. Most available drugs to treat these diseases possess inadequate properties and candidates to fill the drug pipeline are urgently needed. Paullone-N5 -acetamides inhibit trypanothione synthetase (TryS), an essential kinetoplastid enzyme, and exhibit antiparasitic activity in the low micromolar range, but lack the desired selectivity against mammalian cells (selectivity index (SI)<10). With the aim to identify the paullones' moieties responsible for TryS inhibition and bioactivity, we applied molecular simplification and ring disconnection approaches. The new indolylacetamides lost activity against the expected molecular target (TryS) compared to the reference paullone MOL2008 (Leishmania infantum TryS IC50 150â
nM; Trypanosoma brucei bloodstream form EC50 4.3â
µM and SI 2.4). However, several of them retained potency (T.â
b. brucei EC50 2.4-12.0â
µM) and improved selectivity (SI 5 to >25).
Palabras clave
Texto completo:
1
Base de datos:
MEDLINE
Asunto principal:
Trypanosoma brucei brucei
/
Trypanosoma cruzi
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Tripanosomiasis Africana
/
Antiprotozoarios
Límite:
Animals
/
Humans
Idioma:
En
Revista:
ChemMedChem
Asunto de la revista:
FARMACOLOGIA
/
QUIMICA
Año:
2023
Tipo del documento:
Article
País de afiliación:
Alemania