Hit-to-lead optimization of a pyrazinylpiperazine series against Leishmania infantum and Leishmania braziliensis.
Eur J Med Chem
; 256: 115445, 2023 Aug 05.
Article
em En
| MEDLINE
| ID: mdl-37156183
An early hit-to-lead optimization of a novel pyrazinylpiperazine series against L. infantum and L. braziliensis has been performed after an extensive SAR focusing on the benzoyl fragment of hit (4). Deletion of the meta-Cl of (4) led to the obtention of the para-hydroxyl derivative (12), on which the design of most monosubstituted derivatives of the SAR was based. Further optimization of the series, involving disubstituted benzoyl fragments and the hydroxyl substituent of (12), allowed the obtention of a total of 15 compounds with increased antileishmanial potency (IC50 < 10 µM), nine of which displayed activity in the low micromolar range (IC50 < 5 µM). This optimization ultimately identified the ortho, meta-dihydroxyl derivative (46) as an early lead for this series (IC50 (L. infantum) = 2.8 µM, IC50 (L. braziliensis) = 0.2 µM). Additional assessment of some selected compounds against other trypanosomatid parasites revealed that this series is selective towards Leishmania parasites, and in silico ADMET predictions revealed satisfactory profiles for these compounds, allowing further lead optimization of the pyrazinylpiperazine class against Leishmania.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Leishmania braziliensis
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Leishmania infantum
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Antiprotozoários
País/Região como assunto:
America do sul
/
Brasil
Idioma:
En
Revista:
Eur J Med Chem
Ano de publicação:
2023
Tipo de documento:
Article
País de afiliação:
Brasil
País de publicação:
França