Synthesis, design, and optimization of a potent and selective series of pyridylpiperazines as promising antimalarial agents.
Eur J Med Chem
; 275: 116621, 2024 Sep 05.
Article
em En
| MEDLINE
| ID: mdl-38944935
ABSTRACT
An optimization of the pyridylpiperazine series against Plasmodium falciparum has been performed, exploring a structure-activity relationship carried out on the toluyl fragment of hit 1, a compound with low micromolar activity against Plasmodium falciparum discovered by high-throughput screening. After confirming the crucial role played by this aryl fragment in the antiplasmodial activity, the replacement of the ortho-methyl substituent of 1 by halogenated ones led to an improvement for four analogs, either in terms of potency, expected pharmacokinetics profile, or both. Further introduction of endocyclic nitrogens in this fragment identified two more optimized compounds, 20 and 23, which are expected to be much more metabolically stable than 1. Additional assessment of the cytotoxicity, Ligand Lipophilic Efficiency, potency against the chloroquine-resistant Dd2 strain and in silico ADMET predictions revealed a satisfactory profile for most compounds, ultimately identifying the four optimized compounds 7, 9, 20 and 23 as promising compounds for further lead optimization of this series against Plasmodium falciparum.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Piperazinas
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Plasmodium falciparum
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Desenho de Fármacos
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Testes de Sensibilidade Parasitária
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Antimaláricos
Limite:
Animals
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Humans
Idioma:
En
Revista:
Eur J Med Chem
Ano de publicação:
2024
Tipo de documento:
Article
País de afiliação:
Brasil