Synthesis, design, and optimization of a potent and selective series of pyridylpiperazines as promising antimalarial agents

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Oliveira, Douglas Davison da Silva ; Paz, Franciarli ; Brito, Nicolas Peterson Ferreira ; Kruger, Arne ; Martinho, Ana Clara Cassiano ; Lapierre, Thibault Joseph William Jacques Dit ; Souza, Felipe de Oliveira ; Maltarollo, Vinicius G. ; Kronenberger, Thales ; Mendes, Marina Sena ; Nonato, Maria Cristina ; Pilau, Eduardo Jorge ; Wrenger, Carsten ; Wunderlich, Gerhard ; Rezende Junior, Celso de Oliveira

• Tipo de documento: Artigo Científico
• Fonte: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY; v. 275, p. 16-pg., 2024-06-29.

Resumo

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. (AU)

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