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

• Document type: Journal article
• Source: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY; v. 275, p. 16-pg., 2024-06-29.

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. (AU)

• FAPESP's process: 18/08820-0 - Nanoparticle-assisted drug delivery of Vitamin B6 pathway inhibitors in malaria
• Grantee: Arne Kruger
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 21/13727-2 - Towards understanding of expression control in Malaria parasites: from variant gene families in Plasmodium falciparum to pathogeny and inhibition of transmission
• Grantee: Gerhard Wunderlich
• Support Opportunities: Regular Research Grants
• FAPESP's process: 15/26722-8 - Drug discovery against human infectious diseases
• Grantee: Carsten Wrenger
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 17/24267-7 - Role of chromatin modifiers in the transcription dynamics of virulence factors of the human malaria parasite Plasmodium falciparum
• Grantee: Gerhard Wunderlich
• Support Opportunities: Regular Research Grants
• FAPESP's process: 17/03966-4 - Targeting lipoic acid salvage and biosynthesis pathways in MRSA
• Grantee: Carsten Wrenger
• Support Opportunities: Regular Research Grants