2. Academic Validation
  3. Hit-to-lead optimization of a pyrazinylpiperazine series against Leishmania infantum and Leishmania braziliensis

Hit-to-lead optimization of a pyrazinylpiperazine series against Leishmania infantum and Leishmania braziliensis

  • Eur J Med Chem. 2023 Aug 5:256:115445. doi: 10.1016/j.ejmech.2023.115445.
Thibault Joseph William Jacques Dit Lapierre 1,  Mariza Gabriela Faleiro de Moura Lodi Cruz 2,  Nícolas Peterson Ferreira Brito 1,  Daniela de Melo Resende 2,  Felipe de Oliveira Souza 3,  Eduardo Jorge Pilau 3,  Meryck Felipe Brito da Silva 4,  Bruno Junior Neves 4,  Silvane Maria Fonseca Murta 2,  Celso de Oliveira Rezende Júnior 5
Affiliations

Affiliations

  • 1 Laboratório de Síntese de Candidatos a Fármacos, Instituto de Química, Universidade Federal de Uberlândia (UFU), Uberlândia, MG, 38400-902, Brazil.
  • 2 Grupo de Genômica Funcional de Parasitos, Instituto René Rachou, Fundação Oswaldo Cruz (FIOCRUZ Minas), Belo Horizonte, MG, 30190-002, Brazil.
  • 3 Laboratório de Biomoléculas e Espectrometria de Massas (LaBioMass), Universidade Estadual de Maringá (UEM), Maringá, PR, 807020-900, Brazil.
  • 4 Laboratory of Cheminformatics (LabChem), Faculdade de Farmácia, Universidade Federal de Goiás, Goiânia, GO, 74605-170, Brazil.
  • 5 Laboratório de Síntese de Candidatos a Fármacos, Instituto de Química, Universidade Federal de Uberlândia (UFU), Uberlândia, MG, 38400-902, Brazil. Electronic address: [email protected].
PMID: 37156183 DOI: 10.1016/j.ejmech.2023.115445
Abstract

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.

Keywords

ADMET; Hit-to-lead optimization; Leishmania; Neglected tropical disease; Pyrazinylpiperazines.

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