| Author | Lapierre, Thibault Joseph William Jacques Dit | |
| Author | Cruz, Mariza Gabriela Faleiro de Moura Lodi | |
| Author | Brito, Nícolas Peterson Ferreira | |
| Author | Resende, Daniela de Melo | |
| Author | Souza, Felipe de Oliveira | |
| Author | Pilau, Eduardo Jorge | |
| Author | Silva, Meryck Felipe Brito da | |
| Author | Junior Neves, Bruno | |
| Author | Murta, Silvane Maria Fonseca | |
| Author | Rezende Júnior, Celso de Oliveira | |
| Access date | 2023-07-17T14:06:28Z | |
| Available date | 2023-07-17T14:06:28Z | |
| Document date | 2023 | |
| Citation | LAPIERRE, Thibault Joseph William Jacques Dit et al. Hit-to-lead optimization of a pyrazinylpiperazine series against Leishmania infantum and Leishmania braziliensis. European Journal of Medicinal Chemistry, v. 256, p. 115445, 2023.. doi: 10.1016/j.ejmech.2023.115445. | en_US |
| ISSN | 0223-5234 | en_US |
| URI | https://www.arca.fiocruz.br/handle/icict/59616 | |
| Language | eng | en_US |
| Publisher | Editions Scientifiques Elsevier | en_US |
| Rights | restricted access | |
| Title | Hit-to-lead optimization of a pyrazinylpiperazine series against Leishmania infantum and Leishmania braziliensis | en_US |
| Type | Article | |
| 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. | en_US |
| Affilliation | Universidade Federal de Uberlândia. Instituto de Química. Laboratório de Síntese de Candidatos a Fármacos. Uberlândia, MG, Brazil. | en_US |
| Affilliation | Fundação Oswaldo Cruz. Instituto René Rachou. Grupo de Genômica Funcional de Parasitos. Belo Horizonte, MG, Brazil. | en_US |
| Affilliation | Universidade Federal de Uberlândia. Instituto de Química. Laboratório de Síntese de Candidatos a Fármacos. Uberlândia, MG, Brazil. | en_US |
| Affilliation | Fundação Oswaldo Cruz. Instituto René Rachou. Grupo de Genômica Funcional de Parasitos. Belo Horizonte, MG, Brazil. | en_US |
| Affilliation | Universidade Estadual de Maringá. Laboratório de Biomoléculas e Espectrometria de Massas. Maringá, PR, Brazil. | en_US |
| Affilliation | Universidade Estadual de Maringá. Laboratório de Biomoléculas e Espectrometria de Massas. Maringá, PR, Brazil. | en_US |
| Affilliation | Universidade Federal de Goiás. Faculdade de Farmácia. Laboratory of Cheminformatics. Goiânia, GO, Brazil. | en_US |
| Affilliation | Universidade Federal de Goiás. Faculdade de Farmácia. Laboratory of Cheminformatics. Goiânia, GO, Brazil. | en_US |
| Affilliation | Fundação Oswaldo Cruz. Instituto René Rachou. Grupo de Genômica Funcional de Parasitos. Belo Horizonte, MG, Brazil. | en_US |
| Affilliation | Universidade Federal de Uberlândia. Instituto de Química. Laboratório de Síntese de Candidatos a Fármacos. Uberlândia, MG, Brazil. | en_US |
| Subject | Leishmania | en_US |
| Subject | Hit-to-lead optimization | en_US |
| Subject | Neglected tropical disease | en_US |
| Subject | Pyrazinylpiperazines | en_US |
| Subject | ADMET | en_US |
| Embargo date | 2099-12-31 | |
