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

• Published in: European journal of medicinal chemistry Vol. 256; p. 115445
• Main Authors: Jacques Dit Lapierre, Thibault Joseph William, Cruz, Mariza Gabriela Faleiro de Moura Lodi, Brito, Nícolas Peterson Ferreira, Resende, Daniela de Melo, Souza, Felipe de Oliveira, Pilau, Eduardo Jorge, da Silva, Meryck Felipe Brito, Neves, Bruno Junior, Murta, Silvane Maria Fonseca, Rezende Júnior, Celso de Oliveira
• Format: Journal Article
• Language: English
• Published: France Elsevier Masson SAS 05-08-2023
• Subjects: ADMET; Antiprotozoal Agents - pharmacology; Hit-to-lead optimization; Hydroxyl Radical; Leishmania; Leishmania braziliensis; Leishmania infantum; Neglected tropical disease; Pyrazinylpiperazines; Pyrazinylpiperazines; Hit-to-lead optimization; Neglected tropical disease; ADMET; Leishmania
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2023.115445

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.
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•The pyrazinylpiperazine class is a relevant scaffold against Leishmania.•Hit-to-lead approach identified several optimized pyrazinylpiperazines.•Pyrazinylpiperazines delivered one early lead against Leishmania.•The most active compounds have interesting predicted ADMET properties.