Hit-to-Lead Studies of Pyrazinylpiperazines against Visceral Leishmaniasis: Pharmacokinetic Profile and <i>In Vivo</i> Efficacy of Potent Compounds against <i>Leishmania infantum</i>

As part of the hit-to-lead optimization of antileishmanial pyrazinylpiperazines, the Absorption, Distribution, Metabolism, and Excretion (ADME) properties of the initial hit and five candidates for <i>in vivo</i> studies were assessed <i>in vitro</i>. These candidates, which displayed improved potency against <i>Leishmania infantum</i> (IC<sub>50</sub> < 5 μM), were selected from an earlier structure-activity relationship study. Such assessment revealed that, except for the catechol derivative <b>6</b>, all derivatives exhibited an improved overall ADME profile in comparison to the initial hit. The <i>para</i>-hydroxyl analog <b>2</b> stood out as the most promising candidate, being the second most potent compound <i>in vitro</i> against the parasite and showing far superior metabolic stability (more than twice as stable as the initial hit) in mouse liver microsomes, together with a reasonable gastrointestinal absorption and a lack of blood-brain barrier permeation. <i>In vivo</i> assessment of the antileishmanial efficacy of <b>2</b> in a BALB/c mice model of visceral leishmaniasis revealed a reduction in parasitemia by 91.1 and 90.0% in the spleen and liver, respectively, after a 10 day treatment of infected animals with a 100 mg/kg daily dose of <b>2</b>, without any acute toxicity or death among mice treated with <b>2</b>. Flow cytometry demonstrated that the antileishmanial activity of <b>2</b> is linked to a cytostatic effect, marked by cell cycle arrest in the G0/G1 phase and enhanced production of reactive oxygen species. Subsequent <i>in silico</i> studies suggested that the activity of the novel antileishmanial pyrazinylpiperazine lead <b>2</b> could be due to the inhibition of a nonspecific serine/threonine protein kinase in <i>Leishmania infantum</i>; however, <i>in vitro</i> inhibition assays failed to identify a target for <b>2</b> among a set of kinases and other proteins.

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Journal
ACS Pharmacology & Translational Science
Published
2025-07-18
DOI
https://doi.org/10.1021/acsptsci.5c00318
Primary Topic
Research on Leishmaniasis Studies
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article
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article

Hit-to-Lead Studies of Pyrazinylpiperazines against Visceral Leishmaniasis: Pharmacokinetic Profile and In Vivo Efficacy of Potent Compounds against Leishmania infantum

Maria Cristina Nonato, Silvane Maria Fonseca Murta, Adriano D. Andricopulo, Tito Trindade et al.
ACS Pharmacology & Translational Science
Research on Leishmaniasis Studies
article

Hit-to-Lead Studies of Pyrazinylpiperazines against Visceral Leishmaniasis: Pharmacokinetic Profile and In Vivo Efficacy of Potent Compounds against Leishmania infantum

Maria Cristina Nonato, Silvane Maria Fonseca Murta, Adriano D. Andricopulo, Tito Trindade, Eduardo Jorge Pilau, Priscila Zonzini Ramos, Katlin B. Massirer, Mariza Gabriela Faleiro de Moura Lodi Cruz, Lı́dia Moreira Lima, Patrícia Sampaio Tavares Veras, Thamires Quadros Froes, Miguel Á. Chávez‐Fumagalli, Gisele Barbosa, Leonardo L. G. Ferreira, Analu R. Costa, Thibault Joseph William Jacques Dit Lapierre, Celso de Oliveira Rezende Júnior, Paula Derksen Macruz
article en

Abstract

As part of the hit-to-lead optimization of antileishmanial pyrazinylpiperazines, the Absorption, Distribution, Metabolism, and Excretion (ADME) properties of the initial hit and five candidates for <i>in vivo</i> studies were assessed <i>in vitro</i>. These candidates, which displayed improved potency against <i>Leishmania infantum</i> (IC<sub>50</sub> < 5 μM), were selected from an earlier structure-activity relationship study. Such assessment revealed that, except for the catechol derivative <b>6</b>, all derivatives exhibited an improved overall ADME profile in comparison to the initial hit. The <i>para</i>-hydroxyl analog <b>2</b> stood out as the most promising candidate, being the second most potent compound <i>in vitro</i> against the parasite and showing far superior metabolic stability (more than twice as stable as the initial hit) in mouse liver microsomes, together with a reasonable gastrointestinal absorption and a lack of blood-brain barrier permeation. <i>In vivo</i> assessment of the antileishmanial efficacy of <b>2</b> in a BALB/c mice model of visceral leishmaniasis revealed a reduction in parasitemia by 91.1 and 90.0% in the spleen and liver, respectively, after a 10 day treatment of infected animals with a 100 mg/kg daily dose of <b>2</b>, without any acute toxicity or death among mice treated with <b>2</b>. Flow cytometry demonstrated that the antileishmanial activity of <b>2</b> is linked to a cytostatic effect, marked by cell cycle arrest in the G0/G1 phase and enhanced production of reactive oxygen species. Subsequent <i>in silico</i> studies suggested that the activity of the novel antileishmanial pyrazinylpiperazine lead <b>2</b> could be due to the inhibition of a nonspecific serine/threonine protein kinase in <i>Leishmania infantum</i>; however, <i>in vitro</i> inhibition assays failed to identify a target for <b>2</b> among a set of kinases and other proteins.

ACS Pharmacology & Translational ScienceVol. 8(8)
Universidade Federal do Rio de Janeiro (BR), Universidade Estadual de Maringá (BR), Deaconess Hospital (US), Target (United States) (US), Universidade Estadual de Campinas (UNICAMP) (BR), Centro de Genética Clínica (PT), Ação Educativa (BR), Universidad Católica de Santa Fe (AR), Catholic University of Santa María (PE), Instituto Internacional de Ecologia (Brazil) (BR), Brazilian Society of Computational and Applied Mathematics (BR), Rede de Química e Tecnologia (PT), Hospital Universitário da Universidade de São Paulo (BR), Instituto de Medicina Genómica (ES), Centro de Espectrometria de Massas Aplicada (Brazil) (BR), Fundação Oswaldo Cruz (BR), Universidade Federal de Uberlândia (BR)
Fundação de Amparo à Pesquisa do Estado de São Paulo, Conselho Nacional de Desenvolvimento Científico e Tecnológico, Fundação de Amparo à Pesquisa do Estado de Minas Gerais
Zero hunger
Openalex Percentile: Top 72%
Research on Leishmaniasis Studies
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