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Chemical biology & drug design
Apr, 2024;103 (4): e14525.

Evaluation and discovery of novel benzothiazole derivatives as promising hits against Leishmania infantum.

Thibault Joseph William Jacques Dit Lapierre, Danilo Nascimento Farago, Mariza Gabriela Faleiro de Moura Lodi Cruz, Daniela de Melo Resende, Adriane Cristina Rosa de Oliveira, Brenda Rosa Macedo Dos Santos, Felipe de Oliveira Souza, Simone Michelan-Duarte, Rafael C Chelucci, Adriano D Andricopulo, Leonardo L G Ferreira, Eduardo Jorge Pilau, Silvane Maria Fonseca Murta, Celso de Oliveira Rezende Júnior
Author Information
  1. Thibault Joseph William Jacques Dit Lapierre: Laboratório de Síntese de Candidatos a Fármacos, Instituto de Química, Universidade Federal de Uberlândia (UFU), Uberlândia, Minas Gerais, Brazil.
  2. Danilo Nascimento Farago: Laboratório de Síntese de Candidatos a Fármacos, Instituto de Química, Universidade Federal de Uberlândia (UFU), Uberlândia, Minas Gerais, Brazil.
  3. Mariza Gabriela Faleiro de Moura Lodi Cruz: Grupo de Genômica Funcional de Parasitos, Instituto René Rachou, Fundação Oswaldo Cruz (FIOCRUZ Minas), Belo Horizonte, Minas Gerais, Brazil.
  4. Daniela de Melo Resende: Grupo de Genômica Funcional de Parasitos, Instituto René Rachou, Fundação Oswaldo Cruz (FIOCRUZ Minas), Belo Horizonte, Minas Gerais, Brazil.
  5. Adriane Cristina Rosa de Oliveira: Laboratório de Síntese de Candidatos a Fármacos, Instituto de Química, Universidade Federal de Uberlândia (UFU), Uberlândia, Minas Gerais, Brazil.
  6. Brenda Rosa Macedo Dos Santos: Laboratório de Síntese de Candidatos a Fármacos, Instituto de Química, Universidade Federal de Uberlândia (UFU), Uberlândia, Minas Gerais, Brazil.
  7. Felipe de Oliveira Souza: Laboratório de Biomoléculas e Espectrometria de Massas (LaBioMass), Universidade Estadual de Maringá (UEM), Maringá, Paraná, Brazil.
  8. Simone Michelan-Duarte: Laboratório de Química Medicinal e Computacional (LQMC), Instituto de Física de São Carlos (IFSC), Universidade de São Paulo (USP), São Carlos, São Paulo, Brazil.
  9. Rafael C Chelucci: Laboratório de Química Medicinal e Computacional (LQMC), Instituto de Física de São Carlos (IFSC), Universidade de São Paulo (USP), São Carlos, São Paulo, Brazil.
  10. Adriano D Andricopulo: Laboratório de Química Medicinal e Computacional (LQMC), Instituto de Física de São Carlos (IFSC), Universidade de São Paulo (USP), São Carlos, São Paulo, Brazil.
  11. Leonardo L G Ferreira: Laboratório de Química Medicinal e Computacional (LQMC), Instituto de Física de São Carlos (IFSC), Universidade de São Paulo (USP), São Carlos, São Paulo, Brazil.
  12. Eduardo Jorge Pilau: Laboratório de Biomoléculas e Espectrometria de Massas (LaBioMass), Universidade Estadual de Maringá (UEM), Maringá, Paraná, Brazil.
  13. Silvane Maria Fonseca Murta: Grupo de Genômica Funcional de Parasitos, Instituto René Rachou, Fundação Oswaldo Cruz (FIOCRUZ Minas), Belo Horizonte, Minas Gerais, Brazil.
  14. Celso de Oliveira Rezende Júnior: Laboratório de Síntese de Candidatos a Fármacos, Instituto de Química, Universidade Federal de Uberlândia (UFU), Uberlândia, Minas Gerais, Brazil.
PMID: 38627214 DOI: 10.1111/cbdd.14525

Abstract

An early exploration of the benzothiazole class against two kinetoplastid parasites, Leishmania infantum and Trypanosoma cruzi, has been performed after the identification of a benzothiazole derivative as a suitable antileishmanial initial hit. The first series of derivatives focused on the acyl fragment of its class, evaluating diverse linear and cyclic, alkyl and aromatic substituents, and identified two other potent compounds, the phenyl and cyclohexyl derivatives. Subsequently, new compounds were designed to assess the impact of the presence of diverse substituents on the benzothiazole ring or the replacement of the endocyclic sulfur by other heteroatoms. All compounds showed relatively low cytotoxicity, resulting in decent selectivity indexes for the most active compounds. Ultimately, the in vitro ADME properties of these compounds were assessed, revealing a satisfying water solubility, gastrointestinal permeability, despite their low metabolic stability and high lipophilicity. Consequently, compounds 5 and 6 were identified as promising hits for further hit-to-lead exploration within this benzothiazole class against L. infantum, thus providing promising starting points for the development of antileishmanial candidates.

Keywords

Leishmania infantum ADME benzothiazoles hit discovery

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MeSH Term

Leishmania infantum
Antiprotozoal Agents
Trypanosoma cruzi
Benzothiazoles

Chemicals

Antiprotozoal Agents
Benzothiazoles
Journal Article

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