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- Title
Evaluation and discovery of novel benzothiazole derivatives as promising hits against Leishmania infantum.
- Authors
Lapierre, Thibault Joseph William Jacques Dit; Farago, Danilo Nascimento; de Moura Lodi Cruz, Mariza Gabriela Faleiro; de Melo Resende, Daniela; de Oliveira, Adriane Cristina Rosa; dos Santos, Brenda Rosa Macedo; de Oliveira Souza, Felipe; Michelan‐Duarte, Simone; Chelucci, Rafael C.; Andricopulo, Adriano D.; Ferreira, Leonardo L. G.; Pilau, Eduardo Jorge; Murta, Silvane Maria Fonseca; de Oliveira Rezende Júnior, Celso
- 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.
- Subjects
BENZOTHIAZOLE derivatives; TRYPANOSOMA cruzi; LEISHMANIA infantum; CYTOTOXINS; BENZOTHIAZOLE; LIPOPHILICITY
- Publication
Chemical Biology & Drug Design, 2024, Vol 103, Issue 4, p1
- ISSN
1747-0277
- Publication type
Article
- DOI
10.1111/cbdd.14525