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- Molecular Medicine
- Biochemistry
- Drug Discovery
- Pharmacology
- Organic Chemistry
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.