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

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Lapierre, Thibault Joseph William Jacques Dit ; Farago, Danilo Nascimento ; Cruz, Mariza Gabriela Faleiro de Moura Lodi ; Resende, Daniela de Melo ; de Oliveira, Adriane Cristina Rosa ; dos Santos, Brenda Rosa Macedo ; Souza, Felipe de Oliveira ; Michelan-Duarte, Simone ; Chelucci, Rafael C. ; Andricopulo, Adriano D. ; Ferreira, Leonardo L. G. ; Pilau, Eduardo Jorge ; Murta, Silvane Maria Fonseca ; Rezende Junior, Celso de Oliveira

• Document type: Journal article
• Source: CHEMICAL BIOLOGY & DRUG DESIGN; v. 103, n. 4, p. 14-pg., 2024-04-01.

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. (AU)

• FAPESP's process: 18/14268-9 - Converting natural product leads into structure- and ligand-based drug discovery campaigns against Leishmaniasis and Chagas' Disease
• Grantee: Adriano Defini Andricopulo
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 13/07600-3 - CIBFar - Center for Innovation in Biodiversity and Drug Discovery
• Grantee: Glaucius Oliva
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC