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

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 fra...

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Published in:	Chemical biology & drug design Vol. 103; no. 4; p. e14525
Main 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
Format:	Journal Article
Language:	English
Published:	England 01-04-2024
Subjects:	Antiprotozoal Agents - pharmacology Benzothiazoles - pharmacology Leishmania infantum Trypanosoma cruzi Leishmania infantum ADME benzothiazoles hit discovery
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Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1747-0277 1747-0285
DOI:	10.1111/cbdd.14525