Hit-to-lead optimization of a 2-aminobenzimidazole series as new candidates for chagas disease

• Published in: European journal of medicinal chemistry Vol. 246; p. 114925
• Main Authors: de Oliveira Rezende Júnior, Celso, Martinez, Pablo David Grigol, Ferreira, Rafael Augusto Alves, Koovits, Paul John, Miranda Soares, Bruna, Ferreira, Leonardo L.G., Michelan-Duarte, Simone, Chelucci, Rafael Consolin, Andricopulo, Adriano D., Matheeussen, An, Van Pelt, Natascha, Caljon, Guy, Maes, Louis, Campbell, Simon, Kratz, Jadel M., Mowbray, Charles E., Dias, Luiz Carlos
• Format: Journal Article
• Language: English
• Published: France Elsevier Masson SAS 15-01-2023
• Subjects: 2-Aminobenzimidazole derivatives; Animals; Chagas disease; Chagas Disease - drug therapy; Hit-to-lead; Mammals; Multiparametric optimization; Structure-Activity Relationship; Trypanocidal Agents - chemistry; Trypanosoma cruzi; Chagas disease; 2-Aminobenzimidazole derivatives; Hit-to-lead; Multiparametric optimization; Trypanosoma cruzi
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2022.114925

Chagas disease is a neglected tropical disease caused by Trypanosoma cruzi. Because current treatments present several limitations, including long duration, variable efficacy and serious side effects, there is an urgent need to explore new antitrypanosomal drugs. The present study describes the hit-to-lead optimization of a 2-aminobenzimidazole hit 1 identified through in vitro phenotypic screening of a chemical library against intracellular Trypanosoma cruzi amastigotes, which focused on optimizing potency, selectivity, microsomal stability and lipophilicity. Multiparametric Structure−Activity Relationships were investigated using a set of 277 derivatives. Although the physicochemical and biological properties of the initial hits were improved, a combination of low kinetic solubility and in vitro cytotoxicity against mammalian cells prevented progression of the best compounds to an efficacy study using a mouse model of Chagas disease.
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•Hit-to-lead optimization of a 2-aminobenzimidazole series against intracellular Trypanosoma cruzi.•Multiparametric Structure−Activity Relationships using a set of 277 derivatives.•Discovery of multiple highly potent compounds (IC50 < 0.3 μM) and improved ADME properties.