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

Tijdschriftbijdrage - e-publicatie

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-aminoben-zimidazole 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 lip-ophilicity. 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.
Tijdschrift: European journal of medicinal chemistry
ISSN: 0223-5234
Volume: 246
Pagina's: 1 - 10
Jaar van publicatie:2023
Trefwoorden:A1 Journal article
Toegankelijkheid:Open