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

被引：6

作者：

de Oliveira Rezende Jr, Celso ^{[1
]}

Martinez, Pablo David Grigol ^{[1
]}

Ferreira, Rafael Augusto Alves ^{[1
]}

Koovits, Paul John ^{[1
]}

Soares, Bruna Miranda ^{[1
]}

Ferreira, Leonardo L. G. ^{[2
]}

Michelan-Duarte, Simone ^{[2
]}

Chelucci, Rafael Consolin ^{[2
]}

Andricopulo, Adriano D. ^{[2
]}

Matheeussen, An ^{[3
]}

Van Pelt, Natascha ^{[3
]}

Caljon, Guy ^{[3
]}

Maes, Louis ^{[3
]}

Campbell, Simon ^{[4
]}

Kratz, Jadel M. ^{[4
]}

Mowbray, Charles E. ^{[4
]}

Dias, Luiz Carlos ^{[1
]}

机构：

[1] Univ Campinas UNICAMP, Inst Chem, BR-13083861 Campinas, SP, Brazil

[2] Univ Sao Paulo, Phys Inst Sao Carlos, Lab Med & Computat Chem, BR-13563120 Sa Carlos, SP, Brazil

[3] Lab Microbiol Parasitol & Hyg LMPH, Univ Pl 1, B-2610 Antwerp, Belgium

[4] Drugs Neglected Dis Initiat DNDi, 15 Chemin Camille Vidart, CH-1202 Geneva, Switzerland

来源：

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY | 2023年 / 246卷

基金：

巴西圣保罗研究基金会;

关键词：

2-Aminobenzimidazole derivatives; Chagas disease; Hit-to-lead; Multiparametric optimization; Trypanosoma cruzi; DRUG DISCOVERY; BENZNIDAZOLE;

D O I：

10.1016/j.ejmech.2022.114925

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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.

引用

页数：10

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