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

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

  • Eur J Med Chem. 2022 Nov 15;246:114925. doi: 10.1016/j.ejmech.2022.114925.
Celso de Oliveira Rezende Júnior 1,  Pablo David Grigol Martinez 1,  Rafael Augusto Alves Ferreira 1,  Paul John Koovits 1,  Bruna Miranda Soares 1,  Leonardo L G Ferreira 2,  Simone Michelan-Duarte 2,  Rafael Consolin Chelucci 2,  Adriano D Andricopulo 2,  An Matheeussen 3,  Natascha Van Pelt 3,  Guy Caljon 3,  Louis Maes 3,  Simon Campbell 4,  Jadel M Kratz 4,  Charles E Mowbray 4,  Luiz Carlos Dias 5
Affiliations

Affiliations

  • 1 Institute of Chemistry, University of Campinas (UNICAMP), Campinas, SP, 13083-861, Brazil.
  • 2 Laboratory of Medicinal and Computational Chemistry, Physics Institute of São Carlos, University of São Paulo (USP), São Carlos, SP, 13563-120, Brazil.
  • 3 Laboratory of Microbiology, Parasitology and Hygiene (LMPH), Universiteitsplein 1, 2610, Antwerpen, Belgium.
  • 4 Drugs for Neglected Diseases Initiative (DNDi), 15 Chemin Camille-Vidart, 1202, Geneva, Switzerland.
  • 5 Institute of Chemistry, University of Campinas (UNICAMP), Campinas, SP, 13083-861, Brazil. Electronic address: [email protected].
PMID: 36459758 DOI: 10.1016/j.ejmech.2022.114925
Abstract

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.

Keywords

2-Aminobenzimidazole derivatives; Chagas disease; Hit-to-lead; Multiparametric optimization; Trypanosoma cruzi.

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