| Full text | |
| Author(s): Show less - |
de Oliveira Rezende Jr, Celso
;
Martinez, Pablo David Grigol
;
Ferreira, Rafael Augusto Alves
;
Koovits, Paul John
;
Soares, Bruna Miranda
;
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
Total Authors: 17
|
| Document type: | Journal article |
| Source: | EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY; v. 246, p. 10-pg., 2023-01-15. |
| 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-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. (AU) | |
| FAPESP's process: | 13/07600-3 - CIBFar - Center for Innovation in Biodiversity and Drug Discovery |
| Grantee: | Glaucius Oliva |
| Support Opportunities: | Research Grants - Research, Innovation and Dissemination Centers - RIDC |
| FAPESP's process: | 15/50655-9 - FAPESP/MMV/DNDi/UNICAMP/USP Consortium to discover new drugs for the treatment of tropical parasitic diseases |
| Grantee: | Luiz Carlos Dias |
| Support Opportunities: | Research Grants - Research Partnership for Technological Innovation - PITE |
| FAPESP's process: | 15/09080-2 - Evaluation of candidate drugs for the treatment of Leishmaniasis in Brazil |
| Grantee: | Silvia Reni Bortolin Uliana |
| Support Opportunities: | Regular Research Grants |