Disulfide prodrugs of albitiazolium (T3/SAR97276): synthesis and biological activities.
J Med Chem
; 55(10): 4619-28, 2012 May 24.
Article
em En
| MEDLINE
| ID: mdl-22591034
ABSTRACT
We report herein the design, synthesis, and biological screening of a series of 15 disulfide prodrugs as precursors of albitiazolium bromide (T3/SAR97276, compound 1), a choline analogue which is currently being evaluated in clinical trials (phase II) for severe malaria. The corresponding prodrugs are expected to revert back to the active bis-thiazolium salt through an enzymatic reduction of the disulfide bond. To enhance aqueous solubility of these prodrugs, an amino acid residue (valine or lysine) or a phosphate group was introduced on the thiazolium side chain. Most of the novel derivatives exhibited potent in vitro antimalarial activity against P. falciparum. After oral administration, the cyclic disulfide prodrug 8 showed the best improvement of oral efficacy in comparison to the parent drug.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Tiazóis
/
Pró-Fármacos
/
Dissulfetos
/
Antimaláricos
Limite:
Animals
Idioma:
En
Ano de publicação:
2012
Tipo de documento:
Article