Investigation and conformational analysis of fluorinated nucleoside antibiotics targeting siderophore biosynthesis.
J Org Chem
; 80(10): 4835-50, 2015 May 15.
Article
en En
| MEDLINE
| ID: mdl-25916415
ABSTRACT
Antibiotic resistance represents one of the greatest threats to public health. The adenylation inhibitor 5'-O-[N-(salicyl)sulfamoyl]adenosine (SAL-AMS) is the archetype for a new class of nucleoside antibiotics that target iron acquisition in pathogenic microorganisms and is especially effective against Mycobacterium tuberculosis, the causative agent of tuberculosis. Strategic incorporation of fluorine at the 2' and 3' positions of the nucleoside was performed by direct fluorination to enhance activity and improve drug disposition properties. The resulting SAL-AMS analogues were comprehensively assessed for biochemical potency, whole-cell antitubercular activity, and in vivo pharmacokinetic parameters. Conformational analysis suggested a strong preference of fluorinated sugar rings for either a 2'-endo, 3'-exo (South), or a 3'-endo,2'-exo (North) conformation. The structure-activity relationships revealed a strong conformational bias for the C3'-endo conformation to maintain potent biochemical and whole-cell activity, whereas improved pharmacokinetic properties were associated with the C2'-endo conformation.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Adenosina
/
Sideróforos
/
Antibacterianos
/
Mycobacterium tuberculosis
/
Nucleósidos
/
Antituberculosos
Límite:
Humans
Idioma:
En
Revista:
J Org Chem
Año:
2015
Tipo del documento:
Article
País de afiliación:
Estados Unidos