Novel orally active antimalarial thiazoles.
J Med Chem
; 54(21): 7713-9, 2011 Nov 10.
Article
in En
| MEDLINE
| ID: mdl-21966980
ABSTRACT
An aminomethylthiazole pyrazole carboxamide lead 3 with good in vitro antiplasmodial activity [IC(50) 0.08 µM (K1, chloroquine and multidrug resistant strain) and 0.07 µM (NF54, chloroquine sensitive strain)] and microsomal metabolic stability was identified from whole cell screening of a SoftFocus kinase library. Compound 3 also exhibited in vivo activity in the P. berghei mouse model at 4 × 50 mg/kg administration via the oral route, showing 99.5% activity and 9 days survival and showed low in vitro cytotoxicity. Pharmacokinetic studies in rats revealed good oral bioavailability (51% at 22 mg/kg) with a moderate rate of absorption, reasonable half-life (t(1/2) 3 h), and high volume of distribution with moderately high plasma and blood clearance after IV administration. Toward toxicity profiling, 3 exhibited moderate potential to inhibit CYP1A2 (IC(50) = 1.5 µM) and 2D6 (IC(50) = 0.4 µM) as well as having a potential hERG liability (IC(50) = 3.7 µM).
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Thiazoles
/
Antimalarials
Limits:
Animals
/
Humans
/
Male
Language:
En
Journal:
J Med Chem
Journal subject:
QUIMICA
Year:
2011
Document type:
Article
Affiliation country:
Sudáfrica