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An aminomethylthiazole pyrazole carboxamide lead 3 with good in vitro antiplasmodial activity [IC50: 0.08 muM (K1, chloroquine and multidrug resistant strain) and 0.07 muM (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 (t1/2 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 (IC50 = 1.5 muM) and 2D6 (IC50 = 0.4 muM) as well as having a potential hERG liability (IC50 = 3.7 muM).
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Reference：
Pyridazine – Wikipedia,
Pyridazine | C4H4N480 – PubChem