title: Novel orally active antimalarial thiazoles.
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).
authors.affiliation: Department of Chemistry,  University of Cape Town , Rondebosch 7701, South Africa.
authors.forename: Diego
authors.initials: D
authors.lastname: González Cabrera
authors.forename: Frederic
authors.initials: F
authors.lastname: Douelle
authors.forename: Tzu-Shean
authors.initials: TS
authors.lastname: Feng
authors.forename: Aloysius T
authors.initials: AT
authors.lastname: Nchinda
authors.forename: Yassir
authors.initials: Y
authors.lastname: Younis
authors.forename: Karen L
authors.initials: KL
authors.lastname: White
authors.forename: Quoc
authors.initials: Q
authors.lastname: Wu
authors.forename: Eileen
authors.initials: E
authors.lastname: Ryan
authors.forename: Jeremy N
authors.initials: JN
authors.lastname: Burrows
authors.forename: David
authors.initials: D
authors.lastname: Waterson
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Witty
authors.forename: Sergio
authors.initials: S
authors.lastname: Wittlin
authors.forename: Susan A
authors.initials: SA
authors.lastname: Charman
authors.forename: Kelly
authors.initials: K
authors.lastname: Chibale
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001682:Biological Availability; D065609:Cytochrome P-450 CYP1A2 Inhibitors; D004347:Drug Interactions; D004351:Drug Resistance; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors; D006801:Humans; D066298:In Vitro Techniques; D007275:Injections, Intravenous; D008288:Malaria / Q000188:drug therapy; D008297:Male; D051379:Mice; D008861:Microsomes / Q000378:metabolism; D021261:Parasitic Sensitivity Tests; D010962:Plasmodium berghei; D010963:Plasmodium falciparum / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D000962:Antimalarials; D065609:Cytochrome P-450 CYP1A2 Inhibitors; D051638:Ether-A-Go-Go Potassium Channels; D013844:Thiazoles