Novel orally active antimalarial thiazoles

J Med Chem. 2011 Nov 10;54(21):7713-9. doi: 10.1021/jm201108k. Epub 2011 Oct 11.

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).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Animals
  • Antimalarials / chemical synthesis*
  • Antimalarials / pharmacokinetics
  • Antimalarials / pharmacology
  • Biological Availability
  • Cytochrome P-450 CYP1A2 Inhibitors
  • Drug Interactions
  • Drug Resistance
  • Ether-A-Go-Go Potassium Channels / antagonists & inhibitors
  • Humans
  • In Vitro Techniques
  • Injections, Intravenous
  • Malaria / drug therapy
  • Male
  • Mice
  • Microsomes / metabolism
  • Parasitic Sensitivity Tests
  • Plasmodium berghei
  • Plasmodium falciparum / drug effects
  • Rats
  • Rats, Sprague-Dawley
  • Structure-Activity Relationship
  • Thiazoles / chemical synthesis*
  • Thiazoles / pharmacokinetics
  • Thiazoles / pharmacology

Substances

  • Antimalarials
  • Cytochrome P-450 CYP1A2 Inhibitors
  • Ether-A-Go-Go Potassium Channels
  • Thiazoles