title: 3,5-Diaryl-2-aminopyridines as a novel class of orally active antimalarials demonstrating single dose cure in mice and clinical candidate potential.
abstract: A novel class of orally active antimalarial 3,5-diaryl-2-aminopyridines has been identified from phenotypic whole cell high-throughput screening of a commercially available SoftFocus kinase library. The compounds were evaluated in vitro for their antiplasmodial activity against K1 (chloroquine and drug-resistant strain) and NF54 (chloroquine-susceptible strain) as well as for their cytotoxicity. Synthesis and structure-activity studies identified a number of promising compounds with selective antiplasmodial activity. One of these frontrunner compounds, 15, was equipotent across the two strains (K1 = 25.0 nM, NF54 = 28.0 nM) and superior to chloroquine in the K1 strain (chloroquine IC(50) K1 = 194.0 nM). Compound 15 completely cured Plasmodium berghei-infected mice with a single oral dose of 30 mg/kg. Dose-response studies generated ED(50) and ED(90) values of 0.83 and 1.74 mg/kg for 15 in the standard four-dose Peters test. Pharmacokinetic studies in the rat indicated that this compound has good oral bioavailability (51% at 20 mg/kg) and a reasonable half-life (t(1/2) ∼ 7-8 h).
authors.affiliation: Department of Chemistry, University of Cape Town, Rondebosch 7701, South Africa.
authors.forename: Yassir
authors.initials: Y
authors.lastname: Younis
authors.forename: Frederic
authors.initials: F
authors.lastname: Douelle
authors.forename: Tzu-Shean
authors.initials: TS
authors.lastname: Feng
authors.forename: Diego
authors.initials: D
authors.lastname: González Cabrera
authors.forename: Claire
authors.initials: C
authors.lastname: Le Manach
authors.forename: Aloysius T
authors.initials: AT
authors.lastname: Nchinda
authors.forename: Sandra
authors.initials: S
authors.lastname: Duffy
authors.forename: Karen L
authors.initials: KL
authors.lastname: White
authors.forename: David M
authors.initials: DM
authors.lastname: Shackleford
authors.forename: Julia
authors.initials: J
authors.lastname: Morizzi
authors.forename: Janne
authors.initials: J
authors.lastname: Mannila
authors.forename: Kasiram
authors.initials: K
authors.lastname: Katneni
authors.forename: Ravi
authors.initials: R
authors.lastname: Bhamidipati
authors.forename: K Mohammed
authors.initials: KM
authors.lastname: Zabiulla
authors.forename: Jayan T
authors.initials: JT
authors.lastname: Joseph
authors.forename: Sridevi
authors.initials: S
authors.lastname: Bashyam
authors.forename: David
authors.initials: D
authors.lastname: Waterson
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Witty
authors.forename: David
authors.initials: D
authors.lastname: Hardick
authors.forename: Sergio
authors.initials: S
authors.lastname: Wittlin
authors.forename: Vicky
authors.initials: V
authors.lastname: Avery
authors.forename: Susan A
authors.initials: SA
authors.lastname: Charman
authors.forename: Kelly
authors.initials: K
authors.lastname: Chibale
mesh_terms: D000284:Administration, Oral; D000631:Aminopyridines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001682:Biological Availability; D002460:Cell Line; D002738:Chloroquine / Q000494:pharmacology; D065607:Cytochrome P-450 Enzyme Inhibitors; D004351:Drug Resistance; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors; D005260:Female; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D008288:Malaria / Q000188:drug therapy; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D010962:Plasmodium berghei; D010963:Plasmodium falciparum / Q000187:drug effects; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship
chemical_list: D000631:Aminopyridines; D000962:Antimalarials; D065607:Cytochrome P-450 Enzyme Inhibitors; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D007527:Isoenzymes; D002738:Chloroquine