title: Structure-activity relationship studies of orally active antimalarial 3,5-substituted 2-aminopyridines.
abstract: In an effort to address potential cardiotoxicity liabilities identified with earlier frontrunner compounds, a number of new 3,5-diaryl-2-aminopyridine derivatives were synthesized. Several compounds exhibited potent antiplasmodial activity against both the multidrug resistant (K1) and sensitive (NF54) strains in the low nanomolar range. Some compounds displayed a significant reduction in potency in the hERG channel inhibition assay compared to previously reported frontrunner analogues. Several of these new analogues demonstrated promising in vivo efficacy in the  Plasmodium berghei  mouse model and will be further evaluated as potential clinical candidates. The SAR for in vitro antiplasmodial and hERG activity was delineated.
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: Yassir
authors.initials: Y
authors.lastname: Younis
authors.forename: Tzu-Shean
authors.initials: TS
authors.lastname: Feng
authors.forename: Claire
authors.initials: C
authors.lastname: Le Manach
authors.forename: Aloysius T
authors.initials: AT
authors.lastname: Nchinda
authors.forename: Leslie J
authors.initials: LJ
authors.lastname: Street
authors.forename: Christian
authors.initials: C
authors.lastname: Scheurer
authors.forename: Jolanda
authors.initials: J
authors.lastname: Kamber
authors.forename: Karen L
authors.initials: KL
authors.lastname: White
authors.forename: Oliver D
authors.initials: OD
authors.lastname: Montagnat
authors.forename: Eileen
authors.initials: E
authors.lastname: Ryan
authors.forename: Kasiram
authors.initials: K
authors.lastname: Katneni
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: Susan A
authors.initials: SA
authors.lastname: Charman
authors.forename: Sergio
authors.initials: S
authors.lastname: Wittlin
authors.forename: Kelly
authors.initials: K
authors.lastname: Chibale
mesh_terms: D000284:Administration, Oral; D000631:Aminopyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018432:Drug Resistance, Multiple; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors; D006801:Humans; D008288:Malaria / Q000188:drug therapy; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D010962:Plasmodium berghei; D010963:Plasmodium falciparum / Q000187:drug effects; D012995:Solubility; D013329:Structure-Activity Relationship
chemical_list: D000631:Aminopyridines; D000962:Antimalarials; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human