title: Optimization of propafenone analogues as antimalarial leads.
abstract: Propafenone, a class Ic antiarrythmic drug, inhibits growth of cultured  Plasmodium falciparum.  While the drug's potency is significant, further development of propafenone as an antimalarial would require divorcing the antimalarial and cardiac activities as well as improving the pharmacokinetic profile of the drug. A small array of propafenone analogues was designed and synthesized to address the cardiac ion channel and PK liabilities. Testing of this array revealed potent inhibitors of the 3D7 (drug sensitive) and K1 (drug resistant) strains of P. falciparum that possessed significantly reduced ion channel effects and improved metabolic stability. Propafenone analogues are unusual among antimalarial leads in that they are more potent against the multidrug resistant K1 strain of P. falciparum compared to the 3D7 strain.
authors.affiliation: Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Lowes
authors.forename: W Armand
authors.initials: WA
authors.lastname: Guiguemde
authors.forename: Michele C
authors.initials: MC
authors.lastname: Connelly
authors.forename: Fangyi
authors.initials: F
authors.lastname: Zhu
authors.forename: Martina S
authors.initials: MS
authors.lastname: Sigal
authors.forename: Julie A
authors.initials: JA
authors.lastname: Clark
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Lemoff
authors.forename: Joseph L
authors.initials: JL
authors.lastname: Derisi
authors.forename: Emily B
authors.initials: EB
authors.lastname: Wilson
authors.forename: R Kiplin
authors.initials: RK
authors.lastname: Guy
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000494:pharmacology; D002460:Cell Line; D004351:Drug Resistance; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D007473:Ion Channels / Q000037:antagonists & inhibitors; D008297:Male; D008567:Membranes, Artificial; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D021261:Parasitic Sensitivity Tests; D010539:Permeability; D010963:Plasmodium falciparum / Q000187:drug effects; D011405:Propafenone / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D012995:Solubility; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000962:Antimalarials; D007473:Ion Channels; D008567:Membranes, Artificial; D011405:Propafenone