title: Diversity-oriented synthesis-facilitated medicinal chemistry: toward the development of novel antimalarial agents.
abstract: Here, we describe medicinal chemistry that was accelerated by a diversity-oriented synthesis (DOS) pathway, and in vivo studies of our previously reported macrocyclic antimalarial agent that derived from the synthetic pathway. Structure-activity relationships that focused on both appendage and skeletal features yielded a nanomolar inhibitor of P. falciparum asexual blood-stage growth with improved solubility and microsomal stability and reduced hERG binding. The build/couple/pair (B/C/P) synthetic strategy, used in the preparation of the original screening library, facilitated medicinal chemistry optimization of the antimalarial lead.
authors.affiliation: Center for the Science of Therapeutics, Broad Institute , 7 Cambridge Center, Cambridge, Massachusetts 02142, United States.
authors.forename: Eamon
authors.initials: E
authors.lastname: Comer
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Beaudoin
authors.forename: Nobutaka
authors.initials: N
authors.lastname: Kato
authors.forename: Mark E
authors.initials: ME
authors.lastname: Fitzgerald
authors.forename: Richard W
authors.initials: RW
authors.lastname: Heidebrecht
authors.forename: Maurice duPont
authors.initials: Md
authors.lastname: Lee
authors.forename: Daniela
authors.initials: D
authors.lastname: Masi
authors.forename: Marion
authors.initials: M
authors.lastname: Mercier
authors.forename: Carol
authors.initials: C
authors.lastname: Mulrooney
authors.forename: Giovanni
authors.initials: G
authors.lastname: Muncipinto
authors.forename: Ann
authors.initials: A
authors.lastname: Rowley
authors.forename: Keila
authors.initials: K
authors.lastname: Crespo-Llado
authors.forename: Adelfa E
authors.initials: AE
authors.lastname: Serrano
authors.forename: Amanda K
authors.initials: AK
authors.lastname: Lukens
authors.forename: Roger C
authors.initials: RC
authors.lastname: Wiegand
authors.forename: Dyann F
authors.initials: DF
authors.lastname: Wirth
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Palmer
authors.forename: Michael A
authors.initials: MA
authors.lastname: Foley
authors.forename: Benito
authors.initials: B
authors.lastname: Munoz
authors.forename: Christina A
authors.initials: CA
authors.lastname: Scherer
authors.forename: Jeremy R
authors.initials: JR
authors.lastname: Duvall
authors.forename: Stuart L
authors.initials: SL
authors.lastname: Schreiber
mesh_terms: D000962:Antimalarials / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D060326:Chemistry Techniques, Synthetic; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000378:metabolism; D047029:Lactams, Macrocyclic / Q000737:chemistry / Q000494:pharmacology; D010963:Plasmodium falciparum / Q000187:drug effects; D012995:Solubility; D013329:Structure-Activity Relationship
chemical_list: D000962:Antimalarials; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D047029:Lactams, Macrocyclic