title: Imidazolopiperazines: hit to lead optimization of new antimalarial agents.
abstract: Starting from a hit series from a GNF compound library collection and based on a cell-based proliferation assay of Plasmodium falciparum, a novel imidazolopiperazine scaffold was optimized. SAR for this series of compounds is discussed, focusing on optimization of cellular potency against wild-type and drug resistant parasites and improvement of physiochemical and pharmacokinetic properties. The lead compounds in this series showed good potencies in vitro and decent oral exposure levels in vivo. In a Plasmodium berghei mouse infection model, one lead compound lowered the parasitemia level by 99.4% after administration of 100 mg/kg single oral dose and prolonged mice survival by an average of 17.0 days. The lead compounds were also well-tolerated in the preliminary in vitro toxicity studies and represents an interesting lead for drug development.
authors.affiliation: Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, USA.
authors.forename: Tao
authors.initials: T
authors.lastname: Wu
authors.forename: Advait
authors.initials: A
authors.lastname: Nagle
authors.forename: Kelli
authors.initials: K
authors.lastname: Kuhen
authors.forename: Kerstin
authors.initials: K
authors.lastname: Gagaring
authors.forename: Rachel
authors.initials: R
authors.lastname: Borboa
authors.forename: Caroline
authors.initials: C
authors.lastname: Francek
authors.forename: Zhong
authors.initials: Z
authors.lastname: Chen
authors.forename: David
authors.initials: D
authors.lastname: Plouffe
authors.forename: Anne
authors.initials: A
authors.lastname: Goh
authors.forename: Suresh B
authors.initials: SB
authors.lastname: Lakshminarayana
authors.forename: Jeanette
authors.initials: J
authors.lastname: Wu
authors.forename: Hui Qing
authors.initials: HQ
authors.lastname: Ang
authors.forename: Peiting
authors.initials: P
authors.lastname: Zeng
authors.forename: Min Low
authors.initials: ML
authors.lastname: Kang
authors.forename: William
authors.initials: W
authors.lastname: Tan
authors.forename: Maria
authors.initials: M
authors.lastname: Tan
authors.forename: Nicole
authors.initials: N
authors.lastname: Ye
authors.forename: Xuena
authors.initials: X
authors.lastname: Lin
authors.forename: Christopher
authors.initials: C
authors.lastname: Caldwell
authors.forename: Jared
authors.initials: J
authors.lastname: Ek
authors.forename: Suzanne
authors.initials: S
authors.lastname: Skolnik
authors.forename: Fenghua
authors.initials: F
authors.lastname: Liu
authors.forename: Jianling
authors.initials: J
authors.lastname: Wang
authors.forename: Jonathan
authors.initials: J
authors.lastname: Chang
authors.forename: Chun
authors.initials: C
authors.lastname: Li
authors.forename: Thomas
authors.initials: T
authors.lastname: Hollenbeck
authors.forename: Tove
authors.initials: T
authors.lastname: Tuntland
authors.forename: John
authors.initials: J
authors.lastname: Isbell
authors.forename: Christoph
authors.initials: C
authors.lastname: Fischli
authors.forename: Reto
authors.initials: R
authors.lastname: Brun
authors.forename: Matthias
authors.initials: M
authors.lastname: Rottmann
authors.forename: Veronique
authors.initials: V
authors.lastname: Dartois
authors.forename: Thomas
authors.initials: T
authors.lastname: Keller
authors.forename: Thierry
authors.initials: T
authors.lastname: Diagana
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Winzeler
authors.forename: Richard
authors.initials: R
authors.lastname: Glynne
authors.forename: David C
authors.initials: DC
authors.lastname: Tully
authors.forename: Arnab K
authors.initials: AK
authors.lastname: Chatterjee
mesh_terms: D000596:Amino Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000814:Aniline Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001555:Benzene Derivatives / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D004351:Drug Resistance; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D008288:Malaria / Q000188:drug therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010962:Plasmodium berghei; D010963:Plasmodium falciparum / Q000187:drug effects; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D000596:Amino Acids; D000814:Aniline Compounds; D000962:Antimalarials; D001555:Benzene Derivatives; D007093:Imidazoles; D010879:Piperazines