title: Cell-based optimization of novel benzamides as potential antimalarial leads.
abstract: Screening our in-house compound collection using a cell based Plasmodium falciparum proliferation assay we discovered a known pan-kinase inhibitor scaffold as a hit. Further optimization of this series led us to a novel benzamide scaffold which was devoid of human kinase activity while retaining its antiplasmodial activity. The evolution of this compound series leading to optimized candidates with good cellular potency against multiple strains as well as decent in vivo profile is described in this Letter.
authors.affiliation: Genomics Institute of the Novartis Research Foundation, 10675 John J. Hopkins Drive, San Diego, CA 92121, USA.
authors.forename: Tao
authors.initials: T
authors.lastname: Wu
authors.forename: Advait
authors.initials: A
authors.lastname: Nagle
authors.forename: Tomoyo
authors.initials: T
authors.lastname: Sakata
authors.forename: Kerstin
authors.initials: K
authors.lastname: Henson
authors.forename: Rachel
authors.initials: R
authors.lastname: Borboa
authors.forename: Zhong
authors.initials: Z
authors.lastname: Chen
authors.forename: Kelli
authors.initials: K
authors.lastname: Kuhen
authors.forename: David
authors.initials: D
authors.lastname: Plouffe
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Winzeler
authors.forename: Francisco
authors.initials: F
authors.lastname: Adrian
authors.forename: Tove
authors.initials: T
authors.lastname: Tuntland
authors.forename: Jonathan
authors.initials: J
authors.lastname: Chang
authors.forename: Susan
authors.initials: S
authors.lastname: Simerson
authors.forename: Steven
authors.initials: S
authors.lastname: Howard
authors.forename: Jared
authors.initials: J
authors.lastname: Ek
authors.forename: John
authors.initials: J
authors.lastname: Isbell
authors.forename: Xianming
authors.initials: X
authors.lastname: Deng
authors.forename: Nathanael S
authors.initials: NS
authors.lastname: Gray
authors.forename: David C
authors.initials: DC
authors.lastname: Tully
authors.forename: Arnab K
authors.initials: AK
authors.lastname: Chatterjee
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001549:Benzamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D019020:Directed Molecular Evolution; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D051379:Mice; D010770:Phosphotransferases / Q000037:antagonists & inhibitors*; D010963:Plasmodium falciparum / Q000187:drug effects / Q000201:enzymology*
chemical_list: D000962:Antimalarials; D001549:Benzamides; D004791:Enzyme Inhibitors; D010770:Phosphotransferases