Cell-based optimization of novel benzamides as potential antimalarial leads.
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.
Wu
Tao
T
Genomics Institute of the Novartis Research Foundation, 10675 John J. Hopkins Drive, San Diego, CA 92121, USA.
Nagle
Advait
A
Sakata
Tomoyo
T
Henson
Kerstin
K
Borboa
Rachel
R
Chen
Zhong
Z
Kuhen
Kelli
K
Plouffe
David
D
Winzeler
Elizabeth
E
Adrian
Francisco
F
Tuntland
Tove
T
Chang
Jonathan
J
Simerson
Susan
S
Howard
Steven
S
Ek
Jared
J
Isbell
John
J
Deng
Xianming
X
Gray
Nathanael S
NS
Tully
David C
DC
Chatterjee
Arnab K
AK
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*
D000962:Antimalarials; D001549:Benzamides; D004791:Enzyme Inhibitors; D010770:Phosphotransferases