Synthesis and evaluation of 4-quinazolinone compounds as potential antimalarial agents.
Febrifugine is an alkaloid isolated from Dichroa febrifuga as the active component against Plasmodium falciparum. Adverse side effects have precluded febrifugine as a potential clinical drug. As part of an ongoing malaria chemotherapy project, novel febrifugine analogues were designed and synthesized. Lower toxicity of these newly designed compounds was achieved by reducing or eliminating the tendency to form chemically reactive and toxic intermediates. New compounds possess excellent in vivo antimalarial activity and most of them become less toxic than the natural product febrifugine. Some of the compounds possess a therapeutic index over ten times superior to that of febrifugine and the commonly used antimalarial drug chloroquine. These compounds, as well as the underlying design rationale, may find usefulness in the discovery and development of new antimalarial drugs.
Zhu
Shuren
S
Radix Pharmaceuticals Inc., 13303 Sunny Brooke PL, Rm 101, Potomac, MD 20854, USA. shuren.zhu@gmail.com
Wang
Joe
J
Chandrashekar
Gudise
G
Smith
Erika
E
Liu
Xianjun
X
Zhang
Yongshen
Y
D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D002460:Cell Line; D004353:Drug Evaluation, Preclinical; D051379:Mice; D008813:Mice, Inbred ICR; D010963:Plasmodium falciparum / Q000187:drug effects; D052999:Quinazolinones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity
D000962:Antimalarials; D052999:Quinazolinones