Exploration of a new type of antimalarial compounds based on febrifugine.
Febrifugine (1), a quinazoline alkaloid, isolated from Dichroa febrifuga roots, shows powerful antimalarial activity against Plasmodium falciparum. The use of 1 as an antimalarial drug has been precluded because of side effects, such as diarrhea, vomiting, and liver toxicity. However, the potent antimalarial activity of 1 has stimulated medicinal chemists to pursue compounds derived from 1, which may be valuable leads for novel drugs. In this study, we synthesized a new series of febrifugine derivatives formed by structural modifications at (i) the quinazoline ring, (ii) the linker, or (iii) the piperidine ring. Then, we evaluated their antimalarial activities. Thienopyrimidine analogue 15 exhibited a potent antimalarial activity and a high therapeutic selectivity both in vitro and in vivo, suggesting that 15 is a good antimalarial candidate.
Kikuchi
Haruhisa
H
Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba-yama, Sendai 980-8578, Japan.
Yamamoto
Keisuke
K
Horoiwa
Seiko
S
Hirai
Shingo
S
Kasahara
Ryota
R
Hariguchi
Norimitsu
N
Matsumoto
Makoto
M
Oshima
Yoshiteru
Y
D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D008288:Malaria / Q000188:drug therapy; D051379:Mice; D021261:Parasitic Sensitivity Tests; D010880:Piperidines; D010962:Plasmodium berghei / Q000187:drug effects; D010963:Plasmodium falciparum / Q000187:drug effects; D011744:Pyrimidinones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011799:Quinazolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D023382:Toxicity Tests, Acute
C513005:3-(3-(3-hydroxypiperidin-2-yl)-2-oxopropyl)-3H-thiopheno(3,2-d)pyrimidin-4-one; D000962:Antimalarials; D010880:Piperidines; D011744:Pyrimidinones; D011799:Quinazolines; D013876:Thiophenes; C001207:febrifugine