title: Exploration of a new type of antimalarial compounds based on febrifugine.
abstract: 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.
authors.affiliation: Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba-yama, Sendai 980-8578, Japan.
authors.forename: Haruhisa
authors.initials: H
authors.lastname: Kikuchi
authors.forename: Keisuke
authors.initials: K
authors.lastname: Yamamoto
authors.forename: Seiko
authors.initials: S
authors.lastname: Horoiwa
authors.forename: Shingo
authors.initials: S
authors.lastname: Hirai
authors.forename: Ryota
authors.initials: R
authors.lastname: Kasahara
authors.forename: Norimitsu
authors.initials: N
authors.lastname: Hariguchi
authors.forename: Makoto
authors.initials: M
authors.lastname: Matsumoto
authors.forename: Yoshiteru
authors.initials: Y
authors.lastname: Oshima
mesh_terms: 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
chemical_list: 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