title: Potent antimalarial febrifugine analogues against the plasmodium malaria parasite.
abstract: Although febrifugine (1) and isofebrifugine (2), alkaloids isolated from roots of the Dichroa febrifuga plant, show powerful antimalarial activity against Plasmodium falciparum, strong side effects such as the emetic effect have precluded their clinical use against malaria. However, their antimalarial potency makes them attractive substances as leads for developing new types of chemotherapeutic antimalarial drugs. Thus, we have evaluated the in vitro antimalarial activity of the analogues of febrifugine (1) and isofebrifugine (2). The activities of the analogues derived from Df-1 (3) and Df-2 (4), condensation products of 1 and 2 with acetone, respectively, were also obtained. The 3' '-keto derivative (7, EC(50) = 2.0 x 10(-8) M) of 1 was found to exhibit potential antimalarial activity with high selectivity against P. falciparum in vitro. The in vitro activities of the reduction product (8, EC(50) = 2.0 x 10(-8) M) of 1 at C-2' and its cyclic derivatives 9 and 10 (EC(50) = 3.7 x 10(-9) and 8.6 x 10(-9) M, respectively) were found to be strongly active and selective. Additionally, the Dess-Martin oxidation product of 3 was found to be strongly active with high selectivity against P. falciparum. A structure-activity relationship study (SAR) demonstrates that the essential role played by the 4-quinazolinone ring in the appearance of activity and the presence of a 1' '-amino group and C-2', C-3' ' O-functionalities are crucial in the activity of 1. For 7, 8, and 9, prepared as racemic forms, an in vivo study has also been conducted.
authors.affiliation: Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba-yama, Aoba-ku, Sendai 980-8578, Japan.
authors.forename: Haruhisa
authors.initials: H
authors.lastname: Kikuchi
authors.forename: Hidehisa
authors.initials: H
authors.lastname: Tasaka
authors.forename: Shingo
authors.initials: S
authors.lastname: Hirai
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Takaya
authors.forename: Yoshiharu
authors.initials: Y
authors.lastname: Iwabuchi
authors.forename: Hidenori
authors.initials: H
authors.lastname: Ooi
authors.forename: Susumi
authors.initials: S
authors.lastname: Hatakeyama
authors.forename: Hye-Sook
authors.initials: HS
authors.lastname: Kim
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Wataya
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; D010880:Piperidines; D010962:Plasmodium berghei; D010963:Plasmodium falciparum / Q000187:drug effects; D011799:Quinazolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000962:Antimalarials; D010880:Piperidines; D011799:Quinazolines; C001207:febrifugine