Potent antimalarial febrifugine analogues against the Plasmodium malaria parasite

Haruhisa Kikuchi, Hidehisa Tasaka, Shingo Hirai, Yoshiaki Takaya, Yoshiharu Iwabuchi, Hidenori Ooi, Susumi Hatakeyama, Hye Sook Kim, Yusuke Wataya, Yoshiteru Oshima

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93 Citations (Scopus)


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, EC50 = 2.0 × 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, EC50 = 2.0 × 10-8 M) of 1 at C-2′ and its cyclic derivatives 9 and 10 (EC50 = 3.7 × 10-9 and 8.6 × 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-fanctionalities are crucial in the activity of 1. For 7, 8, and 9, prepared as racemic forms, an in vivo study has also been conducted.

Original languageEnglish
Pages (from-to)2563-2570
Number of pages8
JournalJournal of Medicinal Chemistry
Issue number12
Publication statusPublished - 2002 Jun 6
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery


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