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: Haruhisa Kikuchi, Hidehisa Tasaka, Shingo Hirai, Yoshiaki Takaya, Yoshiharu Iwabuchi, Hidenori Ooi, Susumi Hatakeyama, Hye-Sook Kim, Yusuke Wataya, Yoshiteru Oshima
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 45 Issue 12 Pg. 2563-70 (Jun 06 2002) ISSN: 0022-2623 [Print] United States
• PMID: 12036365 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antimalarials
• Piperidines
• Quinazolines
• febrifugine

Topics

• Animals
• Antimalarials (chemical synthesis, chemistry, pharmacology)
• Cell Line
• Malaria (drug therapy)
• Mice
• Piperidines
• Plasmodium berghei
• Plasmodium falciparum (drug effects)
• Quinazolines (chemical synthesis, chemistry, pharmacology)
• Structure-Activity Relationship