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 ant...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2006-07, Vol.49 (15), p.4698-4706
Main Authors: Kikuchi, Haruhisa, Yamamoto, Keisuke, Horoiwa, Seiko, Hirai, Shingo, Kasahara, Ryota, Hariguchi, Norimitsu, Matsumoto, Makoto, Oshima, Yoshiteru
Format: Article
Language:English
Subjects:
Animals
Antibiotics. Antiinfectious agents. Antiparasitic agents
Antimalarials - chemical synthesis
Antimalarials - chemistry
Antimalarials - pharmacology
Antiparasitic agents
Biological and medical sciences
Cell Line
Malaria - drug therapy
Medical sciences
Mice
Parasitic Sensitivity Tests
Pharmacology. Drug treatments
Piperidines
Plasmodium berghei - drug effects
Plasmodium falciparum - drug effects
Pyrimidinones - chemical synthesis
Pyrimidinones - chemistry
Pyrimidinones - pharmacology
Quinazolines - chemical synthesis
Quinazolines - chemistry
Quinazolines - pharmacology
Stereoisomerism
Structure-Activity Relationship
Thiophenes - chemical synthesis
Thiophenes - chemistry
Thiophenes - pharmacology
Toxicity Tests, Acute
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Summary: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.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm0601809