Febrifugine

A Chinese traditional herbal treatment for malaria obtained from the roots of Dichroafebrifuga is called Ch ang Shan and was investigated in the 1940s. Febrifugine (80), the alkaloid responsible for its activity, was isolated and found to be considerably more active than quinine in experimental infections. Unfortunately, the dmg caused nausea and vomiting in humans. Synthesized analogues were generally less effective than the parent. 

The antimalarial properties attributed to preparations from Dichroa febrifuga by the Chinese were confirmed about 1944 and two alkaloids, febrifugine (999) and isofebrifugine (1000), were isolated eventually. After difficult structural elucidations, syntheses of ( )-febrifugine followed it proved to be half as active as the natural material, itself far better than quinine, but the therapeutic index was disappointingly low (67HC(24-l)490). 

The roots and leaves have been re-examined by Koepfli, Mead and Broekman, who have isolated two alkaloids. Febrifugine, CjgHjgOsNg, m.p. 139-140°, + 6° (CHClg), was obtained from both root and... 

Alkaloids containing a quinazoline nucleus form a small but important group of natural products and have been isolated from a number of different families in the plant kingdom. The quinazoline alkaloids are of the four types (48), (49), (50), and (51). The structures of arborine, peganine, febrifugine, rutaecarpine, and evodi-amine have been elucidated by degradation and synthesis and are described in recent reviews on quinazoline alkaloids. ... 

The structure of febrifugine (the famous Chan San alkaloid known since 200 b.c.) has been completely elucidated, but that of the isomer isofebrifugine which occurs with it is still in some doubt. All evidence points to the semiketal structure (52) and, although it is readily converted to febrifugine, it does not react with ketonic reagents. 

Many quinazolines possessing a wide variety of biological activities are known. The antimalarial activity of febrifugine spurred the preparation and testing of a number of quinazolines, and several... 

A tin(II)-catalyzed asymmetric aldol reaction and lanthanide-catalyzed aqueous three-component reaction have been used as the key steps for the synthesis of febrifugine and isofebrifugine (Scheme 8.31).293... 

Substituted and aza analogues of febrifugine have been prepared in the search, with a certain amount of success, for a better anti-malarial activity/ toxicity balance <06BMCL1854>. A number of analogues of rutaecarpine, including substituents in and fusion onto ring D were prepared by condensation reactions on iminothio ethers 55... 

Quinazoline alkaloids contain more than 100 compounds. They have been isolated from animal and plant sources. The plant family Rutaceae is especially rich in these alkaloids. Typical quinazoline alkaloids include, for example, arborine, glomerin, homoglomerin, glycerine, glycosminine, febrifugine and... 

Quinazoline alkaloids are known as biologically active compounds. Arborine inhibits the peripheral action of acetylcholine and induces a fall in blood pressure. Febrifugine is an anti-malarial agent and vasicine acts as a uterine stimulant. Glomerin and homoglomerin are alkaloids of the defensive system in some organisms (e.g., in the glomerid millipede). 

China Hydrangea macrophylla (Thunb.) Seringe Febrifugin, hydrangeic acid, hydrangenol, rutin.50 Antimalarial, antitussive, diuretic. 

Largely on the basis of the magnitude (7 Hz) of J13 (obtained by irradiation at the side chain methylene) in febrifugine acetate di-hydro-chloride [272] this derivative of the hydrangea alkaloid was assigned the trans configuration shown. (173)... 

Thus, (-)-26 was transformed into the diene 58 which, on sequential RCM and deprotection, furnished (+)-conduritol F (Scheme 17).23 On the other hand, (-)-26 was converted into the diene 60, via 59, which gave the ketone 62, the precursor of febrifugine,24 by conversion involving RCM. 

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