Febrifugine antimalarial

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). 

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... 

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

Structure and synthesis of antimalarial quinazoline alkaloid febrifugine 01YGK569. 

As noted earlier in this report, in recent years hundreds of crude plant materials and extracts thereof have been examined for antimalarial activity (9, 90, 91). These investigations have been singularly nonproductive (92). Either the plant products exhibited negative or barely detectable activity when examined in the avian host or failed to possess usable activity because of toxicological habihties (93-95). The circumstances surrounding the development of febrifugine is an excellent case in point. 

Febrifugine has a history as a malaria remedy which dates back to the first recorded use of Ch ang Shan in China, 200 B.C. It is an alkaloid which is apparently fairly widely distributed in the roots and leaves of plants of the family Saxifragaceae, and has been isolated both from the leaves of the common hydrangea in the United States and from the roots of Dichroa febrifuga Lour. The alleged antimalarial activity of the latter crude plant material has been confirmed by a number of modem investigators (93, 96-99). As a consequence of the careful and independent studies of both American and Chinese workers (100-106), the active alkaloid has been... 

Febrifugine (9) is perhaps one of the most interesting quinazoline alkaloids. Information on this alkaloid has been summarized in the earlier reviews published in this treatise (1,2) readers are also referred to the authoritative book by Armarego (33). The antimalarial activity of 9 especially provided a strong stimulus for the synthesis and biological screening of a vast number of quinazoline derivatives. 

The total alkaloid content of the Chinese root is 0.1-0.15% (43, 46), but that of Indian root is only about one tenth as great (46). The leaves of D. febrifuga also contain febrifugine (43, 44, 46), but in much smaller amount than the roots nevertheless, the leaves (known as Shuu Chi, or in Yunnan as Chunine ) have a high antimalarial activity and probably contain some other active alkaloid (44). Febrifugine has also been isolated from hydrangea leaves (51). 

Febrifugine is the first alkaloid to be isolated from a member of the Saxifragaceae, and it is the first known alkaloid outside the cinchona group to possess marked antimalarial activity. Its quinazoline structure is of particular interest in view of the recorded antimalarial activity of some synthetic quinazolines (49). A number of synthetic analogues of XXXII have been prepared and tested as antimalarials (51). 

The enantioselective synthesis of antimalarial (+)-febrifugine and (+)-isofebrifugine alkaloids was achieved through the 1,3-DC of (S)-5-alkoxy-2,3,43-lctrahydropyridine-l-oxide 76 with allyl alcohol followed by hydrogcnolytic N-O bond fission and suitable elaboration of the product <01OL953>. 

Quinazoline alkaloids are known as biologically active compounds. Arbor-ine inhibits the peripheral action of acetylcholine and induces a fall in blood pressure. Febrifugine is an antimalarial 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). 

Fig. 5 Examples of febrifugine metabolites and their antimalarial activities against P.

Several bio-active natural products such as febrifugine (Fig. 13.5) and isofebri-fugine (Fig. 13.6) contain quinazohnone moieties with potential antimalarial [79] activity. 

Yasuo T, Miyo O (2005) Concise Synthesis of dl-Febrifugine. Chem Pharm Bull 53 868-869 Koepfli JB, Mead JF et al (1947) An alkaloid with high antimalarial activity from Dichroa febrifuga. J Am Chem Soc 69 1837... 

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