Febrifugine structure

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). 

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. 

Structure and synthesis of antimalarial quinazoline alkaloid febrifugine 01YGK569. 

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). 

Langer and co-workers generated 2,2 -bis-quinazolin-4-ones by condensing substituted anthranilic esters with substituted bis(imidoyl)-chlorides. These compounds, which are structurally similar to the quinazoline alkaloid febrifUgine, have the potential to serve as anti-malarials. Treatment of methyl-2-amino-4,5-dimethoxybenzoate with bis(p-methoxyl-phenylimidoyl)chloride in the presence of two equivalents of TEA in refluxing toluene gave the desired product in 60% yield. 

After side-chain modification, as in the synthetic 3-[p-keto-y-(3-hydroxy-2-pyridyl)-propyl]-quinazolin-4-one 66), was found to be fruitless, attempts at structural modification of febrifugine were focused on the synthesis of some methylenedioxy analogues by Chien and Cheng 44). The 5,6-, 6,7- and 7,8-methylenedioxy analogues were found to be active against PI. berghei. Toxicity of these compounds in mice is much lower than that of febrifugine and their therapeutic indices are comparable to that of the parent compound. 

Halofuginone (33) is not plant-derived alkaloid. It is halogenated synthetic compound, which shows structural features based on febrifugine (34), a V3-substituted quinazolin-4-one alkaloid [127]. 

Figure 35 Quinazoline alkaloids and related quinolizidine—quinazoline systems +)-febrifugine (1543) (+)-isofebrifugine (1544) (+)-neodichroine (1545) discredited structure for (+)-hydrachine A (1546).

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