Biguanides antimalarial activity

Following the discovery of the antimalarial activity [148) of biguanides and quinoline derivatives, a variety of substituted quinolyl-b anides were synthesised [9, 42, 101, 188, 298, 303, 306, 428, 558, 583, 585) by these procedures. The production of a series of m.m-hexamethylenebi-guanides [724) illustrates the use of secondary amines in this synthesis. 

Ward SA, Helby NA, Skjelbo E. The activation of the biguanide antimalarial proguanil co-segragates with the mephenytoin oxidation polymorphism—a panel study. Br J Clin Pharmacol 1991 31 689-692. 

Another structural requirement considered for antimalarial activity of acridines and quinolines was the planarity of the heterocycles. Simulation of all these facts led Curd and Rose to synthesize 2-(4-chlorophenylamino)pyrimidines of the type 26 and 27 [37,39,40]. Since both these structure contained a guanidino function, though in a cyclic structure, the characteristic tautomeric structures were possible. In a further effort to modify the structure of the pyrimidines, the synthesis of the biguanide... 

The mechanism of the antimalarial activity of proguanil or chlorproguanil is unknown. Proguanil as the biguanide accentuates the mitochondrial membrane-potential-collapsing action of ato-vaquone against P. falciparum but displays no such activity by itself (see Atovaquone, above). 

The analog program on pyrimidines included some open-chain versions of this heterocycle as well. These last, the biguanides, were found to be quite active in their own right. (It was subsequently established that these compounds undergo oxidative cyclization to dihydropyrimidines in the body to give the actual antimalarial—see cycloguanyl). 

Aromatic biguanides such as proguanil (181) have been found useful as antimalarial agents. Investigation of the metabolism of this class of drugs revealed that the active compound was in fact the triazine produced by oxidative cyclization onto the terminal alkyl group. The very rapid excretion of the active entity means that it cannot be used as such in therapy. Consequently, treatment usually consists in administration of either the metabolic precursor or, alternately, the triazine as some very insoluble salt to provide slow but continual release of drug. 

Curd, F.H.S., Davey, D.G. and Rose, F.L. (1945) Studies on synthetic antimalarial drugs-X. Some biguanide derivatives as new types of antimalaiial substances with both therapeutic and causal prophylactic activity. Ann. Trap. Med. 39 208-214. 

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