Synthetic ferrocenic mefloquine and quinine analogues as potential antimalarial agents

A few years ago we proposed a strategy for the synthesis of new ferrocene-c hloroquine analogues replacing the carbon chain of chloroquine by hydrophob ic ferrocenyl moieties. Now, this strategy has been applied to the antimala rial amino-alcohols class to afford new potentially active analogues of mef loquine and quinine bearing a substituted ferrocenic group. The pathway use d for the synthesis of the mefloquine analogues includes the coupling of an aminomethyl substituted ferrocene carboxaldehyde with a lithio quinoline c ompound. On the other hand, the synthesis of quinine analogues was ensured by the 'inverse' reaction of a lithio aminomethyl ferrocene with a quinolin e carboxaldehyde. The configurations of each diastereoisomer were unambiguo usly determined by spectroscopic data. The mechanistic interpretations were fully discussed. Ferrocenyl analogues of mefloquine and quinine exhibited a lower antimalarial activity than mefloquine and quinine themselves. Compa ring optical isomers, those isomers dissimilar to ferrocenyl derivatives pr esented better antimalarial activities than those similar to ferrocenyl. (C ) 2000 Editions scientifiques et medicales Elsevier SAS.