Synthetic ferrocenic mefloquine and quinine analoguesas potential antimalarial agents

Abstract

A few years ago we proposed a strategy for the synthesis of new ferrocene-chloroquine analogues replacing the carbon chain of chloroquine by hydrophobic ferrocenyl moieties. Now, this strategy has been applied to the antimalarial amino-alcohols class to afford new potentially active analogues of mefloquine and quinine bearing a substituted ferrocenic group. The pathway used for the synthesis of the mefloquine analogues includes the coupling of an aminomethyl substituted ferrocene carboxaldehyde with a lithio quinoline compound. On the other hand, the synthesis of quinine analogues was ensured by the ‘inverse’ reaction of a lithio aminomethyl ferrocene with a quinoline carboxaldehyde. The configurations of each diastereoisomer were unambiguously 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. Comparing optical isomers, those isomers dissimilar to ferrocenyl derivatives presented better antimalarial activities than those similar to ferrocenyl.