Synthesis and antiplasmodial activity in vitro of new ferrocene–chloroquine analogues

Abstract

The synthesis of the new compounds (7-chloroquinolin-4-yl)-N′-(1′-dimethylaminomethylferrocen-1-ylmethyl)-amine (4a) and N-(7-chloroquinolin-4-yl)-N′-(1′-dimethylaminomethylferrocen-1-ylmethyl)-ethane-1,2-diamine (6a) is reported. The key step in the synthesis is the cleavage of a ferrocene–Sn bond with n-BuLi to give a lithiumferrocenide species (10), which is then treated with an electrophile. Thus, 1′-dimethylaminomethyl-1-tri-n-butylstannyl-ferrocene (11) and subsequently 1′-dimethylaminomethylferrocene-1-carbaldehyde (7a) were synthesised from 1,1′-bis(tri-n-butylstannyl)ferrocene, employing [CH₂NMe₂]I and DMF to introduce the amine and then the aldehyde functionalities. In addition, the compound 1′-dimethylaminomethyl-1-lithiumferrocenide was isolated and the ¹H and ¹³C NMR data are reported. X-Ray crystal and molecular structures are reported for compound 4a and the related compound N-(7-chloroquinolin-4-yl)-N′-(2-dimethylaminomethylferrocen-1-ylmethyl)-ethane-1,2-diamine (5a). The antiplasmodial activity in vitro against chloroquine sensitive and resistant strains of Plasmodium falciparum is reported and compared to a series of ferrocene, ruthenocene and phenylene analogues.