1,1′-Disubstituted Ferrocenyl Carbohydrate Chloroquine Conjugates as Potential Antimalarials

This work presents a new class of organometallic antimalarials, based on a ferrocene scaffold, bearing a chloroquine derivative and a 1,2;3,5-(diisopropylidene)-alpha-D-glucofuranose moiety in a 1,1'-heteroannular substitution pattern. Synthesis proceeds via orthogonal functionalization of ferrocene, giving 1-acetoxy-1'-(1,3-dioxan-2-yl)ferrocene (15) as the precursor for modular introduction of the carbohydrate (16, 17) followed by subsequent reductive amination with chloroquine building blocks 8-10, yielding the 1-[3-(7-chloroquinolin-4-ylamino)alkylamino]-1'-[6-(1,2;3,5-diisopropylidene)-alpha-D-glucofuranosidyl]ferrocenes 18-20. After complete characterization of these new, trifunctional conjugates, they were examined for their antiplasmodial activity in a chloroquine-susceptible strain of Plasmodium falciparum (D10) and in two chloroquine-resistant strains (Dd2 and K1). Their activity was compared to that of the monosubstituted reference conjugates 1-3 and the 1,2-disubstituted regioisomers 4-6. Compounds 19 and 20 exhibited consistently high activity in in vitro antiplasmodial activity assays performed in Dd2 and K1 strains, performing better than the reference compounds chloroquine and the monosubstituted and 1,2-disubstituted compounds 1-6.