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)-α-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)-α-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.