Modular Synthesis of 1,2- and 1,1′-Disubstituted Ferrocenyl Carbohydrate Chloroquine and Mefloquine Conjugates as Potential Antimalarial Agents

The modular synthesis of novel organometallic antimalarials
based
on a 1,2- or 1,1′-disubstituted ferrocene scaffold (10 and 11) is presented. Ferrocenes were substituted via
an ether linker with either 7-chloroquinoline or 2,8-bis­(trifluoromethyl)­quinoline,
as a chloroquine or mefloquine derivative, respectively. Diisopropylidene-protected
6-amino-6-deoxyglucofuranose (18) or 6-amino-6-deoxygalactopyranose
(21) was coupled via reductive amination to yield the
target conjugates 24–27 and 30. Yields could be substantially increased using a microwave
reactor instead of conventional heating, which reduced the reaction
time as well. After complete characterization these novel trifunctional
conjugates were examined for their antiplasmodial activity in a chloroquine-susceptible
(CQS) strain of Plasmodium falciparum (D10) and a chloroquine-resistant (CQR) strain (Dd2). The determined
IC50 values were in the low micromolar range. Introduction
of the carbohydrate led to an increase in activity (>200 μM
(16, D10) to 1.2 μM (24, D10)). The
best activity was measured for 26 in Dd2 (IC50 = 0.77 μM). Resistance indices (RI) for all measured compounds
were <1, indicating a higher activity in the chloroquine-resistant
Dd2 strain in comparison to the chloroquine-susceptible D10 strain (RI
= 0.93 for 24, RI = 0.15 for 25).