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

• Published in: Organometallics 2012-08, Vol.31 (16), p.5748-5759
• Main Authors: Herrmann, Christoph, Salas, Paloma F, Patrick, Brian O, Kock, Carmen de, Smith, Peter J, Adam, Michael J, Orvig, Chris
• Format: Article
• Language: English
• ISSN: 0276-7333; 1520-6041
• DOI: 10.1021/om300392q

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