Modular synthesis of 1,2- and 1,1′-disubstituted ferrocenyl carbohydrate chloroquine and mefloquine conjugates as potential antimalarial agents

Christoph Herrmann, Paloma F. Salas, Brian O. Patrick, Carmen De Kock, Peter J. Smith, Michael J. Adam, Chris Orvig

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29 Citas (Scopus)

Resumen

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 IC 50 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 (IC 50 = 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).

Idioma originalInglés
Páginas (desde-hasta)5748-5759
Número de páginas12
PublicaciónOrganometallics
Volumen31
N.º16
DOI
EstadoPublicada - 27 ago. 2012
Publicado de forma externa

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