Hydroxychloroquine dimers as inhibitors of Plasmodium falciparum chloroquine resistant transporter and P-glycoprotein

Milata M Abraham, Purdue University


Plasmodium falciparum chloroquine resistance transporter (PfCRT) and P-glycoprotein (P-gp) are efflux proteins that are responsible for multi-drug resistance. The mutations in the protein PfCRT, which is present in malarial parasites, leads to the efflux of antimalarials, like aminoquinolines which leads to resistance. P-gp, a mammalian protein, recognizes a wide variety of drugs and effluxes them out of cells, thereby leading to multi-drug resistance and the inability to treat diseases efficiently. The bivalent strategy has been developed by using substrates of these proteins as starting materials to develop bivalent inhibitors. In this way, a set of quinine dimers has been found to be successful in inhibiting PfCRT CQR, while exhibiting antiplasmodial activity. Also a library of hydroxychloroquine dimers showed tether length dependence on the inhibition of PfCRTCQR . Herein is described a more extensive set of hydroxychloroquine dimers that was synthesized to fill the gaps in the original library. These compounds will be tested against PfCRT in collaboration with Dr. Rowena Martin. The hydroxychloroquine dimers were also tested for P-gp inhibition. Potent inhibition of substrate efflux was observed with the short tethered dimers showing better inhibition than the longer tethered dimers.




Chmielewski, Purdue University.

Subject Area

Chemistry|Organic chemistry

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