Optimization of endochin-like quinolones for antimalarial activity.
Our prior work on tricyclic acridones combined with a desire to minimize the tricyclic system led to an interest in antimalarial quinolones and a reexamination of endochin, an experimental antimalarial from the 1940's. In the present article, we show that endochin is unstable in the presence of murine, rat, and human microsomes which may explain its relatively poor antimalarial activity in mammalian systems. We also profile the structure-activity relationships of ≈ 30 endochin-like quinolone (ELQ) analogs and highlight features that are associated with enhanced metabolic stability, potent antiplasmodial activity against multidrug resistant strains of Plasmodium falciparum, and equal activity against an atovaquone-resistant clinical isolate. Our work also features an ELQ construct containing a polyethylene glycol carbonate pro-moiety that is highly efficacious by oral administration in a murine malaria model. These findings provide compelling evidence that development of ELQ therapeutics is feasible.
Experimental Chemotherapy Laboratory, Mail Code RD-33, VA Medical Center, 3710 SW US Veterans Hospital Road, Portland, OR 97239, USA.
Rolf
R
Winter
Jane X
JX
Kelly
Martin J
MJ
Smilkstein
David
D
Hinrichs
Dennis R
DR
Koop
Michael K
MK
Riscoe
D000818:Animals; D000962:Antimalarials / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D004195:Disease Models, Animal; D004355:Drug Stability; D005260:Female; D006801:Humans; D008288:Malaria / Q000188:drug therapy*; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D010963:Plasmodium falciparum / Q000187:drug effects*; D010967:Plasmodium yoelii / Q000187:drug effects*; D015363:Quinolones / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D013329:Structure-Activity Relationship
D000962:Antimalarials; D015363:Quinolones