Synthesis of spiro-1,2-dioxolanes and their activity against Plasmodium falciparum.
Artemisinin-derived compounds play an integral role in current malaria chemotherapy. Given the virtual certainty of emerging resistance, we have investigated spiro-1,2-dioxolanes as an alternative scaffold. The endoperoxide functionality was generated by the SnCl(4)-mediated annulation of a bis-silylperoxide and an alkene. The first set of eight analogs gave EC(50) values of 50-150 nM against Plasmodium falciparum 3D7 and Dd2 strains, except for the carboxylic acid analog. A second series, synthesized by coupling a spiro-1,2-dioxolane carboxylic acid to four separate amines, afforded the most potent compound (EC(50) approximately 5 nM).
Martyn
Derek C
DC
Broad Institute Infectious Diseases Initiative, 7 Cambridge Center, Cambridge, MA 02142, USA.
Ramirez
Armando P
AP
Beattie
Meaghan J
MJ
Cortese
Joseph F
JF
Patel
Vishal
V
Rush
Margaret A
MA
Woerpel
K A
KA
Clardy
Jon
J
D000588:Amines / Q000737:chemistry; D020816:Amino Acid Motifs; D000818:Animals; D000953:Antigens, Protozoan / Q000737:chemistry; D000962:Antimalarials / Q000138:chemical synthesis / Q000494:pharmacology; D000981:Antiprotozoal Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D002626:Chemistry, Pharmaceutical; D004148:Dioxolanes / Q000737:chemistry*; D015195:Drug Design; D006418:Heme / Q000737:chemistry; D006801:Humans; D008288:Malaria / Q000188:drug therapy; D008956:Models, Chemical; D010545:Peroxides / Q000737:chemistry; D010963:Plasmodium falciparum
D000588:Amines; D000953:Antigens, Protozoan; D000962:Antimalarials; D000981:Antiprotozoal Agents; D004148:Dioxolanes; D010545:Peroxides; D006418:Heme