Structure-activity relationships of the antimalarial agent artemisinin. 4. Effect of substitution at C-3.
Novel antimalarial artemisinin analogs, 3-alkylartemisinins as well as 3-(arylalkyl)- and 3-(carboxyalkyl)artemisinins, were prepared via the synthetic intermediate 2. Formation of the N,N-dimethylhydrazones 5 and 24 and then regio- and chemoselective deprotonation followed by alkylation provided initially alkylated hydrazones that upon chromatography gave ketones 6-13 and 25-30. Direct ozonolysis of the ketones followed by in situ acidification lead directly to the formation of title compounds 14-21 and 31-36. The analogs were tested in vitro against W-2 and D-6 strains of Plasmodium falciparum and found to be in some cases much more active than the natural product (+)-artemisinin. The results were included in structure-activity relationship (CoMFA) studies for further analog design.
Avery
M A
MA
Department of Medicinal Chemistry, School of Pharmacy, University of Mississippi, University 38677, USA.
Mehrotra
S
S
Bonk
J D
JD
Vroman
J A
JA
Goins
D K
DK
Miller
R
R
D000818:Animals; D000962:Antimalarials / Q000737:chemistry / Q000494:pharmacology; D037621:Artemisinins; D004351:Drug Resistance; D006427:Hemin / Q000737:chemistry; D006860:Hydrogen Bonding; D006863:Hydrogen-Ion Concentration; D007659:Ketones / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D015394:Molecular Structure; D010126:Ozone / Q000737:chemistry; D010963:Plasmodium falciparum / Q000187:drug effects; D012717:Sesquiterpenes / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D000962:Antimalarials; D037621:Artemisinins; D007659:Ketones; D012717:Sesquiterpenes; C100727:octahydro-3-(3-ethoxypropionyl)-6-methyl-9-butyl-3,12-epoxy-12H-pyrano(4,3-j)-1,2-benzodioxepin-10(3H)-one; D010126:Ozone; D006427:Hemin; C031327:artemisinin