Structure-activity relationships of the antimalarial agent artemisinin. 7. Direct modification of (+)-artemisinin and in vivo antimalarial screening of new, potential preclinical antimalarial candidates.
On the basis of earlier reported quantitative structure-activity relationship studies, a series of 9beta-16-(arylalkyl)-10-deoxoartemisinins were proposed for synthesis. Several of the new compounds 7 and 10-14 were synthesized employing the key synthetic intermediate 23. In a second approach, the natural product (+)-artemisinic acid was utilized as an acceptor for conjugate addition, and the resultant homologated acids were subjected to singlet oxygenation and acid treatment to provide artemisinin analogues. Under a new approach, we developed a one step reaction for the interconversion of artemisinin 1 into artemisitene 22 that did not employ selenium-based reagents and found that 2-arylethyliodides would undergo facile radical-induced conjugate addition to the exomethylene lactone of 22 in good yield. The lactone carbonyls were removed sequentially by diisobutylaluminum hydride reduction followed directly by a second reduction (BF(3)-etherate/Et(3)SiH) to afford the desired corresponding pyrans. Six additional halogen-substituted aromatic side chains were installed via 22 furnishing the bioassay candidates 15-20. The analogues were examined for in vitro antimalarial activity in the W-2 and D-6 clones of Plasmodium falciparum and were additionally tested in vivo in Plasmodium berghei- and/or Plasmodium yoelii-infected mice. Several of the compounds emerged as highly potent orally active candidates without obvious toxicity. Of these, two were chosen for pharmacokinetic evaluation, 14 and 17.
Avery
Mitchell A
MA
Department of Medicinal Chemistry, School of Pharmacy, National Center for Natural Products Research, University of Mississippi, University, MS 38677, USA. mavery@olemiss.edu
Alvim-Gaston
Maria
M
Vroman
Jeffrey A
JA
Wu
Baogen
B
Ager
Arba
A
Peters
Wallace
W
Robinson
Brian L
BL
Charman
William
W
D000284:Administration, Oral; D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D037621:Artemisinins; D004353:Drug Evaluation, Preclinical; D004351:Drug Resistance; D007275:Injections, Intravenous; D008288:Malaria / Q000188:drug therapy; D051379:Mice; D010962:Plasmodium berghei; D010963:Plasmodium falciparum / Q000187:drug effects; D010967:Plasmodium yoelii; D051381:Rats; D017207:Rats, Sprague-Dawley; D012717:Sesquiterpenes / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000962:Antimalarials; D037621:Artemisinins; D012717:Sesquiterpenes; C465778:octahydro-3,6-dimethyl-3,12-epoxy-9-(3'-(3,4-dichlorphenyl)propyl)-12H-pyrano(4,3-j)-1,2-benzodioxepin; C465779:octahydro-3,6-dimethyl-3,12-epoxy-9-(3'-(3-trifluoromethylphenyl)propyl)-12H-pyrano(4,3-j)-1,2-benzodioxepin; C031327:artemisinin