181884-83-3Relevant academic research and scientific papers
Structure-activity relationships of the antimalarial agent artemisinin. 5. Analogs of 10-deoxoartemisinin substituted at C-3 and C-9
Avery, Mitchell A.,Mehrotra, Sanjiv,Johnson, Theresa L.,Bonk, Jason D.,Vroman, Jeffrey A.,Miller, Robert
, p. 4149 - 4155 (1996)
Novel 3- and 9-substituted analogs (4-19) of 10-deoxoartemisinin, 3, were prepared from the corresponding known lactones by one-pot reduction with sodium borehydride and boron trifiuoride etherate. Reproducibility problems associated with this heterogeneous reaction were encountered on small reaction scales, and thus alternative methodology was sought for this reduction. Conversion of the lactones to tetrahydropyrans via the corresponding intermediate lactols was made more reproducible using a two- step sequence involving low-temperature reduction with diisobutylaluminum hydride followed by deoxygenation with boron trifiuoride etherate in the presence of triethylsilane. In this manner, 10-deoxoartemisinin (3) could be obtained from artemisinin (1) in greater than 95% overall yield. All analogs were tested in vitro against W-2 and D-6 strains of Plasmodium falciparum. Several of the analogs were much more active than the natural product (+)- artemisinin (1) or 10-deoxoartemisinin (3). Conventional structure-activity relationships are discussed in relation to the bioassay data.
Structure-activity relationships of the antimalarial agent artemisinin. 7. Direct modification of (+)-artemisinin and in vivo antimalarial screening of new, potential preclinical antimalarial candidates
Avery, Mitchell A.,Alvim-Gaston, Maria,Vroman, Jeffrey A.,Wu, Baogen,Ager, Arba,Peters, Wallace,Robinson, Brian L.,Charman, William
, p. 4321 - 4335 (2007/10/03)
On the basis of earlier reported quantitative structure-activity relationship studies, a series of 9β-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 (BF3-etherate/Et3SiH) 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.
