Structure−Activity Relationships of the Antimalarial Agent Artemisinin. 7. Direct Modification of (+)-Artemisinin and In Vivo Antimalarial Screening of New, Potential Preclinical Antimalarial Candidates

Abstract

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.

Orally Active Antimalarials: Hydrolytically Stable Derivatives of 10-Trifluoromethyl Anhydrodihydroartemisinin

“…The organic phase was washed with brine, dried (MgSO4), and concentrated under reduced pressure. The residue was purified on a SiO2 column (6:1 petroleum ether-EtOAc) to afford ester 13a (810 mg, 90%) as a white solid: mp 84°C (petroleum ether-Et2O); [R] 26 …”

“…However most of these derivatives still possess the acetal pattern at C-10. [22][23][24][25][26] The objective of our study was to develop an inexpensive, orally available antimalarial non-acetal artemisinin derivative, protected from metabolism at C-10 by a fluoroalkyl substituent and substituted at C-16, using the 16-substituted functionalization approach. To achieve this goal, we utilized a fluorinated substituent (Rf) because the strong C-F bond is known to impart greater protection against metabolic (oxidative and proteolytic) degradation.…”

Quinolines and Artemisinin: Chemistry, Biology and History

“…With an ever increasing number of artemisinin analogues prepared by semi-syntheses and elegant total synthesis Avery (Avery et al 1989;Vroman et al 1999) has developed predictive 3-D quantitative SAR (CoMFA) analyses for the artemisinin class of antimalarial (Avery et al 1994(Avery et al , 2002. This information coupled with the ADME approach described above should permit highly potent and orally bioavailable semi-synthetic analogues to be designed by a truly rational approach (Haynes, 2001).…”

A golden phoenix arising from the herbal nest — A review and reflection on the study of antimalarial drug Qinghaosu

“…The analogs were tested in vitro against W-2 and D-6 strains of P. falciparum and found to be, in some cases, much more active than the natural product QHS [239][240][241]. …”