Synthesis, antimalarial activity, biomimetic iron(II) chemistry, and in vivo metabolism of novel, potent C-10-phenoxy derivatives of dihydroartemisinin.
The combination of TMSOTf and AgClO(4) promotes the efficient C-10-phenoxylation of dihydroartemisinin (3) in good chemical yield and excellent stereoselectivity. All of the new phenoxy derivatives have potent in vitro antimalarial activity. On the basis of the excellent yield and stereoselectivity obtained for the p-trifluoromethyl derivative 7b, this compound and the parent phenyl-substituted derivative 5b were selected for in vivo biological evaluation against Plasmodium berghei in the mouse model and for metabolism studies in rats. Compound 7b demonstrated excellent in vivo antimalarial potency with an ED(50) of 2.12 mg/kg (cf. artemether = 6 mg/kg) versus P. berghei. Furthermore, from preliminary metabolism studies, this compound was not metabolized to dihydroartemisinin; suggesting it should have a longer half-life and potentially lower toxicity than the first-generation derivatives artemether and arteether. From biomimetic Fe(II)-catalyzed decomposition studies and ESR spectroscopy, the mechanism of action of these new lead antimalarials is proposed to involve the formation of both primary and secondary C-centered cytotoxic radicals which presumably react with vital parasite thiol-containing cellular macromolecules.
O'Neill
P M
PM
Robert Robinson Laboratories, University of Liverpool, Liverpool L69 7ZD, England. p.m.oneill01@liv.ac.uk
Miller
A
A
Bishop
L P
LP
Hindley
S
S
Maggs
J L
JL
Ward
S A
SA
Roberts
S M
SM
Scheinmann
F
F
Stachulski
A V
AV
Posner
G H
GH
Park
B K
BK
D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D037621:Artemisinins; D001646:Bile / Q000378:metabolism; D018360:Crystallography, X-Ray; D004578:Electron Spin Resonance Spectroscopy; D005296:Ferrous Compounds / Q000737:chemistry; D005609:Free Radicals / Q000737:chemistry; D008288:Malaria / Q000188:drug therapy / Q000469:parasitology; D008297:Male; D051379:Mice; D010647:Phenyl Ethers / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D010962:Plasmodium berghei; D010963:Plasmodium falciparum / Q000187:drug effects; D010967:Plasmodium yoelii / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D012717:Sesquiterpenes / Q000138:chemical synthesis* / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
C419403:10-(4-trifluoromethylphenoxy)dihydroartemisinin; C419402:10-phenoxydihydroartemisinin; D000962:Antimalarials; D037621:Artemisinins; D005296:Ferrous Compounds; D005609:Free Radicals; D010647:Phenyl Ethers; D012717:Sesquiterpenes; C020748:ferrous sulfate; C039060:artenimol