title: Mechanism-based design of parasite-targeted artemisinin derivatives: synthesis and antimalarial activity of new diamine containing analogues.
abstract: The potent antimalarial activity of chloroquine against chloroquine-sensitive strains can be attributed, in part, to its high accumulation in the acidic environment of the heme-rich parasite food vacuole. A key component of this intraparasitic chloroquine accumulation mechanism is a weak base "ion-trapping" effect whereupon the basic drug is concentrated in the acidic food vacuole in its membrane-impermeable diprotonated form. By the incorporation of amino functionality into target artemisinin analogues, we hoped to prepare a new series of analogues that, by virtue of increased accumulation into the ferrous-rich vacuole, would display enhanced antimalarial potency. The initial part of the project focused on the preparation of piperazine-linked analogues (series 1 (7-16)). Antimalarial evaluation of these derivatives demonstrated potent activity versus both chloroquine-sensitive and chloroquine-resistant parasites. On the basis of these observations, we then set about preparing a series of C-10 carba-linked amino derivatives. Optimization of the key synthetic step using a newly developed coupling protocol provided a key intermediate, allyldeoxoartemisinin (17) in 90% yield. Further elaboration, in three steps, provided nine target C-10 carba analogues (series 2 (21-29)) in good overall yields. Antimalarial assessment demonstrated that these compounds were 4-fold more potent than artemisinin and about twice as active as artemether in vitro versus chloroquine-resistant parasites. On the basis of the products obtained from biomimetic Fe(II) degradation of the C-10 carba analogue (23), we propose that these analogues may have a mode of action subtly different from that of the parent drug artemisinin (series 1 (7-16)) and other C-10 ether derivatives such as artemether. Preliminary in vivo testing by the WHO demonstrated that four of these compounds are active orally at doses of less than 10 mg/kg. Since these analogues are available as water-soluble salts and cannot form dihydroartemisinin by P450-catalyzed oxidation, they represent useful leads that might prove to be superior to the currently used derivatives, artemether and artesunate.
authors.affiliation: Department of Chemistry, The Robert Robinson Laboratories, University of Liverpool, Liverpool L69 7ZD, UK.
authors.forename: Stephen
authors.initials: S
authors.lastname: Hindley
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Ward
authors.forename: Richard C
authors.initials: RC
authors.lastname: Storr
authors.forename: Natalie L
authors.initials: NL
authors.lastname: Searle
authors.forename: Patrick G
authors.initials: PG
authors.lastname: Bray
authors.forename: B Kevin
authors.initials: BK
authors.lastname: Park
authors.forename: Jill
authors.initials: J
authors.lastname: Davies
authors.forename: Paul M
authors.initials: PM
authors.lastname: O'Neill
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D037621:Artemisinins; D006576:Heterocyclic Compounds, 4 or More Rings / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008288:Malaria / Q000188:drug therapy; D008297:Male; D051379:Mice; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010962:Plasmodium berghei; D010963:Plasmodium falciparum / Q000187:drug effects; D012717:Sesquiterpenes / Q000737:chemistry*
chemical_list: C450154:10-(2-(3-trifluoromethylphenylpiperazyl)ethyl)deoxoartemisinin; D000962:Antimalarials; D037621:Artemisinins; D006576:Heterocyclic Compounds, 4 or More Rings; D010879:Piperazines; D012717:Sesquiterpenes; C031327:artemisinin