Mechanism-Based Design of Parasite-Targeted Artemisinin Derivatives: Synthesis and Antimalarial Activity of New Diamine Containing Analogues

Citations Over TimeTop 10% of 2002 papers

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.

Related Papers

• → The interaction of artemisinin with malarial hemozoin(1994)178 cited
• → The pH of the digestive vacuole ofPlasmodium falciparumis not associated with chloroquine resistance(2006)133 cited
• → Hemozoin production by Plasmodium falciparum: variation with strain and exposure to chloroquine(1993)98 cited
• → Trioxaquines and Heme-Artemisinin Adducts Inhibit the In Vitro Formation of Hemozoin Better than Chloroquine(2007)67 cited
• → Revealing Chloroquine’s Antimalarial Mechanism: The Suppression of Nucleation Events during Heme to Hemozoin Transformation(2023)1 cited