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.

Functionalisation of Artemisinin and Its Ring-contracted Derivatives

“…The β-allyl derivative 6 was prepared in good yield starting from the benzoate of 2 using the literature procedure [2]. The dehydrodeoxy analog 8 was formed at the same time as a side product (10 %).…”

“…Melting points were determined with a Boetius Block apparatus and are uncorrected. Compounds 6 [2] and 7 [3] were prepared according to the literature procedures.…”

“…Great efforts have been focused on chemical modifications of the artemisinin structure in order to improve the biological activity. Semisynthetic analogues of 1, such as the lactol dihydroartemisinin (2) and its ether derivatives β-artemether (3), β-arteether (4) and sodium artesunate (5) have received significant attention in this context [1]. One problem is the metabolic instability of the ethers 3-5 and their analogs, that undergo fast transformation into the neurotoxic 2.…”

“…One problem is the metabolic instability of the ethers 3-5 and their analogs, that undergo fast transformation into the neurotoxic 2. We propose a synthetic exploration of the known carbonconnected artemisinin derivatives 6 [2] and 7 [3] to prepare a variety of derivatives by 1,3-dipolar cycloaddition or other reactions. …”

Weak Base Dispiro‐1,2,4‐trioxolanes: Potent Antimalarial Ozonides.

“…4 The first attempts to improve synthetic peroxide 5 and semisynthetic artemisinin 6 antimalarial specificity and biopharmaceutical properties by incorporating weak base functional groups and heterocycles were largely unsuccessful. Since that time, however, continued work [7][8][9][10][11][12] in this area has produced some encouraging results as illustrated by synthetic peroxides 1 (OZ209) 13 and 2 (trioxaquine), 14 and semisynthetic artemisinin 3 (artemisone) 15 ( Fig. 2).…”