sodium-artesunate and Malaria

A new series of 6 dimeric trioxane sulfones has been prepared from the natural trioxane artemisinin in five or six chemical steps. One of these thermally and hydrolytically stable new chemical entities (4c) completely cured malaria-infected mice via a single oral dose of 144 mg/kg. At a much lower single oral dose of only 54 mg/kg combined with 13 mg/kg of mefloquine hydrochloride, this trioxane dimer 4c as well as its parent trioxane dimer 4b also completely cured malaria-infected mice. Both dimers 4c and 4b were potently and selectively cytotoxic toward five cancer cell lines.

Topics: Administration, Oral; Animals; Antimalarials; Antineoplastic Agents; Artemisinins; Cell Line, Tumor; Drug Screening Assays, Antitumor; Drug Stability; Drug Therapy, Combination; Humans; Malaria; Mefloquine; Mice; Sulfones

In only two steps and in 70% overall yield, naturally occurring trioxane artemisinin (1) was converted on a gram scale into C-10-carba trioxane dimer 3. This new, very stable dimer was then transformed easily in one additional step into four different dimers 4-7. Alcohol and diol dimers 4 and 5 and ketone dimer 7 are 10 times more antimalarially potent in vitro than artemisinin (1), and alcohol and diol dimers 4 and 5 are strongly growth inhibitory but not cytotoxic toward several human cancer cell lines. Water-soluble carboxylic acid derivatives 8aand 9 were easily prepared in one additional step from dimers 4 and 5. Carboxylic acid dimers 8a and 9 are thermally stable even at 60 degrees C for 24 h, are more orally efficacious as antimalarials in rodents than either artelinic acid or sodium artesunate, and are strongly inhibitory but not cytotoxic toward several human cancer cell lines.

Topics: Administration, Oral; Animals; Antimalarials; Antineoplastic Agents; Artemisinins; Drug Screening Assays, Antitumor; Humans; Malaria; Mice; Plasmodium berghei; Plasmodium falciparum; Polymers; Solubility; Structure-Activity Relationship; Tumor Cells, Cultured; Water

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.

Topics: Animals; Antimalarials; Artemisinins; Heterocyclic Compounds, 4 or More Rings; Malaria; Male; Mice; Piperazines; Plasmodium berghei; Plasmodium falciparum; Sesquiterpenes

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.

Topics: Administration, Oral; Animals; Antimalarials; Artemisinins; Drug Evaluation, Preclinical; Drug Resistance; Injections, Intravenous; Malaria; Mice; Plasmodium berghei; Plasmodium falciparum; Plasmodium yoelii; Rats; Rats, Sprague-Dawley; Sesquiterpenes; Stereoisomerism; Structure-Activity Relationship

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.

Topics: Animals; Antimalarials; Artemisinins; Bile; Crystallography, X-Ray; Electron Spin Resonance Spectroscopy; Ferrous Compounds; Free Radicals; Malaria; Male; Mice; Phenyl Ethers; Plasmodium berghei; Plasmodium falciparum; Plasmodium yoelii; Rats; Rats, Wistar; Sesquiterpenes; Stereoisomerism; Structure-Activity Relationship

Arteether (6) has been prepared from dihydroquinghaosu (3) by etherification with ethanol in the presence of Lewis acid and separated from its chromatographically slower moving alpha-dihydroqinghaosu ethyl ether (7). The absolute stereochemistry at C-12 has been determined by 1H NMR data (J11,12, NOESY). Ethyl ethers 6 and 7 showed potent in vitro inhibition of Plasmodium falciparum, and both compounds were highly potent antimalarials in mice infected with a drug-sensitive strain of Plasmodium berghei. Crystalline arteether (6) and its oily epimer 7 were 2-3 times more potent schizontocides than quinghaosu (1), but deoxy compounds 8, 9, and 11 were 100-300 times less potent in vitro than their corresponding peroxy precursors. Pharmacological studies have shown arteether(6) to have antimalarial activity in animals comparable to artesunate (2) and artemether (4), both of which are fast-acting blood schizontocides in humans. Arteether (6) has now been chosen for a clinical evaluation in high-risk malaria patients.

Topics: Animals; Antimalarials; Artemisinins; Magnetic Resonance Spectroscopy; Malaria; Mice; Models, Molecular; Plasmodium berghei; Plasmodium falciparum; Sesquiterpenes