A new route to N-Substituted 11-azaartemisinins

Mekonnen, Belew; Ziffer, Herman

doi:10.1016/s0040-4039(96)02417-3

Cited by 31 publications

(17 citation statements)

References 6 publications

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“…Thus, the parent 11-azaartemisinin 24 may be modified by deprotonation with bases such as sodium hydroxide in THF or DMAP in acetonitrile in the presence of Michael acceptors, Fig. (12) [ [113][114][115]. These are potentially useful reactions, as they can be exploited to provide azaartemisinins bearing polar groups, of importance from a drug optimization viewpoint.…”

Section: Other Derivatives a From Artemisininmentioning

confidence: 99%

From Artemisinin to New Artemisinin Antimalarials: Biosynthesis, Extraction, Old and New Derivatives, Stereochemistry and Medicinal Chemistry Requirements

Haynes

2006

CTMC

209

108

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The artemisinin derivatives, dihydroartemisinin (DHA), artesunate, atemether and arteether, are currently used for treatment of malaria in artemisinin combination therapies (ACT) with longer half-life drugs. The demand is enormous--in 2005, the estimated global demand for one such ACT alone, artemether-lumifantrine, which constitutes about 70% of all current clinically-used ACTs, is for 120 million adult treatment courses. At 0.5 gm of artemether per total dose regimen, the amount of artemisinin required is approximately 114 tons. This has placed substantial stress on total artemisinin supplies world-wide, and considerable attention is being focussed on enhancing availability of artemisinin by improvement in horticultural practice and extraction of artemisinin from Artemisia annua. Artemisinic acid, which also occurs in A. annua, can be converted into artemisinin and is the ultimate target of a biotechnological approach, which if successful, will augment artemisinin supply in the future. The conversion of artemisinin into the known artemisinin derivatives, and problems with the methods are critically reviewed. Some attention is paid to mechanistic aspects which clarify stereochemistry. The current artemisinins are by no means ideal drugs. Artesunate in particular is incompatible with basic quinolines by virtue of proton transfer, and has intrinsic chemical instability. At pH 1.2, conversion to DHA is rapid, with t(1/2) 26 min, and at pH 7.4, t(1/2) is about 10 hours. With a pK(a) of 4.6, over 99% of artesunate will be ionized at pH 7.4, and thus uptake by passive diffusion from the intestinal tract will be minimal. Although a considerable effort has been vested in the search for new artemisinins, largely through functionalization of artemisinin at C-10, O-11 or at C-15 via artemisitene, or of DHA at C-10, deliberate enhancement of the 'druggability' of artemisinins by reducing lipophilicity, which at the same time will attenuate the neurotoxicity characteristic of the current derivatives, and enhance absorption, by and large has not been considered. A review of the various types of newer derivatives is given together with a consideration of medicinal chemistry aspects.

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Section: Other Derivatives a From Artemisininmentioning

confidence: 99%

From Artemisinin to New Artemisinin Antimalarials: Biosynthesis, Extraction, Old and New Derivatives, Stereochemistry and Medicinal Chemistry Requirements

Haynes

2006

CTMC

209

108

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“…The parent 11-azaartemisinin 5 can be modified by attaching substituents at N11 by reactions with Michael acceptors in the presence of weak bases. [12][13][14][15] Because 11-azaartemisinins display such good in vitro antimalarial activities, will possess a different metabolic profile, and are likely to have a toxicity profile different from those of the current artemisinins, we sought to prepare thermally stable derivatives bearing polar electron-withdrawing groups attached to the nitrogen atom. We also planned for the eventual removal of the carbonyl group in such azaartemisinins by using reagents that are effective in the removal of the carbonyl group in lactams or amides.…”

Section: Introductionmentioning

confidence: 99%

Preparation of N‐Sulfonyl‐ and N‐Carbonyl‐11‐Azaartemisinins with Greatly Enhanced Thermal Stabilities: in vitro Antimalarial Activities

et al. 2007

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As the clinically used artemisinins do not withstand the thermal stress testing required to evaluate shelf life for storage in tropical countries where malaria is prevalent, there is a need to develop thermally more robust artemisinin derivatives. Herein we describe the attachment of electron-withdrawing arene- and alkanesulfonyl and -carbonyl groups to the nitrogen atom of the readily accessible Ziffer 11-azaartemisinin to provide the corresponding N-sulfonyl- and -carbonylazaartemisinins. Two acylurea analogues were also prepared by treatment of the 11-azaartemisinin with arylisocyanates. Several of the N-sulfonylazaartemisinins have melting points above 200 degrees C and possess substantially greater thermal stabilities than the artemisinins in current clinical use, with the antimalarial activities of several of the arylsulfonyl derivatives being similar to that of artesunate against the drug-sensitive 3D7 clone of the NF54 isolate and the multidrug-resistant K1 strain of P. falciparum. The compounds possess relatively low cytotoxicities. The carbonyl derivatives are less crystalline than the N-sulfonyl derivatives, but are generally more active as antimalarials. The N-nitroarylcarbonyl and arylurea derivatives possess sub-ng ml(-1) activities. Although several of the azaartemisinins possess log P values below 3.5, the compounds have poor aqueous solubility (<1 mg L(-1) at pH 7). The greatly enhanced thermal stability of our artemisinins suggests that strategic incorporation of electron-withdrawing polar groups into both new artemisinin derivatives and totally synthetic trioxanes or trioxolanes may assist in the generation of practical new antimalarial drugs which will be stable to storage conditions in the field, while retaining favorable physicochemical properties.

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“…9 Considering that treatment with alkylation agents was not an option (as this approach leads to the O-alkyl derivatives), the Michael addition to 6a was investigated as an alternative. Reaction of 6a with catalytic amounts of sodium hydroxide, and ethyl acrylate in THF at room temperature, yielded the desired N-alkyl derivative 13 in 86 % yield (Scheme 5, left arrow).…”

Section: Michael Additions To 11-azaartemisininsmentioning

confidence: 99%

Synthesis, reactions and biological activity of 11-azaartemisinin and derivatives

Alen¹,

Truong²,

Nguyễn³

et al. 2011

Arkivoc

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In this review, we will give an overview of the synthesis and reactions of 11-azaartemisinins and their derivatives, from the first report in 1995 till now. The desoxo as well as the 9-desmethyl analogues are included. The biological activity of the azaartemisinins is also briefly discussed, with an emphasis on their potency as antimalarials. Computational studies on this type of compounds are beyond the scope of this review and will not be discussed, nor referenced.

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A new route to N-Substituted 11-azaartemisinins

Cited by 31 publications

References 6 publications

From Artemisinin to New Artemisinin Antimalarials: Biosynthesis, Extraction, Old and New Derivatives, Stereochemistry and Medicinal Chemistry Requirements

From Artemisinin to New Artemisinin Antimalarials: Biosynthesis, Extraction, Old and New Derivatives, Stereochemistry and Medicinal Chemistry Requirements

Preparation of N‐Sulfonyl‐ and N‐Carbonyl‐11‐Azaartemisinins with Greatly Enhanced Thermal Stabilities: in vitro Antimalarial Activities

Synthesis, reactions and biological activity of 11-azaartemisinin and derivatives

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