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

Abstract

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.

Elimination of Schistosoma mansoni in infected mice by slow release of artemisone

“…Artemiside and CKW03 were prepared as previously described (Haynes et al., 2007, Guo et al., 2012). Artemisone was prepared as previously described (Haynes et al., 2006) or kindly donated by Cipla Mumbai, India.…”

“…Artemisone has improved pharmacokinetics and anti-plasmodial activity, and reduced toxicity compared to the artemisinin derivatives clinically used against malaria (Haynes et al., 2006, Guiguemde et al., 2014). We also include the newer N-sulfonyl aza-artemisinin derivative CKW03, that previously has also been shown to be potently active against Pf and like other N-sulfonyl azaartemisinin derivatives, has notable thermal stability (Haynes et al., 2007). Finally, we have examined the effect of controlled artemisone release from biodegradable gels on S. mansoni in mice, with the aim of improving treatment by exposing the parasites for a longer period of time to a drug concentration sufficient to eliminate the pathogen, but at dose levels non-toxic to the host.…”

Based on a review of the data, use of the term ‘cypridinid’ solves the Cypridina/Vargula dilemma for naming the constituents of the luminescent system of ostracods in the family Cypridinidae

“…The electronically coupled processes shown in Scheme rely on transmission of inductive effects via the non‐peroxidic oxygen atom of the trioxane core to the more remote oxygen atoms that renders O1, but not O2 , susceptible to addition of hydride (or of the dihydroflavin, if adduct formation occurs). Examples of the manner in which such inductive effects modulate the properties of artemisinins have been described previously 48. The importance of the trioxane in modulating antimalarial properties is incisively demonstrated in elegant synthetic studies wherein replacement of the non‐peroxidic oxygen atom of the trioxane core by a methylene group suppresses antimalarial activities to 3–24 % of those of the corresponding artemisinin, even though the parent artemisinins and derived structures are superimposable 49.…”

Activities of 11‐Azaartemisinin and N‐Sulfonyl Derivatives against Asexual and Transmissible Malaria Parasites

“…The parent compound 11-azaartemisinin 5 was obtained in good yield (73 %) from artemisinin and aqueous ammonia in a tetrahydrofuran/methanol mixture below 0 °C according to the literature method. 19 It was deprotonated under aprotic conditions with lithium N,N-diisopropylamide (LDA) as previously described and then treated with the sulfonyl chloride to yield the known alkanesulfonyl azaartemisinins 6 and 8, 19 and the new N-sulfonyl-11-azaartemisinin derivatives 7 and 9-18 (Scheme 2).…”

“…Therefore, azaartemisinin and its derivatives fulfil the criterion of not providing DHA and are potentially attractive as follow up drugs to the current clinical artemisinins. We have already demonstrated that certain azaartemisinin derivatives possess greatly enhanced thermal stabilities 19 and several have good antimalarial activities. 17,20 We describe here the preparation of selected N-alkane-and arenesulfonyl-11azaartemisinins that are screened against asexual and sexual blood stages of P. falciparum.…”