Arteether antimalarial

In addition to artemisinin, other synthetic trioxanes and endoperoxides (fenozan BO-7 4 and arteflene 5 " ) have enjoyed some success arteflene reached Phase II pre-clinical trials. More recently, Vennerstrom and coworkers have reported on the outstanding antimalarial properties of several 1,2,4-trioxolanes, one of which, OZ 277 (6), has entered clinical trials in man . These exciting, easily prepared drugs will be discussed in detail later in this chapter. In order to determine the parasiticidal action of this class of antimalarial, many research groups have focused their efforts on artemisinin and its semi-synthetic derivatives (artemether, arteether and artesunate Ic, Id and le), and this is the point where our discussion will begin. 

Knowledge of local resistance patterns is important to determine the treatment regimen. There is increasing chloroquine and pyrimethamine-sulfado-xine (Fansidar) resistance in Africa and in some areas at the border of Thailand there is resistance for almost all antimalarial drugs including halofantrine, mefloquine and quinine. In these areas only the artemisinin derivatives (artemether, arteether, arte-sunate, dihydroartemisinin) are effective. 

Despite these significant advances and an overall pattern of clinical acceptability and low toxicity in animals, recent studies of arteether 6 have uncovered an unsettling neurotoxicity in animals leading to death at higher than therapeutic doses.9,10 This toxicity, a lethal degeneration of the brain stem, has resulted in a reexamination of these antimalarial drugs, particularly structure-activity relationships (SAR) as directed toward potency, oral administration, and neurotoxicity. 

A conformational study of /3-arteether 11, by H and 13C NMR, showed that the solution of /3-arteether 11 is similar to that of its X-ray structure <1999J(P2)2089>. The interaction of artemisinin 1 with manganese tetraphenylpor-phorin, in the presence of a reducing agent, was studied by UV-visible (UV-Vis) and H NMR <1997CR59>. A series of rules using 1-D and 2-D NMR spectroscopy for identification of relative stereochemistry of substituted antimalarials, related to artemisinin 1, were reported <1997SPL241>. 

In conclusion, the vast literature and its derivatives, particularly artesunate, artemether, and arteether, point out to the need to make these derivatives in quantities that would reduce their current production cost to make these drugs accessible to the economically underprivileged societies that are often the victims of malaria. A recent promising method in which artemisinic acid, a precursor to artemisinin, has been produced in engineered yeast. Therefore, microbially produced artemisinic acid holds promise to the syntheses of antimalarial drugs at affordable prices <2006N940>. Furthermore, anticancer activities of artemisinin 1 and its derivatives have been reviewed <2005MI995>. 

In summary, a stereoselective 10-step total synthetic route to the antimalarial sesquiterpene (+)-artemisinin (1) was developed. Crucial elements of the approach included diastereoselective trimethylsilylanion addition to a,p-unsaturated aldehyde 16, and a tandem Claisen ester-enolate rearrangement-dianion alkylation to afford the diastereomerically pure erythro acid 41. Finally, acid 41 was converted in a one-pot procedure involving sequential treatment with ozone followed by wet acidic silica gel to effect a complex process of dioxetane formation, ketal deprotection, and multiple cyclization to the natural product (+)-artemisinin (1). The route was designed for the late incorporation of a carbon-14 label and the production of a variety of analogues for structure-activity-relationship (SAR) studies. We were successful in preparing two millimoles of l4C-l73 which was used for conversion to I4C-arteether for metabolism75 and mode of action studies.76,77... 

Very early studies by other workers19-22,88 described the higher potency of arteether relative to artemisinin (1). This had forecast the selective reduction of the lactone of our novel analogues as a routine method, with the likely potential to increase antimalarial activity. Previous transformations of artemisinin are summarized in Scheme 10. 

To search for stable, water-soluble dihydroartemisinin derivatives with higher efficacy and longer plasma half-life than artesunate and artelinic acid, deoxoarteli-nic acid 134 was prepared (Scheme 5-18) and tested in vitro and in vivo. It was reported that 134 showed superior antimalarial activity and was more stable in simulated stomach acid than arteether. In 1992, Haynes et al. already reported on the synthesis of 5-carba-4-deoxoartesunic acid (135) from artemisinic acid (20) in a similar way, but they did not mention its activity at that time. ... 

Avery MA, McLean G, Edwards G, Ager A. Structure-activity relationships of peroxide-based artemisinin antimalarials. In Biologically Active Natural Products Pharmaceuticals. Cutler SI, Cutler HG, eds. 2000. CRC Press, Boca Raton, EL, pp. 121-132. Pareek A, Nandy A, Kochar D, Patel KH, Mishra SK, Mathur PC. Efficacy and safety of f -arteether and a/f -arteether for treatment of acute Plasmodium falciparum malaria. Am. J. Trop. Med. 2006 75 139-142. http //mednet3.who.int/EMUb/. 

Dihydroqinghaosu (32) (Scheme 1) is a key intermediate in the synthesis of artemisinin analogues / derivatives, which have shown antimalarial activity. Following the Chinese scientists s work, Lin et al. [95] synthesized a series of water soluble derivatives of artemisinin of which artenilic acid (36d) was found to exhibit activity and better stability than artemisinin or artesunate. Brossi et al. [96] reported the synthesis of arteether (36b), which after preclinical studies is now in clinical evaluation in India [96a], Deoxyqinghaosu described in scheme 11 has been reported to have high antimalarial activity. Synthesis of (+)-12-butyldeoxoartemisinin (99) and some tricyclic analogues (100) of artemisinin has recently been achieved [97,98]. 

V. Melendez, J.O. Peggins, T.G. Brewer and A.D. Theoharides, Determination of the antimalarial arteether and its deethylated metabolite dihydroartemisinin in plasma by high-performance liquid chromatography with reductive electrochemical detection, 7. Pharm. ScL, 1991, 80, 132-138. 

Drew, M.G.B. et al. (2006) Reactions of artemisinin and arteether with acid Implications for stability and mode of action of antimalarial action. J. Med. Chem. 49, 6065-6073... 

A series of artemisinin-based semisynthetic antimalarial derivatives, with all of them maintaining the key endoperoxide bridge, such as arteether (18), artemether (19), artesunate (20), and dihydroartemisinin (21), have been designed to improve the water solubility and the metabolic stability of artemisinin [53, 54], Among them, dihydroartemisinin (artenimol), is considered as a common active metaboUte of artemisinin derivatives [53, 54]. Currently, artemisinin-based therapies eombined with standard antimalarials such as amodiaquine, sulfadoxine-pyrimethamine, mefloquine, and lumefantrine are recommended by the World Health Organization (WHO) as first-line therapies for malaria [55, 56]. 

Baker, J.K. McChesney, J.D. Chi, H.T. Decomposition of arteether in simulated stomach acid yielding compounds retaining antimalarial activity, Pharm.Res., 1993,10, 662-666. 

Chi, H.T. Ramu, K. Baker, J.K. Hufford, C.D. Lee, I.S. Zeng, Y.-L. McChesney, J.D. Identification of the in vivo metabolites of the antimalarial arteether by thermospray high-performance liquid chromatography/mass spectrometry, Biol.Mass Spectrom., 1991,20, 609-628. 

Microbial production represented the only convenient source of most of the animal metabolites (11 of them were known for arteether) and, in addition, an appropriate method for providing new analogs that may serve as prospective candidates for antimalarial evaluation or as starting materials for hemisynthesis of derivatives. Arteether (96) was converted by A. niger or Nocardia coralUna mainly into deoxy metabolites such as 98, the hydroxylation products 99 and 100, and rearrangement products [127,128]. 

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