Artemisinin antimalarial activity

Titanium tetrachloride-catalysed Michael additions of trimethylsilyl enol ethers to artemisitene afforded a neat route to 14-substituted artemisinin derivatives of type 125 (eg. R = allyl) and to 9-epiartemisinin derivatives 126 some of these compounds were more active against Plasmodium falciparum than artemisinin <00BMCL1601>. A series of 11-azaartemisinins also have better activity than artemisinin <00BMC1111>. On the other hand, epiartemisinin, prepared by base-catalysed epimerisation of artemisinin, has been shown to have poor antimalarial activity <00HCA1239>. 

Nevertheless, in order to improve their effectiveness, a second generation of artemisinin analogs, obtained by the derivatization of artemisinin, has been prepared. Figure 4 shows some selected second-generation artemisinin analogs that have displayed strong antimalarial activity although none of them has ever been clinically used. 

Walsh JJ, Coughlan D, Heneghan N, Gayor C, BeU A. (2007) A novel artemisinin-quinine hybrid with potent antimalarial activity. Bioorg Med Chem Lett 11 3599-3602. 

Jones M, Mercer AE, Stocks PA, La Pensee LJ, Cosstick R, Park BK, Kennedy ME, Piantanida 1, Ward SA, Davies J, Bray PO Rawe SL, Baird J, Charidza T, Janneh O, O Neill PM. (2009) Antitumor and antimalarial activity of artemisinin-acridine hybrids. Bioorg Med Chem Lett 19 2033-2037. 

The ozonide (176) was prepared as part of a synthetic study towards the antimalarial natural product artemisinin (177) <92JCS(Pl)325l>. It proved stable enough to allow x-ray crystal structure determination (see Section 4.16.3.1). Other, more complex, polycyclic ozonides were prepared in order to investigate possible antimalarial properties. Compounds were evaluated in vitro for antimalarial activity using a multiresistant strain of Plasmodium falciparum. Most were found to be weakly active although a thousand times less active than artemisinin. 

In 1972, Chinese researchers isolated, by extraction at low temperature from a plant, a crystalline compound that they named qinghaosu [the name artemisinin (la) is preferred by Chemical Abstracts, RN 63968-64-9]. The plant source of artemisinin is a herb, Artemisia annua (Sweet wormwood), and the fact that artemisinin is a stable, easily crystallizable compound renders the extraction and purification processes reasonably straightforward. The key pharmacophore of this natural product is the 1,2,4-trioxane unit (2) and, in particular, the endoperoxide bridge. Reduction of the peroxide bridge to an ether provides an analogue, deoxyartemisinin 3, that is devoid of antimalarial activity. ... 

In order to determine the significance of the 1,5-H shift and the secondary radical species for antimalarial activity, the trioxanes 22a-c were synthesized and tested . The diastereomeric trioxanes 22a and 22b possessed very different antimalarial activity against both chloroqnine-resistant and chloroqnine-sensitive strains of the parasite the A-fi isomer was approximately twice as active as artemisinin while the A-a isomer and the disubsti-tnted trioxane were more than sixty times less potent. The anthors proposed that the a-snbstitnent prevented the snprafacial 1,5-H shift and therefore snppressed the activity of these componnds. 

Since the first series of compounds were poorly soluble in water, the next crucial phase of the project set out to increase the water solubility of the drug candidates in order to increase absorption from the gastrointestinal tract. Further refinements led to a candidate that was not only well absorbed when administered orally to animals, but also had outstanding antimalarial profiles both in vitro and in vivo. In comparison to available semi-synthetic artemisinins, the drug candidate OZ 277 (Scheme 27) exhibits structural simplicity, an economically feasible and scalable synthesis, superior antimalarial activity and an improved pharmaceutical profile. The toxicological profiles are also acceptable and this drug candidate entered first into man studies during 2004. 

Aerobic Co(II) catalysed hydroperoxysiiyiation of allylic alcohols provides silyl peroxides that can be condensed with ketones to produce 1,2,4-trioxanes or 1,2,4-trioxepanes by a simple one-pot procedure (Scheme 35A). A recent improvement in the use of Co(acac)2 is the use of Co(thd)2 (thd = bis (2,2,6,6-tetramethyl-3,5-heptanedionato)). This more reactive catalyst allows cyclic allylic alcohols to be oxygenated and the resulting peroxysilyl alcohol can be transformed to spiro trioxanes, some of which have potent in vitro antimalarial activity (Scheme 35B). For example, compound 87 expresses activity around 20 nM (artemisinin = 10 nM). 

G3 factor, 199, 201, 202 mechanisms, 1309, 1310 NMR spectroscopy, 710 OZ 277 drug candidate, 1317, 1319, 1331 Plasmodium falciparum resistance, 608 synthetic, 1282, 1317-31 antimalarial activities, 1332 semi-synthetic artemisinin derivatives, 1313-17, 1332... 

Artemisinin (qinghaosu) antimalarial activity, 1309, 1313 biological targets, 1311-13 ESR spin-trapping agents, 1291 Feai) degradation, 1283, 1293, 1295-6 heme adducts, 1298, 1311-12 heterolyhc cleavage of peroxide bond, 1301-2, 1309... 

Figure 4.16 In vitro and in vivo antimalarial activities of glycols derived from artemisinin.

Ozonolysis of the +-allyl-substituted product 309 (R = allyl) gave +-(2 -acetaldehydo)-ll-azaartemisinin in 60% yield, which showed significantly higher antimalarial activity than artemisinin <1995JME5045>. 

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