Ho-Wai Chan

C-10 Ester and Ether Derivatives of Dihydroartemisinin − 10-α Artesunate, Preparation of Authentic 10-β Artesunate, and of Other Ester and Ether Derivatives Bearing Potential Aromatic Intercalating Groups at C-10

Preparative and stereochemical aspects of reactions providing new C-10 ester and ether derivatives of the antimalarial drug dihydroartemisinin (DHA, 2) have been examined. β-Artesunate has been prepared for the first time, and has been differentiated from the antimalarial α-artesunate; the latter has been incorrectly designated as the β-epimer in Chemical Abstracts and some primary literature. New ester and ether derivatives bearing potential intercalating groups have been synthesised by means of the Schmidt, Mitsunobu and DCC coupling procedures, by acylation in the presence of DMAP, or by hydroxy activation with BF3 as catalyst. When the hydroxy group of DHA acts as a nucleophile towards activated carboxy groups in acylating agents or the DCC intermediate, α-esters are obtained exclusively. When the hydroxy group is activated for displacement by nucleophiles, as in the Schmidt or Mitsunobu procedures, β-esters and β-ethers are obtained either exclusively or predominantly. An exception is represented by the Mitsunobu procedure involving DHA and 1- and 2-naphthols, in which mixtures of epimers are obtained; however, exclusive formation of β-aryl ethers takes place when the Schmidt procedure is used, with activation of the intermediate trichloracetimidate by SnCl2. The latter method is therefore superior to patented procedures for the preparation of β-aryl ethers from nonbasic aryl alcohols without detectable rearrangement to C-aryl compounds. However, the Mitsunobu procedure is better when basic aromatic alcohols are used as nucleophiles. The formation of α-products in which the hydroxy group of DHA acts as a nucleophile is of biological significance in relation to enzyme-mediated Phase II glucuronidation of DHA, in which only the α-DHA glucuronide is formed.

Artemisone effective against murine cerebral malaria

BackgroundArtemisinins are the newest class of drug approved for malaria treatment. Due to their unique mechanism of action, rapid effect on Plasmodium, and high efficacy in vivo, artemisinins have become essential components of malaria treatment. Administration of artemisinin derivatives in combination with other anti-plasmodials has become the first-line treatment for uncomplicated falciparum malaria. However, their efficiency in cases of cerebral malaria (CM) remains to be determined.MethodsThe efficacy of several artemisinin derivatives for treatment of experimental CM was evaluated in ICR or C57BL/6 mice infected by Plasmodium berghei ANKA. Both mouse strains serve as murine models for CM.ResultsArtemisone was the most efficient drug tested, and could prevent death even when administered at relatively late stages of cerebral pathogenesis. No parasite resistance to artemisone was detected in recrudescence. Co-administration of artemisone together with chloroquine was more effective than monotherapy with either drug, and led to complete cure. Artemiside was even more effective than artemisone, but this substance has yet to be submitted to preclinical toxicological evaluation.ConclusionsAltogether, the results support the use of artemisone for combined therapy of CM.

Interactions between Artemisinins and other Antimalarial Drugs in Relation to the Cofactor Model—A Unifying Proposal for Drug Action

Artemisinins are proposed to act in the malaria parasite cytosol by oxidizing dihydroflavin cofactors of redox‐active flavoenzymes, and under aerobic conditions by inducing their autoxidation. Perturbation of redox homeostasis coupled with the generation of reactive oxygen species (ROS) ensues. Ascorbic acid–methylene blue (MB), N‐benzyl‐1,4‐dihydronicotinamide (BNAH)–MB, BNAH–lumiflavine, BNAH–riboflavin (RF), and NADPH–FAD–E. coli flavin reductase (Fre) systems at pH 7.4 generate leucomethylene blue (LMB) and reduced flavins that are rapidly oxidized in situ by artemisinins. These oxidations are inhibited by the 4‐aminoquinolines piperaquine (PPQ), chloroquine (CQ), and others. In contrast, the arylmethanols lumefantrine, mefloquine (MFQ), and quinine (QN) have little or no effect. Inhibition correlates with the antagonism exerted by 4‐aminoquinolines on the antimalarial activities of MB, RF, and artemisinins. Lack of inhibition correlates with the additivity/synergism between the arylmethanols and artemisinins. We propose association via π complex formation between the 4‐aminoquinolines and LMB or the dihydroflavins; this hinders hydride transfer from the reduced conjugates to the artemisinins. The arylmethanols have a decreased tendency to form π complexes, and so exert no effect. The parallel between chemical reactivity and antagonism or additivity/synergism draws attention to the mechanism of action of all drugs described herein. CQ and QN inhibit the formation of hemozoin in the parasite digestive vacuole (DV). The buildup of heme–FeIII results in an enhanced efflux from the DV into the cytosol. In addition, the lipophilic heme–FeIII complexes of CQ and QN that form in the DV are proposed to diffuse across the DV membrane. At the higher pH of the cytosol, the complexes decompose to liberate heme–FeIII. The quinoline or arylmethanol reenters the DV, and so transfers more heme–FeIII out of the DV. In this way, the 4‐aminoquinolines and arylmethanols exert antimalarial activities by enhancing heme–FeIII and thence free FeIII concentrations in the cytosol. The iron species enter into redox cycles through reduction of FeIII to FeII largely mediated by reduced flavin cofactors and likely also by NAD(P)H–Fre. Generation of ROS through oxidation of FeII by oxygen will also result. The cytotoxicities of artemisinins are thereby reinforced by the iron. Other aspects of drug action are emphasized. In the cytosol or DV, association by π complex formation between pairs of lipophilic drugs must adversely influence the pharmacokinetics of each drug. This explains the antagonism between PPQ and MFQ, for example. The basis for the antimalarial activity of RF mirrors that of MB, wherein it participates in redox cycling that involves flavoenzymes or Fre, resulting in attrition of NAD(P)H. The generation of ROS by artemisinins and ensuing Fenton chemistry accommodate the ability of artemisinins to induce membrane damage and to affect the parasite SERCA PfATP6 Ca2+ transporter. Thus, the effect exerted by artemisinins is more likely a downstream event involving ROS that will also be modulated by mutations in PfATP6. Such mutations attenuate, but cannot abrogate, antimalarial activities of artemisinins. Overall, parasite resistance to artemisinins arises through enhancement of antioxidant defense mechanisms.

PROSTANOID ACTION ON THE HUMAN PULMONARY VASCULAR SYSTEM

1. Four types of prostanoid receptor are present on pulmonary arterial vessels of man. Thromboxane (TP) receptors mediate constriction and are blocked by antagonists such as BAY u‐3405, GR 32191 and EP169. Prostaglandin (PG) EP3 receptors also mediate constriction, the agonist potency ranking being SC 46275 > sulprostone > misoprostol≥PGE2; this action needs to be borne in mind when PGE analogues are used therapeutically.

Relaxant actions of nonprostanoid prostacyclin mimetics on human pulmonary artery.

The specific prostacyclin (IP) receptor agonist cicaprost relaxed human pulmonary artery preparations precontracted with phenylephrine [50% inhibitory concentration (IC50) approximately 0.6 nM], U-46619 (IC50 approximately 0.9 nM), and K+ (approximately 40% maximal relaxation); endothelium removal had little effect on relaxant activity. Ranking of relaxant potencies for prostacyclin and five of its analogs was 17 alpha, 20-dimethyl-delta 6,6a-6a-carba PGI1 (TEI-9063) > or = cicaprost > iloprost > prostacyclin > taprostene > benzodioxane prostacyclin > 15-deoxy-16 alpha-hydroxy-16 beta,20-dimethyl-delta 6,6a-6a-carba PGI1 (TEI-3356). The potency of the isocarbacyclin TEI-3356 may have been under-estimated because of its contractile (EP3 receptor agonist) activity. The potency ranking of four nonprostanoid prostacyclin mimetics was 3-[4-(4,5-diphenyl-2-oxazolyl)-5-oxazolyl]phenoxy] acetic acid (BMY 45778; IC50 approximately 2.5 nM) > > 2-[3-[2-(4, 5-diphenyl-2-oxazolyl)ethyl]phenoxy]acetic acid (BMY 42393) > octimibate > CU 23 (a novel diphenylindole). From IP receptor binding affinities obtained on human platelet membranes, it is suggested that the slightly shallower log concentration-response curves for BMY 45778, BMY 42393, and CU 23 may reflect the near-maximal receptor occupancy required for complete relaxation. A fifth nonprostanoid, CU 602, had much shallower log concentration-response curves than cicaprost against phenylephrine tone but not against U-46619 tone; this may indicate IP receptor partial agonism coupled with TP receptor antagonism. The relaxant actions of the nonprostanoid mimetics were more persistent than those of the prostacyclin analogs on washout of the organ bath; by the inhalation route, this type of compound may be retained within pulmonary tissue and thus afford greater pulmonary/systemic selectivity than currently used pulmonary vasodilators.

Convenient Access Both to Highly Antimalaria‐Active 10‐Arylaminoartemisinins, and to 10‐Alkyl Ethers Including Artemether, Arteether, and Artelinate

An economical phase‐transfer method is used to prepare 10‐arylaminoartemisinins from DHA and arylamines, and artemether, arteether, and artelinate from the corresponding alcohols. In vivo sc screens against Plasmodium berghei and P. yoelii in mice reveal that the p‐fluorophenylamino derivative 5 g is some 13 and 70 times, respectively, more active than artesunate; this reflects the very high sc activity of 10‐alkylaminoartemisinins. However, through the po route, the compounds are less active than the alkylaminoartemisinins, but still approximately equipotent with artesunate.