Biomedical subjects
Publications and source records attributed to N Acton.
3-beta-Hydroxyartemisinin (5) was synthesized from 3-beta-hydroxydihydroartemisinic acid (7c) via singlet oxygen oxidation followed by air (triplet oxygen) oxidation. Compound 7c was synthesized in two steps from dihydroartemisinic acid, 7a.
Several 9-substituted derivatives of the antimalarial drug artemisinin have been prepared by functionalizing the double bond of artemisitene and related compounds. Stereochemical assignments for these compounds were made using a combination of NMR experiments, an X-ray diffraction study of one compound, and chemical correlations of several other compounds with this one compound of unambiguous structure and with its epimer. The compounds synthesized show a wide variation in in vitro antimalarial activity.
To further explore the antimalarial activity of peroxides (e.g. artemisinin 1), twenty-three peroxides (all the compounds shown in Figures 3 and 4) of diverse chemical structure and acceptable stability were selected and tested for antimalarial activity in vitro against Plasmodium falciparum, and in mice against P. berghei. Included were hydroperoxides, dialkyl peroxides, acyl and diacylperoxides, peroxyketals, peroxycarbonates, and endoperoxides. None was active in vivo, although several were reasonably potent in vitro.
A series of 3-acetylisoquinoline thiosemicarbazones and their related thiosemicarbazides was prepared for evaluation as potential antimalarial agents. The former were synthesized by the reaction of 3-acetylisoquinoline with methyl hydrazinecarbodithioate to give methyl 3-[1-(3-isoquinolinyl)ethylidene]hydrazinecarbodithioate, IV. Displacement of the S-methyl group of this intermediate by the requisite amines gave 3-acetylisoquinoline thiosemicarbazones, V. The corresponding thiosemicarbazides, in which the azomethine bond was reduced, were prepared by the reduction of IV with sodium borohydride to give methyl 3-[1-(3-isoquinolinyl)ethyl]hydrazinecarbodithioate, VI. Reaction of this dithioester with amines gave 1-[1-(3-isoquinolinyl)ethyl-3-thiosemicarbazides, VII. The antimalarial properties of series V and VII were evaluated in mice infected with Plasmodium berghei. Significant curative activity could be observed at doses as low as 40 mg/kg for 3 of 10 compounds in series V and at 160 mg/kg for 3 of 11 compounds in series VII.
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Treatment of all-trans-retinal with a series of 1,3-diketones using Knoevenagel conditions gave the expected condensation products. These retinylidene 1,3-diketones were characterized and their biological activities in the hamster tracheal organ culture test measured. It was found that the cyclohexane- 1,3-dione derivatives are highly active in this in vitro assay, while other 1,3-diketones are less active. Retinylidenedimedone has been chosen for further evaluation.
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Artemisinic acid [1] has been converted into artemisinin [3] in 2 steps via reduction of the exocyclic methylene group and photooxidation of the resulting dihydroartemisinic acid [2].