The herb
Artemisia annua
has been used for many centuries in Chinese traditional medicine as a treatment for fever and malaria. In 1971, Chinese chemists isolated from the leafy portions of the plant the substance responsible for its reputed medicinal action. This compound, called
qinghaosu
(QHS, artemisinin), is a sesquiterpene lactone that bears a peroxide grouping and, unlike most other antimalarials, lacks a nitrogen-containing heterocyclic ring system. The compound has been used successfully in several thousand malaria patients in China, including those with both chloroquine-sensitive and chloroquine-resistant strains of
Plasmodium falciparum
. Derivatives of QHS, such as dihydroqinghaosu, artemether, and the water-soluble sodium artesunate, appear to be more potent than QHS itself. Sodium artesunate acts rapidly in restoring to consciousness comatose patients with cerebral malaria. Thus QHS and its derivatives offer promise as a totally new class of antimalarials.
Based on the antimalarial properties observed for 2-acetylpyridine 4-phenyl-3-thiosemicarbazone (1), an extensive series of related thiosemicarbazones was prepared and tested against Plasmodium berghei in mice. Screening results indicated that the presence of the 2-pyridylethylidene group was critical and that certain phenyl, benzyl, phenethyl, or cycloalkyl groups at N4 of the thiosemicarbazone moiety also contribute to antimalarial activity.
Elemental powdered selenium and sodium borohydride react very readily in water or ethanol to give either sodium hydrogen selenide or sodium diselenide, depending on the ratio of the reactants. The sodium hydrogen selenide and sodium diselenide solutions, thus prepared, can be utilized directly in typical nucleophilic displacement reactions. Alkali metal borohydrides have been combined l with the chalcogen elements by direct fusion1•2 and in aprotic solvents such as ether,2 dioxane,8 tetrahydrofuran,4•5 and diglyme.4•5 Under the latter conditions, sulfur, selenium, and tellurium were incorporated directly into the borohydride.4•5 The product of the reaction between selenium and sodium borohydride
Reaction of the 2-acetylpyridine thiosemicarbazones, 3-azabicyclo[3.2.2]nonane-3-thiocarboxylic acid 2-[1-(2-pyridyl)ethylidene]hydrazide (IIIa), its selenium analogue (IIIb), 1H-hexahydroazepine-1-thiocarboxylic acid 2-[1-(2-pyridyl)ethylidene]hydrazide (IV), and 1H-octahydroazocine-1-thiocarboxylic acid 2-[1-(2-pyridyl)ethylidene]hydrazide (V) with Cu(II), Ni(II), Fe(III), and Mn(II) salts gave crystalline complexes. Relative to the free ligands, these complexes show reduced antimalarial activity in mice infected with Plasmodium berghei; however, antileukemic properties are enhanced by coordination with the above-mentioned metals.
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