Journal of medicinal chemistry
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Comparative Study
2-Acetylpyridine thiosemicarbazones. 8. Derivatives of 1-acetylisoquinoline as potential antimalarial agents.
A series of 1-acetylisoquinoline thiosemicarbazones was prepared in order to evaluate their antimalarial properties. This was achieved by the reaction of 1-acetylisoquinoline with methyl hydrazinecarbodithioate to give methyl 3-[1-(1-isoquinolinyl)ethylidene]hydrazinecarbodithioate (II). ⋯ Reaction of VII with the appropriate amine gave 1-[1-(1-isoquinolinyl)ethyl]thiosemicarbazides (IX). Evaluation of the antimalarial activity of series III and IX in mice infected with Plasmodium berghei indicated that cures were attainable at dose levels of 40-160 mg/kg.
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Metyrapone, 2-methyl-1,2-di-3-pyridyl-1-propanone (1a), is a potent reversible inhibitor of the cytochrome P-450 11 beta-hydroxylase enzyme system (P-450(11) beta) of the adrenal cortex. The structural features of the metyrapone molecule have been systemically altered to determine the requirements necessary for inhibition of P-450(11) beta activity. ⋯ The inhibition of P-450(11) beta activity with these derivatives demonstrated that (1) the A-ring phenyl derivatives 2a-d were better inhibitors than the respective dipyridyl analogues, (2) the ketone in the 1-position can be replaced by various functionalities without markedly reducing inhibition, and (3) at least one methyl group should be present in the 2-position to maintain inhibition. The observed inhibition of P450(11) beta activity with the metyrapone analogues suggest that A-ring phenyl metyrapone analogues 2a-d would be candidates for radioiodination and subsequently used as adrenal cortical imaging agents.
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Comparative Study
2-Acetylpyridine thiosemicarbazones. 9. Derivatives of 2-acetylpyridine 1-oxide as potential antimalarial agents.
In view of the antimalarial activity in mice of 2-acetylpyridine thiosemicarbazones, a series of analogous 1-oxides was prepared for evaluation. Their synthesis was achieved by the reaction of 2-acetylpyridine 1-oxide with methyl hydrazinecarbodithioate to give methyl 3-[1-(2-pyridinyl 1-oxide)ethylidene]hydrazinecarbodithioate (II). Reaction of the latter intermediate with secondary amines afforded the desired 2-acetylpyridine 1-oxide thiosemicarbazones (III). ⋯ Antimalarial activity of III was evaluated against both Plasmodium berghei in the mouse and Plasmodium falciparum in an automated in vitro test system. In both cases, 2-acetylpyridine 1-oxide thiosemicarbazones were found to be less active than the corresponding de-1-oxide analogues. When compounds V were evaluated against Plasmodium berghei in the mouse, a diminution of activity was similarly seen in comparison to the analogues not bearing the 1-oxide moiety.