2-Acetylpyridine thiosemicarbazones. 5. 1-[1-(2-Pyridyl)ethyl]-3-thiosemicarbazides as potential antimalarial agents

Abstract

Reduction of the azomethine bond of 2-acetylpyridine thio- and selenosemicarbazones with sodium borohydride readily afforded the corresponding thio- or selenosemicarbazides when they were N4,N4-disubstituted. This conversion failed, however, when the thio- or selenosemicarbazones were N4-substituted or unsubstituted. A more general route to the desired thio- or selenosemicarbazides consisted of reduction with sodium borohydride of methyl 3-[1-(2-pyridyl)ethylidene]hydrazinecarbodithioate to give the 2-pyridylethyl derivative. Displacement of methyl mercaptan from the thio ester moiety of the latter by amines produced 1-[1-(2-pyridyl)ethyl]-3-thiosemicarbazides. These compounds were somewhat more active as antimalarial agents in Plasmodium berghei infected mice than the corresponding thiosemicarbazones; however, the enhancement of activity was accompanied by an increase in toxicity. Compound 7, 3-azabicyclo[3.2.2]nonane-3-carbothioic acid 2-[1-(2-pyridyl)ethyl]hydrazide, is the most potent derivative of 2-acetylpyridine we have evaluated to date.