2-Acetylpyridine thiosemicarbazones. II. N4,N4-disubstituted derivatives as potential antimalarial agents

Article abstract of DOI:10.1021/jm00197a017

The most effective antimalarial agents among the N⁴-monosubstituted 2-acetylpyridine thiosemicarbazones recently described by us have a cyclohexyl or a phenyl substituent and produce cures in Plasmodium berghei infected mice at a dose of 160 and 320 mg/kg, respectively. We report here on a related series of N⁴,N⁴-disubstituted 2-acetylpyridine thiosemicarbazones. Several members of this group bearing alkyl or cycloalkyl substituents at N⁴ show activity superior to the most active monosubstituted 2-acetylpyridine thiosemicarbazones. However, the greatest improvement in potency was seen when the N⁴-nitrogen atom was incorporated into a six- or seven-membered ring, such as the piperidine, piperazine, or azabicyclo[3.2.2]nonane systems, to give compounds with curative properties at a dose level as low as 20 mg/kg.