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

Abstract

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.

Inhibition of clinically significant bacterial organisms in vitro by 2-acetylpyridine thiosemicarbazones

“…2-Acetylpyridine thiosemicarbazones have been found by Klayman et al (4,5) to exhibit antimalarial activity in mice infected with Plasmodium berghei (Fig. 1).…”

“…(This work was presented in part at the 79th Annual Meeting of the American Society for Microbiology, [4][5][6][7][8] (Table 5).…”

Synthesis and Structural Studies of Mn(II), Co(III), and Ni(II) Complexes with Schiff Base Ligands Derived from 2-Acetylpyridine

“…Schiff bases containing N, S donor atoms and their metal complexes have received considerable attention owing to their potent biological activity as anti-fungals, [1][2][3][4] anti-virals, 5 anti-malarials, 6,7 and most notably, as anti-tumor agents.…”

Activity of 2-acetylpyridine thiosemicarbazones against Trypanosoma rhodesiense in vitro

“…Many 2-acetylpyridine thiosemicarbazones have recently been shown to exhibit antimalarial activity against Plasmodium berghei in mice (7,8). These compounds also inhibit Staphylococcus aureus, Neisseria meningitidis, and Neisseria gonorrhoeae in vitro (3).…”