2-Acetylpyridine thiosemicarbazone

An extensive series of thiosemicarbazones obtained from 2-acetylpyridine was tested by Klayman et al. [4, 85] for antimalarial activity against Plasmodium berghei in mice. The molecular features essential for activity were found to be a 2-pyridylethylidene moiety, the presence of the thiocarbonyl sulfur, and certain, bulky or cyclic substituents at the terminal AT-atom. The most active 2-acetylpyridine thiosemicarbazones were " N-phenyl- and those with azacycUc substituents. For example, iV-substituents of 4-methylpiperidine, piperazine, and azabicyclo[3.2.2.]nonyl-, 4, were curative at a dose level as low as 20 mg/kg. 

Treatment via chelation has been observed for 2-acetylpyridine thiosemi-carbazone derivatives, which have been found to possess inhibitory activity for the RNA-polymerases of the influenza virus [133]. The iron(III) complexes were shown to be 3 to 6 times more active as inhibitors of partially purified ribonucleotide reductase (no added iron) compared to uncomplexed thiosemi-carbazone [128]. Raina and Srivastava [134] prepared and characterized low spin iron(III) complexes of 2-acetylpyridine thiosemicarbazone, [Fe(8-H)2A] (A = NO3, OH, Cl, N3, NCS or NO2), which were proposed as being seven-coordinate. However, all but the azide complex are 1 1 electrolytes in DMF and their solid ESR spectra are rhombic with the g-values being about 2.20,2.15 and 2.00. Of the six complexes, the azide ion seems to interact ihost strongly with the iron(III) center. 

An iron(III) complex of 2-acetylpyridine 3-azabicyclononylthiosemi-carbazone, 4, the thiosemicarbazone that was found to have the most potent antimalarial activity of a large number of 2-acetylpyridine thiosemicarbazones tested [88], was originally formulated as 5-coordinate [Fe(4-H)Cl2], [135], but more recent studies have shown it to be [Fe(4-H)2] [FeCl4] [117]. This complex has similar antimalarial activity to that of the uncomplexed ligand, but possesses enhanced antitumor activity [136]. 

While iron(III) complexes of thiosemicarbazones with different functional groups involving have been prepared from 2-acetylpyridine, substitution on the ring has been more popular with thiosemicarbazones derived from 2-formylpyridine. The only thiosemicarbazones in which the 2-acetylpyridine ring has been substituted are 15a and 15b, prepared from 6-methyl-2-acetyl-pyridine [120]. Both of these iron(III) complexes have rhombic spectra and values of g, are similar to those found for the 2-acetylpyridine thiosemicarbazones. Solution studies have been carried out on the iron(III) complex of 2,6-diacetylpyridine mono-thiosemicarbazone, but the solid complex was not isolated [143]. 

The first copper(II) complexes prepared with a 2-acetylpyridine thiosemicarbazone were those of the 3-azabicyclononyl-derivative, 4, as well as the analogous selenosemicarbazone [175]. Monomeric [Cu(4-H) A] where A = Cl, Br, I, OAc and NO3 were characterized by their magnetic and spectral measurements. A second report [128] on copper(II) complexes of 4 included [Cu(4) (4-H)]BF4 as... 

Two copper(II) complexes of 2-acetylpyridine thiosemicarbazone, 8, were included in a study of complexes of 2-formylpyridine thiosemicarbazone [169]. [Cu(8-H)OAc] has a magnetic moment consistent with a monomeric copperfll) center and both it and [Cu(8)Cl2] have d,2-y2 ground state ESR spectra (Table 2). A d-d envelope and a magnetic moment of 1.68 B.M. have led others [178] to propose a distorted tetrahedral environment with metal-metal interaction for the brown complex, [Cu(8)Cl2]. 

Seven different copper(II) complexes [181] of 2-acetylpyridine iV-phenyl-thiosemicarbazone, 14, all having the general formula, [Cu(14-H)A] have been prepared and characterized. Their spectral data are included in Table 2 and g is similar to other copper(II) complexes of 2-acetylpyridine thiosemicarbazones. However, the d-d spectra all show two bands, suggesting planar stereochemistry these bands are of higher energy than the analogous complexes of the bicyclononyl derivative, 4 [128, 175]. 

Copper(II) complexes have been prepared with the 2-acetylpyridine N-oxide 3-azabicyclo[3.2.2.]nonylthiosemicarbazone, 25, and bonding occurs via the pyridine N-oxide oxygen, azomethine nitrogen and thiol sulfur [128]. Based on electronic and ESR spectra, bonding to copper(II) of uninegative, tridentate 25-H is considerably weaker than the related 2-acetylpyridine thiosemicarbazone, 4-H. The other copper(II) complexes reported to date have been prepared... 

Preparations of heterocyclic thiosemicarbazone complexes with cobalt(II) salts of weakly coordinating anions (e.g., perchlorate and tetrafluoroborate) often result in cobalt(III) complexes due to air oxidation. The first 2-acetylpyridine thiosemicarbazone cobalt(III) complex was the diamagnetic [Co(15b-H)2]C104... 

Acetylpyridine thiosemicarbazone forms [Co(8)2Cl2], which is isolated from hot ethanol [178], Based on infrared spectra the pyridyl nitrogen is coordinated and bonding is NS with two chlorines bringing the coordination number to six. The complex is a non-electrolyte in DMF, has a magnetic moment of 4.13 B.M., and the electronic spectrum has bands at about 8160 and 17 860 cm consistent with octahedral stereochemistry. 

The anti-tubercular properties of 2-acetylpyridine thiosemicarbazones are enhanced by co-ordination with iron or copper (Scovill, Klayman and Franchino, 1982). 

---