Thiosemicarbazones, inhibiting

The thiophene analog of chloramphenicol (255) has been synthesized,as also have been similar structures. The antibacterial activity of all was much lower than that of the natural antibiotic. The thioamide of 2-thenoic acid has been prepared in a study of potential antitubercular compounds. It did not surpass thioisonico-tinamide in antitubercular activity. The thiosemicarbazones of thio-phenealdehydes and ketones (cf. Section VII,D) show high activity against Mycobacterium tuberculosis, but are very toxic. The thiosemi-carbazone of 4-(2-thienyl)-3-buten-2-one has been reported to be capable of completely inhibiting the in vitro growth of M. tuberculosis even in relatively low concentrations. ... 

A copper(II) complexes of 5-phenylazo-3-methoxy salicylidene thiosemicarbazone has been shown to have promising growth inhibition activity against P388 lymphocytic leukemia cells sensitive and resistant to adriamycin [196], The complex involves ON coordination of two deprotonated ligands and v(CS) is reported to be unaltered in intensity and position in the complex from its position in the spectrum of the ligand. Inhibition studies with the uncomplexed thiosemicarbazone indicating an important role for the copper(II). 

In 1992, Crabtree and co-workers reported the first nickel catalyst effective for silane alcoholysis.161 The complex, [Ni(tss)]2 (tss = salicylaldehyde thiosemicarbazone), bears a ligand that contains O and N donor groups and a semicarbazide sulfur. Alcoholysis of Et3SiH with ethanol or methanol occurs at room temperature in 50% dimethyl sulfoxide-benzene. However, the reaction is inhibited in the presence of strong donor ligands, H2, or atmospheric pressure of CO. 

Administration of copper dimethylglyoxime143), copper 2-keto-3-ethoxybutyralde-hyde bis(thiosemicabazone)144) or copper pyruvaldehyde bis(thiosemicarbazone)145) to rodents has led to inhibition of tumour growth. The copper(II) complex of 2-keto-3-ethoxybutyraldehyde bis(thiosemicarbazone) transports copper into neoplastic cells where it is deposited and inhibits a number of enzymes responsible for the synthesis of DNA146-. ... 

Germanium and silicon derivatives of furfural semicarbazone and thiosemicarbazone exhibited similar antitumor activity to melanoma B16 in mice (40-48% inhibition of the growth)138. 

Several compounds capable of metal chelation inhibit the non-heme iron ribonucleotide reductases with many of these chelators the mechanism of inhibition appears to be more complex than simple competition for the iron atom required by the enzyme. The most potent members of one such group of inhibitors are the thiosemicarbazones of 1-formyl-isoquinoline (I) and 2-formylpyridine (II). 

Thiosemicarbazones have long been used as antiviral agents, principally against pox viruses of the vaccinia family. One compound of this series, the isatin derivative (6) C9HgN4OS, has been used prophylactically to prevent outbreaks of smallpox in humans (10) and to inhibit the protein synthesis in poxvirus-infected cells. The molecular mechanics relating to this property are still not known (11), though the binding of a metal ion may be a key factor... 

Replacement of the sulfur atom in the thiosemicarbazone moiety by an oxygen atom leads to a loss of antiviral activity. Methisazone has no significant effect on vaccinia virus DNA synthesis (14) but seems to inhibit late protein synthesis by a mechanism that remains to be elucidated. 

Isoniazid, one of the most active of the tuberculostatic drugs, was discovered because it had been shown that nicotinamide exerted some tuberculostatic action (J). A deliberate search for more effective but related chemicals revealed that many pyridine derivatives, including congeners of isonicotinic acid, also were active. Further, it was known that the thiosemicarbazones could inhibit the growth of M. tuberculosis. An attempt to synthesize the thiosemicarbazone of isonicotinaldehyde provided, as the first intermediate compound, isonicotinylhydrazine, or isoniazid. 

Mono- and bis(thiosemicarbazones) were among the first compounds that were deliberately constructed as metal-binding ligands for the purpose of inhibiting and killing tumor cells (Figure They have formed the basis for... 

More recent work on metbisazone (Y-methylisatin-l -thiosemicarbazone) has extended its antiviral spectrum from purely DNA viruses to certain RNA viruses in tissue culture. These include foot-and-mouth disease, polio, certain rhinoviruses, some arboviruses and influenza A and B. The extent of inhibition is dose dependent and is said not to be due to any toxic effect on the cells in which the viruses are grown [165]. The possibility of using any of this class of compound for treatment of these diseases in man was thought improbable. 

Methisazone 6.19) (l-methylisatin-3-thiosemicarbazone, Marboran ) inhibits the multiplication of vaccinia virus in experimental animals. The antiviral action is extraordinarily high. Mice infected intracerebrally with 1000 mean lethal doses (LD50) of vaccinia (cowpox) virus required only 0.5 mg/kg for protection, and only 10 mg/kg was needed for protection against variola major... 

Thiosemicarbazones of 2-acetylpyridine strongly inhibit the in vivo replication of herpes simplex virus, types 1 and 2, without greatly affecting cellular DNA or protein synthesis (Shipman etal., 1981). 

Lukovits, I., A. Shaban, and E. Kalman, Thiosemicarbazides and thiosemicarbazones Non-linear quantitative stiricture-efficiency model of corrosion inhibition. Electrochimica Acta, 2005.50(20) p. 4128-4133. 

The First systematic approach to evaluate the effects of various substituents on the heterocyclic ring on the biological activity of these agents was undertaken by Agrawal, Booth and Sartorelli [34]. The candidate deemed most appropriate for such a study was l-formylisoquinoline thiosemicarbazone (1), since it was extensively employed in biochemical studies as the model agent of the series and had been shown to cause pronounced inhibition of the growth of a relatively... 

Two of the derivatives (i.e., those containing 5-methylamino and 5-ethyl-amino groups) demonstrated impressive antitumour activity against Sarcoma 180 ascites cells and several others were potent inhibitors of ribonucleoside diphosphate reductase, requiring concentrations in the range of 10" to 10" M for 50% inhibition [43], 5-Methylamino-l-formylisoquinoline thiosemicarbazone, which was the most effective of the newly synthesized compounds required a concentration of 3 10" M for 50% inhibition of reductase activity and increased the life span of tumour-bearing mice over untreated animals by a factor of 2.5 at the optimal daily dose. 

A second enzymatic site, which has been selected as a target to direct the chelating potential of the thiosemicarbazone molecule, is pyiidoxal phospho-kinase [65]. This catalyst is a zinc-requiring enzyme [66] that catalyzes the phosphorylation of pyridoxine at position 5 to form the active coenzyme form. In an effort to accomplish inhibition, 2-formyl-3-hydroxy-4,5-bis(hydroxy-methyOpyridine thiosemicarbazone (117) was synthesized [65]. This was accomplished by two different procedures. The common intermediate, 3-acetoxy-2,4,5-tris(acetoxymethyl)pyridine (111) [67], upon acid hydrolysis afforded 3-hydroxy-2,4,5-tris(hydroxymethyl)pyridine hydrochloride (112), which was treated with hydrogen chloride as a suspension in acetone [68). The amount of hydrogen chloride taken up by the suspension is a critical factor and. 

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