Thiosemicarbazones, antiviral

Virus replication comprises numerous biochemieal transformations that might provide suitable targets for antiviral therapy. The antiviral effect of thiosemicarbazones was first demonstrated by Hamre et al. [53, 54], who showed that p-aminobenzaldehyde-3-thiosemicarbazone and several of its derivatives were active against vaccinia virus in mice. These studies were extended to include thiosemicarbazones of isatin, benzene, thiophene, pyridine, and quinoline derivatives, which also showed activity against vaccinia-induced encephalitis. The nature of the aldehyde/ketone moiety was not as significant as the presence of the thiosemicarbazide side chain the latter was deemed essential for antiviral activity. 

Methods for the analysis of the antiviral JV-methylisatin-3-thiosemi-carbazone have been reported.376 Metabolic removal of the sulfur from iV-methylisatin-3-thiosemicarbazone has been reported377 to give syn-and cmti-N-methylisatin-3-semicarbazone. 

The aromatic and heteroaromatic thiosemicarbazones (39) are powerful chelating agents which have been rather neglected in the mainstream of chelation chemistry. Perrin and Stiinzi43) have reviewed their role as antiviral agents and noted their use in 1950 to reduce the severity of vaccinia infections of chick embryos and mice. The thiosemicarbazones have been used prophylactically to prevent outbreaks of smallpox in persons who had been in contact with the disease295). Pfauz96) has reviewed the pharmaceutical applications of thiosemicarbazones. 

The other thiosemicarbazones are less well studied and as yet the link between antiviral action and chelation is not fully established. It has been proposed that the chelation of iron(II), a cofactor of ribonucleoside diphosphate reductase, could be the principal mode of action of the thiosemicarbazones300. However, other mechanisms are possible. Investigations of the ESR spectra of copper(II) complexes of thiosemicarbazones has been used to follow the intracellular reactions of the complexes - see Antholine et al.301 for a review. In Ehrlich cells the chelate becomes localized in the cell membrane302. This spectroscopic technique could also be used to monitor the antimala-rial action of 2-acetylpyridine thiosemicarbazones303. ... 

Among biologically active compounds - derivatives of isatin - there is methisazone (1-methylisatin 3-thiosemicarbazone), which has been used as a prophylactic agent against the smallpox virus [139-141], Methods for the synthesis of compounds with the general formula 146 have been developed in the search for new antiviral and antimicrobial agents [142] ... 

Eucka-Sobstel, B.. Zeic. A., Borysiewicz, J., and I )tec. Z., In vitro antiviral activity of Mannich ba.ses derived from 5-bromoisatin and its p-thiosemicarbazone, Acta Pharm. Jiigosi, 4,95. 1974 Chem. Ahstr, 82,25652, 1975. 

The thiosemicarbazone of 7-azaisatin lacked antiviral activity isatin and pyridinecarboxaldehyde derivatives are active. ... 

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. 

Isatin-j8-thiosemicarbazone was originally found to be a potent antivaccinia viral agent in mice and the activity of this compound was attributed to complex formation [545]. Subsequently, a derivative, jV-methylisatin-3-thiosemicarbazone (M-IBT), proved to be a very effective antiviral agent in humans for the prevention of morbidity and mortality due to smallpox epide-... 

Some aromatic thiosemicarbazones are active against smallpox virus, while phosphonoformic acid (PFA) and phosphonoacetic acid (PAA) are active against herpes viruses. Consequently, some acylphosphonate thiosemicarbazones, (47), in which the two types of structural moieties appear together, were synthesized and tested for antiviral activity. However, no inhibitory activity was observed against herpes and/or pox viruses . 

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... 

The a-(AO-heterocycIic carboxaldehyde thiosemicarbazones constitute a class of agents which possess both antineoplastic and antiviral activity [1], The first agent of this series to be examined for biological activity, 2-formylpyridine thio-... 

Thus, the antiviral activity of the thiosemicarbazones has been correlated, in one study, with their ability to inhibit ribonucleotide reductase [8]. Methisazone inhibits the RNA-dependent DNA polymerase of Rous sarcoma virus (RSV) and inactivates its ability to transform chick-embryo cells [9], as well as inactivating herpes simplex [10] and some RNA viruses [11]. The activity against RSV is Cu-dependent [9], the Cu complex also being capable of inhibition of the polymerase [12]. Since these enzymes are zinc-dependent, interference with the role of zinc is possible. The inhibition of influenza virus-associated RNA transcriptase by... 

Chelating agents may manifest their antiviral activity by metal sequestration and, as with bacteria and parasites, the natural differences between the host and invading cells may be exploited. Chelating agents with antiviral activity include the thiosemicarbazones, 1,10-phenanthrolines and phosphonoacetates. The latter compounds may act by zinc chelation. Metal complexes with antiviral action are platinum and palladium amines, as well as the antibacterial silver and mercury species. 

Pharmacologically Active Compounds.— Benzo[6]thiophen-2- and -3-carbox-aldehyde thiosemicarbazones have been prepared and screened for antiviral activity. 3-Benzo[fe]thiophenoxyaminopropanols and the complex benzo[6]-... 

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