[Bis((2,4-dioxo-1,2,3,4-tetrahydroquinazolin-3-yl)alkyl)disulfane and 3-(mercaptoalkyl)quinazolin-2,4(1H,3H)-dione: synthesis by ring transformation and antiviral activity. 42. Heterocyclic azines with heteroatoms in the 1- and 3- positions]. / Bis[(2,4-dioxo-1,2,3,4-tetrahydrochinazolin-3-yl)alkyl]disulfane and 3-(Mercaptoalkyl)chinazolin02,4,(1H,3H)-dione: Synthese durch Ringtransformation and antivirale Aktivität. 42. Mitteilung: Mehrcyclische Azine mit Heteroatomen in 1- and 3-Stellung.

Reaction of N-(sulfonyloxy)phtalimide derivatives 1, 2, with cystamine and homocystamine, respectively, affords bis[2,4-dioxol-1,2,3,4-tetra-hydroquinazolin-3-yl)alkyl] disulfanes [sequence: see text] 3, which could be reduced to 3-(mercaptoalkyl)quinazoline-2,4(1H,3H)-diones. 5. (3-(2-Mercaptoethyl)quinazoline-2,4(1H,3H)-dione (5a) was also obtained in a one-pot reaction from 1 or 2 and cysteamine. 2-Ethoxy-4H-3,1-benzoxazin-4-ones 4a-c were converted with cysteamine to 3-(mercaptoethyl)quinazoline-2,4-diones 5a-c by a new ringtransformation reaction. 3-(2-Mercaptoethyl)quinazoline-2,4(1H,3H)dione (5a) and the corresponding disulfane 3a were evaluated for antiviral activity in vitro. Compounds 3a and 5a showed significant antiviral activity against some DNA- and RNA-viruses (vaccinia-, herpes simplex virus type 1; influenza A virus) at concentrations that were nontoxic to the host cell cultures.

On the antiviral activity of diffusomycin (oxazolomycin).

The effect of the beta-lactone antibiotic diffusomycin (oxazolomycin) was investigated against vaccinia (Lister), herpes simplex type 1 (Kupka), influenza A (WSN; H1N1), and Coxsackie A9 viruses. Diffusomycin reduced significantly the plaque formation of enveloped DNA and RNA viruses by more than 90% in the range of the maximally tolerated dose. As could be shown with vaccinia virus, the antiviral action was not caused by virucidal effect on virions or by interaction with virus adsorption and penetration. In one-step growth cycle assays diffusomycin prevented the replication of herpes simplex type 1, vaccinia and influenza A viruses in a dose-dependent manner. The replication of influenza A viruses was blocked immediately after addition of the compound during zero to six hr p.i. Partial reversibility of the antiviral action was established by washing off the antibiotic from chicken embryo cells (CEC) infected with influenza A virus. Finally, replication of Coxsackie A9 virus was not inhibited by diffusomycin. Electron-optical studies revealed a reduced synthesis of HSV-1 nucleocapsids in dependence on the concentration of the compound.

[Griseochelin methyl ester, a new polyether derivative with antiviral activity]. / Griseochelinmethylester, ein neues Polyether-Derivat mit antiviraler Wirksamkeit.

The methylester of griseochelin (1) is a new chemically-made antiviral derivate of the antibiotic griseochelin isolated from fermentations of Streptomyces griseus. It belongs to the polyether group and possesses antiviral activity against enveloped RNA and DNA viruses cultivated in chicken embryo cells (CEC), namely influenzavirus A/WSN, vesicularstomatitis virus (Indiana), vaccinia virus (Lister) and herpes simplex hominis virus type 1 (Kupka). The methylester of griseochelin failed to show virucidal effects on extracellular influenza vacciniavirus particles or to influence virus adsorption and penetration processes. The antibiotic in concentrations of 125-15 micrograms/ml inhibited the virus-induced cytopathic effect of the above mentioned viruses and caused over 90 per cent plaque reduction. Addition of 1 during a one-step growth cycle of influenzavirus A at 4 and 6 h p.i. resulted in complete suppression of virus multiplication at the control niveau of the virus yield accumulated to the same time point. A partial reversibility of the antiviral action against influenzavirus A could be achieved. Coxsackie A9 virus growth in human fibroblast cells was not affected by the inhibitor. Electron-optical observations showed a failure of the formation of the viral capside proteins of HSV type 1 at the second halftime of the replication cycle in CEC-infected and 1-treated cultures.

[Biological effects of coordinated compounds of transitional metals. 7. Antiviral activity of 4-methyl-2-aminopyridine palladium chloride against herpes simplex virus type 1 and type 2 in vitro and in vivo]. / Uber biologische Wirkungen von Koordinationsverbindungen der Ubergangsmetalle. 7. Zur antiviralen Wirksamkeit von 4-Methyl-2-amino-pyridinpalladiumchlorid gegenüber Herpes simplex-Virus Typ 1 und Typ 2 in vitro und in vivo.

4-Methyl-2-amino-pyridine-palladium chloride (MAP) showed an antiviral activity against herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) in a serum-free medium under in vitro conditions. The replication of these viruses on primary rabbit testes cells was completely suppressed by 10(-5) M/l MAP. In animal tests using ABD2-mice the course of HSV-1 and HSV-2 encephalitis was not influenced by MAP indicated by mean survival time and lethality.

Cyclic AMP metabolism and interferon induction in mice after treatment with 10-carboxymethyl-9-acridanone.

The low molecular weight substance 10-carboxymethyl-9-acridanone (CMA) is capable to induce interferon (IFN) production. In order to determine the effect of CMA on cyclic AMP alterations in relation to IFN production, male ABD2F1 hybrid mice were orally treated with several concentrations of CMA (400, 600 and 800 mg/kg) for varying periods of time up to 24 hr. IFN titres were detected as early as 3 and 4 hr, respectively, in mouse plasma after CMA administration, and their production continued for at least 24 hr. Maximum IFN titres were assayed in the presence of 800 mg/kg (3,200 IU/ml) CMA. Measuring of the intracellular concentrations of cyclic AMP in thymus and spleen revealed that in early stage (0.5 to 2 hr) CMA exhibited a dose dependent increase. The drug acted as an inhibitor of low Km cAMP phosphodiesterase in cell homogenates; a significantly enhanced enzyme activity (1 to 4 hr) was found after exposure to CMA in vivo.

[The biological effects of coordination compounds of transitional metals. 6. Effect of 4-methyl-2-aminopyridine-palladium chloride and cis-dichlorodiammine-platinum(II) on retroviruses and the virus-associated RNA polymerase of the influenza virus]. / Uber biologische Wirkungen von Koordinationsverbindungen der Ubergangsmetalle. 6. Wirkung von 4-Methyl-2-aminopyridin-palladiumchlorid und cis-dichloro-diammin-Platin(II) auf Retroviren und die virus-assoziierte RNS-Polymerase von Influenzavirus.

The effect on retroviruses of two transition metal complexes of known antiviral activity, 4-methyl-2-amino-pyridine-palladium-chloride (MAP) and cis-dichloro-diammine-platinum(II) (cis-DDP) has been investigated. The experiments included the evaluation of the action of compounds on virus particle-associated reverse transcriptase in exogenous assays, on virus propagation in persistently infected cell cultures and on virus infectivity in mice. In disrupted viruses and in the absence of excess protein, the reverse transcriptase was inhibited by MAP but not by cis-DDP. The same results were obtained when examining the activity of the virus-associated RNA polymerase of influenza virus A/WSN. Both compounds did not inhibit the replication of retroviruses in cell cultures, except at high dose levels which exerted toxic action on both cells and virus formation. The leukemogenicity of Rauscher murine leukemia virus was strongly inhibited when the virus had been incubated with MAP before inoculation. A similar treatment with cis-DDP did not influence viral leukemogenicity. Despite somewhat different results with both compounds tested, we conclude from the present results that the above mentioned compounds cannot be considered as antiretroviral drugs.

[In vitro effectiveness of new antiviral substances. 1. Results of screening studies against selected picornaviruses]. / Uber die In-vitro-Wirksamkeit neuer antiviraler Substanzen. 1. Mitteilung. Ergebnisse von Screeninguntersuchungen gegenüber ausgewählten Picornaviren.

A number of 3108 new synthetic compounds were subjected to a screening for antiviral activity. The screening resulted in the selection of numerous drugs active against mengovirus in vitro. Some drugs were also active against Coxsackie viruses A9 and B1; most of the drugs efficient against Coxsackie virus A9 also showed activity against mengovirus. Quantitative investigations--such as the determination of a therapeutic index or of the inhibition of infectious virus yields in one-step growth cycle experiments--allowed the selection of the compounds with the highest in vitro efficacy.

[In vitro effectiveness of new antiviral substances. 2. studies with enteroviruses and rhinovirus lB]. / Uber die In-vitro-Wirksamkeit neuer antiviraler Substanzen. 2. Mitteilung. Untersuchungen mit Enteroviren und Rhinovirus 1B.

The antiviral efficacy of several compounds was demonstrated against Coxsackie viruses type A9, B1, B3, B4 and B5, echoviruses type 6, 11, 30, and 33, attenuated polioviruses and rhinovirus 1B. In one-step growth cycle experiments virus multiplication was clearly inhibited by application of the compounds immediately after virus adsorption.

[Biological activity of transition metal complexes. 5. Effect of dimethyl sulfoxide on the cytotoxic, antiviral and antitumoral properties of cis-dichlorodiammineplatinum (II): "cisplatin"]. / Uber biologische Wirkungen von Koordinationsverbindungen der Ubergangsmetalle. 5. Zum Einfluss von Dimethylsulfoxid auf die zytotoxischen, antiviralen und antitumoralen Eigenschaften von Cis-dichloro-diammin-platin (II): "Cis-Platin".

In water or dimethyl sulfoxide solutions cis-platinum is subject of time depending solvolytic reactions leading to compounds with different biological effectivity. Whereas the inactivation of vaccinia, vesicular stomatitis and adeno virus type 5 was not changed if dimethyl sulfoxide or dimethyl formamide instead of destilled water were used as solvents, long time stored solutions of cis-platinum in dimethyl sulfoxide were tolerated by cells cultivated in vitro in 8-25 times higher concentrations in comparison with a freshly solved preparation. Their antiviral effectivity was maintained. On the other hand experiments with mice showed that simultaneously with the decrease of toxicity of an aged cis-platinum solution in DMSO also its antileukemic activity disappeared. In a 5 weeks old cis-platinum solution in destilled water antitumor activity was preserved in spite of enhanced toxicity.

Effect of dipyridamole on immune response in mice.

Dipyridamole in the dose of 50 mg/kg body weight stimulated the primary humoral response in BALB/c and C57Bl mice. The cell-mediated immune response was not influenced in BALB/c mice.

Effects of streptovirudin on influenza viruses type A and B: inhibition of the lipid-linked oligosaccharide synthesis of fowl plague virus.

Antibiotics of the streptovirudin complex (SV) inhibited the growth of influenza A and B viruses such as influenza A/fowl plague virus (FPV), strain Weybridge (Hav1 Neq1), influenza A/England 42/72 (H3N2), influenza A/Port Chalmers 1/73 (H3N2), influenza B/Leningrad 235/74, influenza B/Tokyo 7/66, and influenza B/Jamagata in chick embryo cell (CEC) cultures, in permanent canine kidney cells (MDCK), and in suspended fragments of chick embryo chorioallantoic membranes (CAM). As revealed by spectrophotometric turbidity measurements, SV completely inhibited the FPV-induced cytopathic effect (CPE). A 99.99% reduction of infectious virus yield was obtained in one-step growth cycle experiments and in the plaque reduction test. The haemagglutination inhibition titres of influenza viruses in suspended CAM fragment cultures in the presence of SV drugs were also substantially reduced. The incorporation assays indicated that SV exhibited no effect on virus-induced RNA synthesis, but influenced virus maturation by inhibition of lipid-linked oligosaccharide synthesis. A partial protection from infection was found in influenza virus A/England infected mice.

[Induction of immune interferon by erythrogenic toxins A and B from Streptococcus pyogenes]. / Induktion von Immuninterferon durch erythrogene Toxine A und B des Streptococcus pyogenes.

By interaction of streptococcal erythrogenic toxins A and B with chick embryo fibroblasts and human amnion (FL) cells an antiviral interferon-like factor was secreted. It inhibited the replication of vesicular stomatitis, vaccinia and Mengo viruses. The streptococcal toxin type B was 50 times more cytotoxic for both cell cultures in comparison with streptococcal toxin A. The maximum tolerated doses of the two types of streptococcal toxins induced approximately the same antiviral protection effect. The production curve of the antiviral factor showed a maximum at the 12th hour after incubation at 37 degrees C with graduate decrease up to the 24th hour using a 6 hours induction time. The interferons induced by the streptococcal erythrogenic toxins A and B were thermostable at 56 degrees C for 30 min and were partially destroyed at pH 2 as tested against Mengo virus in FL cells. The antiviral effect could be reversed by addition of streptococcal erythrogenic toxin A at the maximum tolerated dose simultaneously with the glycosylating inhibitors streptovirudin and D-glucosamine by 90 and 100 per cent, respectively.

Antiviral action of dipyridamole and its derivatives against influenza virus A.

Dipyridamole proved to be active against influenza viruses A/England 42/72, A/Bangkok 1/79 and A/fowl plague (FPV). The antiviral activities assayed by various methods varied from 90-99 per cent. No inhibition was found against influenza virus B/Leningrad 235/74 in vitro. Three dipyridamole derivatives were significantly active in tissue cultures against influenza virus A/England 42/72 and A/FPV. In white mice infected with influenza virus A/England 42/72 dipyridamole administered orally showed a protection rate of 62.5 per cent.

Antiviral activity of hetarylhydrazones.

Some hetarylhydrazones showed antiviral activity against Mengo virus in vitro. The replication of influenza A and B viruses was affected neither in vitro (chick chorioallantoic membranes) nor in vivo (mice). Based on dose response curves of the active hetarylhydrazones the compound Z 98/69 appeared most effective in vitro. This compound neither inactivated the extracellular virus nor inhibited its adsorption and penetration; it reduced virus replication when added 1-3 hr after Mengo virus inoculation. As shown by plaque reduction test vaccinia virus was also inhibited. A partial inhibition of rhinovirus 1B multiplication was observed whereas other picornaviruses were not affected.

[On the biological action of transition metal complexes. 3. About the antiviral activity of cis-dichloro diammine platinum (II) (author's transl)]. / Uber biologische Wirkungen von Koordinationsverbindungen der Ubergangsmetalle 3. Zur antiviralen Wirkung von Vis-dichloro-diammin-platin (II): "Cis-Platin".

The coordination compound cis-dichlorodiammineplatinum(II) (cis-DDP) was shown by Rosenberg et al. (17) to exhibit antitumour activity. Several authors have indicated limited virustatic properties of cis-DDP against bacterial, oncogenic, avipox and paramyxo viruses. In our investigations, cis-DDP significantly showed an antiviral action in vitro against enveloped DNA and RNA viruses, such as vaccinia, pseudorabies, herpes simplex type 1, Newcastle disease, influenza A/fowl plague, influenza A/Victoria 3/75, influenza A/Jena 48/78, influenza B/Johannesburg and vesicular stomatitis viruses. Out of the group of nonenveloped viruses, adenovirus type 4 and 5 were inhibited, whereas no inhibition against naked cardiovirus Mengo could be estimated. The antiviral action was proved against extracellular virus by dialysis experiments with vaccinia virus and also during the replication cycles of enveloped viruses. In trials with cell-free viruses the plaque reduction of all sensitive viruses mentioned above amounted to 100 per cent in comparison to the untreated controls caused by virus inactivation with loss of infectivity in contact with several concentrations of cis-DDP. On the other hand, the addition of the compound for one hour only immediately after infection or up to 8 hrs later produced a complete depression of further multiplication of vaccinia virus. Likewise, the replication of influenza virus A/FPV or VSV was inhibited whereas the multiplication of adenoviruses was not influenced in a comparable manner.

[On the biological action of transition metal complexes. 4. The antiviral activity of metallocene dichlorides of titanium and molybdenum (author's transl)]. / Uber biologische Wirkungen von Koordinationsverbindungen der Ubergangsmetalle 4. Zur antiviralen Wirkung der Metallocendihalogenide des Titans und Molybdäns.

In view of the fact that bis cyclopentadienyl metal dihalides are known to be anti-tumour drugs, we have investigated the antiviral activity of this type of coordination compounds. Bis cyclopentadienyl titanium dichloride (a) has shown significant antiviral efficiency in vitro against representatives of a nuber of enveloped DNA and RNA viruses. Inhibition of orthopoxvirus (vaccinia), herpes virus (pseudorabies), orthomyxoviruses (influenza A/fowl plague [FPV], influenza A/Victoria 3/75, influenza A/jena 48/78 and influenza B/Johannesburg), paramyxovirus (Newcastle disease [NDV]) and rhabdovirus (vesicular stomatitis [VSV]) was observed after direct contact with the compound under loss of infectivity up to 100%. Regarding the group of unenveloped viruses only adenovirus type 4 became influenced but not type 5. No antiviral activity could be found against the cardiovirus Mengo. The compound bis cyclopentadienyl molybdenum dichloride failed to show an antiviral action versus vaccinia, influenza A/FPV and influenza viruses B/Johannesburg. Application of the inhibitor (a) during the replication of vaccinia and influenza viruses A/FPV in cell cultures produced an additional effect of inhibition of virus multiplication. On the other hand, adenovirus type 4 and VSV replication was not affected by titanocene dichloride.

[On the biological action of transition metal complexes. 1. The antiviral activity of palladium aminopyridin-complexes (author's transl)]. / Uber biologische Wirkungen von Koordinationsverbindungen der Ubergangsmetalle. 1. Antivirale Wirkung von 2-Aminopyridinkomplexen des Palladiums.

Some aminopyridine complexes of palladium and PdCl2 showed an antiviral in vitro activity against enveloped DNA and RNA viruses such as vaccinia virus, pseudorabies virus, NDV and FPV. In contrast, naked RNA virus as mengovirus was not affected. The compounds were compatible for chicken embryo as well as FL cells in concentrations of 100-250 microM. The therapeutical index calculated from the maximally tolerated dose and the concentration causing a 50 per cent plaque reduction was determined with more than 45 for vaccinia virus, for example.