Synthesis of substituted 1-norbornylamines with antiviral activity.

The reaction of (+/-)-camphor (7) with triflic anhydride (Tf2O) yields the bridgehead triflate 8. The Nametkin rearrangement of 8 to 3 was realized by treatment with triflic acid (TfOH). The solvolysis of the bridgehead triflates 3 and 8 in acetonitrile affords the N-acetyl-1-norbornylamines 4 and 9. The Pd(0)-catalyzed hydrogenation of 4 and 9 gives the amides 5 and 10. The corresponding 1-norbornylamines 2 and 13 and the N-ethyl derivatives 1, 6, 11, and 12 were obtained by basic hydrolysis or reduction with LiAlH4, respectively, of the amides 4, 5, 9, and 10. The antiviral activity of the hydrochlorides of some of the obtained 1-norbornylamines was evaluated against influenza A, herpes simplex 2, and African swine fever virus. Particularly noticeable is the activity of the hydrochlorides of 1 and 11 against influenza A virus (SI (selectivity index) = 1000).

Antiviral activity of uridine 5'-diphosphate glucose analogues against some enveloped viruses in cell culture.

Twenty five analogues of uridine 5'-diphosphate glucose were screened against herpes simplex type 2, vaccinia virus, Sindbis virus and African swine fever virus. After screening, the compound 5'-[[[[(2",3",4",6"-tetra-O-benzoyl-alpha-D- glucopyranosyl)oxi]carbonyl]amino]sulfonyl]uridine (2), the synthesis of which has been reported (Camarasa et al., J. Med. Chem. 28, 40-46, 1985), was selected for further study. This compound showed in vitro activity against all viruses tested. The replication of herpes virus type 2 and African swine fever virus was completely inhibited at 100 micrograms/ml and 150 micrograms/ml respectively; vaccinia virus and Sindbis virus were inhibited to a lesser extent. The compound may inhibit several steps in the viral replication process.

Antiviral action of 5-amino-2-(2-dimethyl-aminoethyl)benzo-[de]-isoquinolin-1,3-dion e.

A newly synthesized imide derivative of 3-nitro-1,8-naphthalic acid, 5-amino-2-(2-dimethylaminoethyl)benzo-[de]-isoquinolin-1,3-dione (designated M-FA-142), was tested on chick embryo cells against herpes simplex virus type 1 (HSV-1) and vaccinia virus (VV), and on Vero cells against African swine fever virus (ASFV). At a concentration of 4 micrograms/ml the drug inhibited VV replication by about one order of magnitude, and that of HSV-1 by about three orders of magnitude. A minor effect was shown against ASFV. Virus inhibition was found to depend on the amount of drug and multiplicity of infection. No virucidal effect was observed on the viruses tested, except for a slight effect on HSV-1. Inhibition of virus growth could be reversed when the drug was removed from the cell culture medium. Serial passages of HSV-1 and VV in the presence of the drug caused the appearance of drug-resistant viruses.

Suppression of persistent varicella-zoster virus infection in Vero cells by acyclovir.

Persistent infection was established in Vero cells inoculated with varicella-zoster virus (VZV)-infected WI-38 cells. Treatment with 9-(2-hydroxy-ethoxymethyl)guanine (acyclovir) at doses of 100, 80, 40, and 10 micrograms/ml eliminated the infectious virus, lower doses such as 0.1 and 0.01 micrograms/ml were ineffective.

Plaque formation by African swine fever virus in chick embryo fibroblasts in the absence of CO2 atmosphere.

A plaque assay method using ASFV previously adapted to growth in chick embryo fibroblasts is described. Chick embryo fibroblast monolayers under bactoagar or methylcellulose have been employed using cysteine, arginine, DEAE-Dextran and HEPES as additives. Plaque production was optimal under methylcellulose. HEPES rendered the plaques more clear when used with the overlay. Arginine enhances plaque formation with bactoagar, and DEAE-Dextran doubles the plaque size. The growth curve of ASFV in chick embryo monolayers has been studied.

Antiviral action of benzo[de]isoquinoline-1,3-diones: 5-nitro-2-(2-dimethylaminoethyl) and 5-nitro-2-[2-(1-pyrrolidine)-ethyl] derivatives.

Two benzo[de]isoquinoline-diones, namely 5-nitro-2-(2-dimethylaminoethyl)-benzo[de]isoquinoline-1,3-dione and 5-nitro-2-[2-(1-pyrrolidine)-ethyl]-benzo[de]isoquinoline-1,3-dione, caused inhibition of the viral replication, when assayed against herpes simplex and vaccinia viruses in chick embryo cell cultures. Influenza and Sindbis virus replication were unaffected by these chemicals. Virucidal effects were unobserved. The inhibitory activity is time-related. Ocular and dermal infections with vaccinia virus in rabbits were prevented or disease severity reduced whenever they were treated with either one of these two drugs.

Inactivation and inhibition of African swine fever virus by monoolein, monolinolein, and gamma-linolenyl alcohol. Brief report.

Monoolein, monolinolein and (most strongly) gamma-linolenyl alcohol inactivate ASF virus and inhibit its replication in Vero cells at 25 micrograms/ml while at 10 micrograms/ml no inactivation occurs but inhibition of replication in tissue culture is observed. This suggests two possibly different action mechanisms.