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Biomedical subjects

L B Allen

Publications and source records attributed to L B Allen.

At least 37 records · Page 2Linked to original sources
PubMed1978

Synthesis and antiviral acticity of some phosphates of the broad-spectrum antiviral nucleoside, 1-beta-D-ribofuranosyl-1,2,4-triazole-3-carboxamide (ribavirin).

1-beta-D-Ribofuranosyl-1,2,4-triazole-3-carboxamide 5'-phosphate (2) was prepared and converted into the following derivatives: the 5'-phosphoramidate 3, the 5'-diphosphate 4, the 5'-triphosphate 5, and the cyclic 3',5'-phosphate 6. The cyclic 2',3'-phosphate 7 was prepared from the parent nucleoside, 1-beta-D-ribofuranosyl-1,2,4-triazole-3-carboxamide (1), and was opened to the 2'(3')-phosphate 8. These compounds were found to exhibit significant antiviral activity against several viruses in cell culture. Ribavirin 5'-phosphate (2) was shown to be effective when tested against lethal infections in mice caused by influenza A2, influenza B, and murine hepatitis viruses.

Adenoviridae↗
PubMed1978

Imidazo[1,2-a]-s-triazine nucleosides. Synthesis and antiviral activity of the N-bridgehead guanine, guanosine, and guanosine monophosphate analogues of imidazo[1,2-a]-s-triazine.

The first chemical synthesis of 2-aminoimidazo[1,2-a]-s-triazin-4-one (8), the corresponding nucleoside and nucleotide, and certain related derivatives of a new class of purine analogues containing a bridgehead nitrogen atom is described. Condensation of 2-amino-4-chloro-6-hydroxy-s-triazine (2) with aminoacetaldehyde dimethyl acetal followed by the ring annulation gave the guanine analogue 8. A similar ring annulation of 4-(2,2-dimethoxyethylamino)-s-triazine-2,6-dione (5) gave imidazo[1,2-a]-s-triazine-4,6-dione (9). Direct glycosylation of the trimethylsilyl derivative of 8 with 1-O-acetyl-2,3,5-tri-O-benzoyl-beta-D-ribofuranose in the presence of stannic chloride, followed by debenzoylation, gave the guanosine analogue 2-amino-8-(beta-D-ribofuranosyl)imidazo[1,2-a]-s-triazin-4-one (12b), which on deamination gave the xanthosine analogue 13. Phosphorylation of 12b gave 2-amino-8-(beta-D-ribofuranosyl)imidazo[1,2-a]-s-triazin-4-one 5'-monophosphate (II). The anomeric configuration has been determined unequivocally by using NMR of the 2',3'-O-isopropylidene derivate 10 and the site of ribosylation has been established by using 13C NMR spectroscopy. These compounds were tested against type 1 herpes, type 13 rhino, and type 3 parainfluenza viruses in tissue culture. Moderate rhinovirus activity was observed for several compounds at nontoxic dosage levels.

Antiviral Agents↗
PubMed1977

Comparison of the development of resistant strains of Type 1 herpes simplex virus to in vitro antiviral activity of 5-iodo-2'-deoxyuridine or ribavirin.

Exposure of HSV/1 to low concentrations of ribavirin during 4--5 passages does not produce ribavirin-resistant virus. IDU resistance was developed by HSV/1 while it was being passed simultaneously. This resistance was seen to develop in both KB and Vero cells. The IDU-resistant virus is also resistant to ribavirin in KB cells.

Drug Resistance, Microbial↗
PubMed1977

Effect of ribavirin on Type 2 Herpesvirus hominis (HVH/2) in vitro and in vivo.

Ribavirin was found to inhibit five strains of HVH/2 tested in KB cells with the M1C range being 10-100 microgram/ml. In a mouse tail animal model, it effectively reduced HVH/2-induced lesions particularly at the peak lesion periods. Ribavirin was remarkably effective when intravaginal treatment was initiated late in the infection, which suggests that it may have potential for treatment of human cutaneous infections.

Animals↗
PubMed1977

Acceleration of scrapie in mice by target-organ treatment with interferon inducers.

Interferon inducers were used in the target-organ treatment of scrapie in mice. Intracerebral treatments began 24 hr prior to intracerebral inoculation of 10(4.8) LD50 of the Chandler strain of scrapie agent. The treatments included 30 and 0.3 microgram poly(I:C) given weekly 9 times, 45 microgram statolon given biweekly 7 times, or 1.5 HA units of Sendai virus given biweekly 6 times. All treatments except the lower dose of poly(I:C) accelerated death in scrapie-affected mice. Compared to saline-treated control groups, 30 microgram poly(I:C), given weekly, shortened the mean survival time 13.5 days. Groups treated with statolon or Sendai virus had their mean survival times shortened 18.5 and 21.7 days, respectively. Infected mice were also evaluated for signs of disease at approximately weekly intervals using a numerical scoring method. Acceleration was also apparent using this parameter of disease. When treatment occurred only once, Sendai virus was the only inducer to significantly shorten the survival of mice.

Animals↗
PubMed1977

Synthesis and antiviral activity of certain thiazole C-nucleosides.

A general reaction of glycosyl cyanides with liquid hydrogen sulfide in the presence of 4-dimethylaminopyridine to provide the corresponding glycosylthiocarboxamides is described. These glycosylthiocarboxamides were utilized as the precursors for the synthesis of 2-D-ribofuranosylthiazole-4-carboxamide and 2-beta-D-ribofuranosylthiazole-5-carboxamide (23). The structural modification of 2-beta-D-ribofuranosylthiazole-4-carboxamide (12) into 2-(2,3,5-tri-O-acetyl-beta-D-ribofuranosyl)thiazole-4-carboxamide (15), 2-beta-D-ribofuranosylthiazole-4-thiocarboxamide (17), and 2-(5-deoxy-beta-D-ribofuranosyl)thiazole-4-carboxamide (19) is also described. These thiazole nucleosides were tested for in vitro activity against type 1 herpes virus, type 3 parainfluenza virus, and type 13 rhinovirus and an in vivo experiment was run against parainfluenza virus. They were also evaluated as potential inhibitors of purine nucleotide biosynthesis. It was shown that the compounds (12 and 15) which possessed the most significant antiviral activity were also active inhibitors (40-70%) of guanine nucleotide biosynthesis.

Animals↗
PubMed1977

Antiviral activity of 3-deazaguanine, 3-deazaguanosine, and 3-deazaguanylic acid.

3-Deazaguanine (ICN 4221), 3-deazaguanosine (ICN 4793), and 3-deazaguanylic acid (ICN 5412) represent a new class of synthetic guanine analogs having antiviral activity. In vitro, nine ribonucleic acid and seven deoxyribonucleic acid viruses were inhibited, including influenza, parainfluenza, rhino-, vesicular stomatitis, adeno-, herpes-, cytomegalo-, vaccinia, pseudorabies, and myxoma viruses. They were effective orally against influenza types A and B and parainfluenza type 1 (Sendai) virus infections in mice, with a therapeutic index of 16 against the latter two viruses. The course of herpes encephalitis was altered only when the drugs were applied directly into the brain. In addition, these drugs were effective inhibitors of Friend leukemia virus-induced splenomegaly in mice; treatment also produced extensions of life in these animals.

Animals↗
PubMed1976

Synthesis and antiviral and antimicrobial activity of certain 1-beta-D-ribofuranosyl-4,5-disubstituted imidazoles.

Starting with AICA ribonucleoside the following nucleosides were prepared. Methyl 5-amino-1-(2,3,5-tri-O-acetyl-beta-D-ribofuranosyl)imidazole-4-carboxylate (5) was converted into methyl 5-chloro-1-(2,3,5-tri-O-acetyl-beta-D-ribofuranosyl)imidazole-4-carboxylate (6) via diazotization in the presence of cuprous chloride. Similarly, 5-amino-1-(2,3,5-tri-O-acetyl-beta-D-ribofuanosyl)imidazole-4-carbonitrile (9) was converted into 5-chloro-, 5-bromo-, and 5-iodo-1-(2,3,5-tri-O-acetyl-beta-D-ribofuranosyl)imidazole-4-carbonitrile derivatives. These 5-halogenated imidazole nucleosides were treated with several nucleophiles such as ammonia, hydroxylamine, and hydrogen sulfide to provide, respectively, 5-haloimidazole-4-carboxamide, 5-haloimidazole-4-carboxamidoxime, and 5-haloimidazole-4-thiocarboxamide ribonucleosides. 5-Chloro- or 5-bromo-1-(2,3,5-tri-O-acetyl-beta-D-ribofuranosyl)imidazole-4-carbonitrile was treated with potassium hydrosulfide to yield 5-mercapto-1-beta-D-ribofuranosylimidazole-4-thiocarboxamide (16). The catalytic reduction of 5-chloro- or 5-bromo-1-beta-D-ribofuranosylimidazole-4-carboxamidoxime provided 1-beta-D-ribofuranosylimidazole-4-carboxamidines as their hydrochloride and hydrobromide salts, respectively. These nucleosides were tested for in vitro antiviral, antifungal, and antibacterial activity. The 5-halo analogues of 1-beta-D-ribofuranosylimidazole-4-carboxamide showed significant antiviral activity whereas compound 16 was found inhibitory to fungi.

Adenine Nucleotides↗
PubMed1976

Synthesis and anti-DNA -virus activity of the 5'-monophosphate and the cyclic 3',5'-monophosphate of 9-(beta-D-xylofuranosyl) guanine.

9-(beta-TD-xylofuranosyl)guanine (xylo-G) was converted chemically to the 9-(beta-D-xylofuranosyl)guanine 5'-monophosphate (xylo-GMP) and 9-(beta-D-xylofuranosyl)guanine cyclic 3',5'-monophosphate (c-xylo-GMP). These compounds were tested against a variety of DNA viruses in tissue culture in parallel with 9-(beta-D-arabinofuranosyl)adenine (ara-A). This evaluation revealed that xylo-G, xylo-GMP, and c-xylo-GMP were all moderately active but less effective than ara-A. When the four compounds were administered intracerebrally as a treatment for herpes virus, type 1 induced encephalitis in mice, c-xylo-GMP exhibited superior activity to that shown by the other three. When administered intraperitoneally, c-xylo-GMP was found to have a therapeutic index of about 4, which is less than that for ara-A (approximately 30) in the same system.

Animals↗
PubMed1976

Effect of 9-beta-D-arabinofuranosylhypoxanthine 5'-monophosphate on genital lesions and encephalitis induced by Herpesvirus hominis type 2 in female mice.

9-beta-D-Arabinofuranosylhypoxanthine 5'-monophosphate, administered orally or topically, increased the number of survivors and mean day of death in mice inoculated intravaginally with Herpesvirus hominis type 2. Topical application of the drug in ointment significantly reduced the severity of genital lesions. Orally administered drug did not appreciably reduce genital lesions, but it did cause significant increases in the number of survivors and mean day of death, even when administration was started as late as three days after inoculation of virus. Drug applied both topically and orally was more effective than drug applied by either route along. For topical application an ointment was found to be a better vehicle than polyvinyl alcohol or dimethysulfoxide. In some circumstances the vehicle of drug administration itself had some efficacy.

Administration, Oral↗
PubMed1975

Synthesis and antiviral activity of certain 5'-monophosphates of 9-D-arabinofuranosyladenine and 9-D-arabinofuranosylhypoxanthine.

A number of 5'-phosphates of 9-D-arabinofuranosyladenine and 9-D-arabinofuranosylhypoxanthine were prepared and tested against a variety of DNA viruses in tissue culture. The syntheses of the antiviral agent 9-beta-D-arabinofuranosylhypoxanthine 5'-monophosphate (6) and a series of related nucleotides, 9-beta-D-arabinofuranosyladenine 5'-O-methylphosphate (3), 9-beta-D-arabinofuranosylhypoxanthine 5'-O-methylphosphate (7), 9-beta-D-arabinofuranosylhypaxanthine cyclic 3',5'-phosphate (13), and 9-alpha-D-arabinofuranosylhypoxanthine 5'-monophosphate (17), are described. The concepts underlying the development of these antiviral agents are discussed. Comparison of the anti-DNA viral activity is made with 9-beta-D-arabinofuranosyladenine (ara-A). Reproducible antiviral activity against three DNA viruses in vitro at nontoxic dosage levels is demonstrated by 3,6, and other related nucleotides.

Adenine Nucleotides↗
PubMed1975

Viral keratitis-inhibitory effect of 9-beta-D-arabinofuranosylhypoxanthine 5'-monophosphate.

Topical application of 9-beta-d-arabinofuranosylhypoxanthine 5'-monophosphate (ara-HxMP) significantly inhibited the development of keratitis induced by types 1 and 2 herpes simplex virus and vaccinia virus in the eyes of rabbits. Parameters for evaluation of efficacy were infectivity (corneal opacity, lesion size, and type), Draize (erythema, conjunctival swelling, and discharge), and reduction in titer of recoverable virus from the eye. When the relative efficacy of the related compounds 9-beta-d-arabinofuranosyladenine (ara-A), ara-A 5'-monophosphate (ara-AMP), and ara-Hx was determined against type 1 herpes simplex virus in a parallel experiment, the more water-soluble compounds (ara-HxMP, ara-AMP) were the most effective. The relative efficacy of ara-A was also determined against type 2 herpes and vaccinia virus-induced keratitis. Mortality in rabbits due to central nervous system involvement caused by types 1 and 2 herpes simplex virus was inhibited. Ara-HxMP was not discernibly toxic to the eye at concentrations of at least 20%; efficacy was still discernible with a 0.1% solution.

Animals↗
PubMed1975

Inhibition of experimental deoxyribonucleic acid virus-induced encephalitis by 9-beta-D-arabinofuranosylhypoxanthine 5'-monophosphate.

9-beta-d-Arabinofuranosylhypoxanthine 5'-monophosphate (ara-HxMP) significantly controlled the development of encephalitis produced by deoxyribonucleic acid viruses in mice. In most experiments the activities of ara-HxMP and 9-beta-d-arabinofuranosyladenine (ara-A) were determined simultaneously. In the intracerebral (target organ) and intravenous therapy experiments, ara-HxMP had a pronounced advantage over ara-A since the water solubility of ara-HxMP enabled it to be used in much higher concentrations. In experiments where the two drugs were administered intraperitoneally or orally they exhibited similar activity. In several intraperitoneal therapy experiments ara-HxMP was tested alone, using various treatment schedules and dosages. In these experiments, efficacy was observed in groups that had treatments initiated as late as 72 h after virus inoculation.

Animals↗
PubMed1975

Efficacy of 9-beta-D-arabinofuranosylhypoxanthine 5'-monophosphate in therapy of equine abortion virus-induced hepatitis in hamsters.

Equine abortion virus (EAV)-induced hepatitis in hamsters presents an interesting animal model for the evaluation of drugs possessing anti-deoxyribonucleic acid virus activity. These experiments demonstrate that 9-beta-d-arabinofuranosylhypoxanthine 5'-monophosphate (ara-HxMP), a new synthetic, water-soluble, antiviral agent, effectively controls this disease in hamsters with a therapeutic index of approximately 60. Ara-HxMP prevented hepatitis-associated deaths in hamsters, reduced the titer of EAV developing in hamsters, and inhibited the increase of serum glutamic pyruvic transaminase in EAV-infected hamsters.

Alanine Transaminase↗