Seventeen fresh clinical isolates of human cytomegalovirus (HCMV) were examined for their in vitro susceptibility to different potential anti-HCMV drugs, including a series of acyclic nucleoside ...phosphonate analogues as well as the reference compounds ganciclovir, foscarnet and acyclovir. Three sulfated polysaccharides (heparin, dextran sulfate and pentosan polysulfate) known for their ability to inhibit adsorption of enveloped viruses to the cells were also included in these comparative tests. Of the reference compounds, ganciclovir was the most potent. However, it was about five-fold less potent than the phosphonate derivative (s)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine (HPMPC) and its cyclic form (cHPMPC). All test compounds, including the sulfated polysaccharides, were as active against the clinical isolates as they were against the laboratory strains of HCMV. Furthermore, the choice of the cell line (HEL or MRC-5) did not influence the anti-HCMV activity of the compounds.
Nucleoside analogues containing a 2-deoxy-1,5-anhydro-D-mannitol and a pyrimidine base moiety were synthesized starting from D-glucose via a nucleophilic opening of an epoxide with the heterocyclic ...base and an inversion of configuration at the 3′-position. Study of the conformation of these molecules, that show some activity against herpesviruses (HSV, VZV, CMV) should increase our understanding of the structural requirements of hexitol nucleosides for antiviral activity.
Nucleosides with a D-altritol and D-mannitol structure were synhtesized from D-glucose. These molecules show moderate antiherpes activity.
The presence of HIV-1 RNA in the plasma and serum of European and African patients was monitored using RNA-polymerase chain reaction (RNA-PCR) and the new isothermal NASBA nucleic acid amplification ...system encompassing a gel-based detection assay (ELGA). Identical RNA extraction procedures, provided by the NASBA amplification system, were used for both methods. The detection limit for HIV-1 RNA, measured on a 10-fold dilution series of spiked HIV
IIIB in negative plasma, was about 0.05 CCID
50 per test for both methods. Both NASBA and RNA-PCR were more sensitive than a p24 assay for the detection of circulating HIV-1 virus in blood: 17 of the 34 (50%) p24 antigen-tested seropositives were p24-positive while 32 (94%) were positive by NASBA and 30 (88%) by RNA-PCR. Among the 45 seropositives, 34 of which were tested for p24 antigen, 43 (96%) were positive by NASBA and 41 (91%) by RNA-PCR. Almost all seropositives had a detectable viral load in 100 μl plasma. Lower viral loads were only encountered in some healthy seropositives with a higher CD4 count. There was no cross-reactivity with HIV-2 or HTLV-I with both the RNA-PCR and NASBA. The extraction method used permitted the detection of HIV-1 RNA equally well in serum and in plasma with heparin or EDTA.
A series of base-modified pyrimidine 3'-azido-2',3'-dideoxynucleosides and 3'-substituted purine and pyrimidine 2',3'-dideoxynucleosides have been synthesized and evaluated for their inhibitory ...activity against human immunodeficiency virus (HIV) replication in MT-4 cells. The following pyrimidine derivatives emerged as the most potent and/or selective inhibitors of HIV-induced cytopathogenicity (in order of decreasing selectivity: 3'-azido-3'-deoxythymidine (AZT), 3'-azido-2',3'-dideoxyuridine (AzddUrd), 3'-azido-2',3'-dideoxy-5-methylcytidine (AzddMeCyd), 3'-fluoro-ddUrd (FddUrd), 3'-fluoro-ddThd (FddThd), the N4-hydroxylated derivative of AzddMeCyd and the N4-methylated derivative of AzddMeCyd. Among the purine 2',3'-dideoxynucleosides, 3'-azido-2',3'-dideoxyguanosine (AzddGuo), 3'-fluoro-ddGuo (FddGuo), and 3'-fluoro-2,6-diaminopurine 2',3'-dideoxynucleoside (FddDAPR) were the most selective inhibitors of HIV replication.
A variety of imidazo1,5-a-1,3,5-triazine derivatives carrying C-, O-, and S-benzyl and/or 4-methylbenzyl groups were synthesized and examined for their inhibitory effects on the replication of ortho- ...and paramyxoviruses. The key compounds 8-R-2-thioxo-2,3-dihydroimidazo 1,5-a-1,3,5-triazin-4(1H)-ones 3a,b,d were synthesized by chlorotrimethylsilane/HMDS-effected cyclization--rearrangement of the corresponding 6-amino-5-(formylamino)-5-R-2-mercaptopyrimidin-4(5H)-ones 2a,b,d (R = benzyl, 4-methylbenzyl and 5-(benzyloxy)pentyl). Compounds 3a,b were further transformed into 4-thiones 5a,b and 4-dimethylamino derivatives 7a,b. Preparation of S-methyl, S-benzyl, and S-(4-methylbenzyl) derivatives 12-19 was carried out by the treatment of thioxo compounds 3b,d, 5b, and 8b in an alcohol/potassium carbonate system with methyl iodide or the appropriate aralkyl bromide. Simultaneous presence of the benzyl and thio structural units was found to be indispensable for any selective biological activity. Some 2-thio substituted compounds were specifically inhibitory to some viruses, e.g., 8-(4-methylbenzyl)-2-(4-methylbenzyl) thioimidazo1,5-a-1,3,5-triazin-4-one (13) and 8-5-(benzyloxy)pentyl-2-(4-methylbenzyl)thioimidazo 1,5-a-1,3,5-triazin-4-one (15) inhibited influenza A virus at a concentration of 4.1 and 5.3 microM, and 2-(benzylthio)-6, 8-dimethylimidazo1,5-a-1,3,5-triazin-4-one (16) and 6, 8-dimethyl-2-(4-methylbenzyl)thioimidazo1,5-a1,3, 5-triazin-4-one (17) inhibited respiratory syncytial virus at a concentration of 21.9 and 15.7 microM, respectively, that is, at concentrations that were 20-50-fold lower than the cytotoxic concentrations. Compound 13 was inhibitory to respiratory syncytial virus at a concentration of 1.4 microM, that is, at a concentration that was 180-fold lower than the cytotoxic concentration to MDCK or Vero cells but only 7-fold lower than the cytotoxic concentration to HeLa cells. The 4-thiones 5a,b were nonselectively inhibitory to ortho-and paramyxoviruses at concentrations that coincided with their cytotoxic concentrations.
A large variety of antiherpes compounds was compared for their inhibitory activity against laboratory strains and clinical isolates of herpes simplex virus (HSV) type 1 and type 2. From studies ...performed in primary rabbit kidney cell cultures, six, E-5-(2-bromovinyl)-2′-deoxyuridine, E-5-(2-iodovinyl)-2′-deoxyuridine, 5-vinyl-2′deoxyuridine, 2′-fluoro-5-iodoaracytosine, acycloguanosine, and 5-iodo-2′-deoxycytidine, emerged as the most potent and selective antiherpes agents. For HSV type 1, the 50% inhibitory doses (m so) were 0.008, 0.012, 0.018, 0.017, 0.04, and 0.06 μg/ml, respectively; those for HSV type 2 were 1,2,0.1,0.05,0.04, and 0.3 μg/ml, respectively. These compounds did not inhibit host-cell metabolism or replication of vaccinia virus except at concentrations 100–10,000 times greater than the ID50 for any HSV. All were significantly less inhibitory for a thymidine kinase (TK)-deficient mutant of HSV type 1 than for normal strains, suggesting that phosphorylation by virus-induced TK was required to produce specific inhibition of HSV replication.
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