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EICAR (5-ethynyl-1-beta-D-ribofuranosylimidazole-4-carboxamide) is a cytostatic agent that inhibits murine leukemia L1210 and human lymphocyte CEM cells at a 50% inhibitory concentration of 0.80-1.4 microM, respectively. EICAR causes a rapid and marked inhibition of inosinate (IMP) dehydrogenase (EC 1.1.1.205) activity in intact L1210 and CEM cells reflected by a concentration-dependent accumulation of IMP and depletion of GTP and dGTP levels. EICAR 5'-monophosphate is a potent inhibitor of purified L1210 cell IMP dehydrogenase (Ki/Km 0.06). Inhibition of IMP dehydrogenase by EICAR 5'-monophosphate is competitive with respect to IMP. L1210 cells that were selected for resistance to the cytostatic action of EICAR proved to be adenosine kinase-deficient. Also, studies with other mutant L1210 and CEM cell lines revealed that adenosine kinase, as well as an alternative pathway, may be responsible for the conversion of EICAR to its 5'-monophosphate. Purified 2'-deoxycytidine kinase, 2'-deoxyguanosine kinase, cytosolic 5'-nucleotidase, and nicotinamide dinucleotide (NAD) pyrophosphorylase do not seem to be markedly involved in the metabolism of EICAR.
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No abstract is provided for this article.
Reverse Engineering is the process to construct a CAD-model from a physical model and consists of three steps: measuring or digitising the physical model, CAD modelling from the digitised points and completion of the CAD-model. This CAD model should be suitable for...
ABSTRACT: 1,3-Thiazolidine-4-ones have been known to possess anti-HIV and anti-HCV activityas they are, respectively, HIV-1 non-nucleoside reverse transcriptase inhibitors and HCVNS5B RNA-dependent RNA-polymerase inhibitors. Some novel 1-[2-(benzoylamino)-3-methylbutyryl]-4-alkyl/arylalkylthiosemicarbazides, 2-[2-(benzoylamino)-3-methylbutyrylhydrazono]-3-alkyl-/arylalkyl- 5-non substituted/methyl-1,3-thiazolidinones, were synthesizedand evaluated for their antiviral activity. Antiviral activity of the synthesized compounds werescreened against various types of viruses (Feline Corona Virus (FIPV), Feline Herpes Virus,HSV-1(KOS), HSV-1(TK-KOS ACVr), HSV-2(G), Vaccinia virus, Vesicular stomatitis virus, Varicella-ZosterVirus TK+VZV, Varicella-ZosterVirus TK-VZV, Cytomegalovirus, Respiratory syncytial virus,Coxsackie B4 virus, Parainfluenza-3 virus, Reovirus-1, Sindbis virus and Punta Toro virus) inCRFK, HEL, HeLa and Vero cell cultures. Anti-HIV and cytotoxicity data were also obtainedwith the compounds using the strains HIV-1 (IIIB) and HIV-2 (ROD) in an MT-4/MTT based assay.None of the tested compounds showed antiviral activity at subtoxic concentrations. Forall the synthesized compounds anti-HCV NS5B RdRp activity was not observed at the concentrationof 100 μM which was the highest concentration tested.KEYWORDS: 4-Thiazolidinones, L-valine, anti-HIV activity, anti-HCV activity.
The cyclosaligenyl (cycloSal) derivatives of the monophosphates of three acyclic or carbocyclic guanosine analogues, for example, acyclovir (ACV), carbovir (CBV) and abacavir (ABC), were investigated for their activity against retrovirus (HIV, Moloney sarcoma virus) and herpes simplex virus (HSV) activity in cell culture. The extent of the antiviral potency of the prodrugs depended on the nature of the nucleoside, the substituent on the cycloSal moiety and the virus investigated. Most notably, and unlike the parent compound ACV, cycloSal-ACV monophosphate (MP) prodrugs retained pronounced activity against ACV-resistant (thymidine kinase-deficient) HSV-1 and also gained anti-HIV activity. While the cycloSal-CBVMP prodrugs did not show enhanced activity compared with the parent compound CBV, the cycloSal-ABCMP prodrugs afforded markedly increased potency against both HSV and HIV. Our data indicate that the cycloSal prodrug approach can be useful to deliver directly the MP derivatives of nucleoside analogues into the intact, virus-infected cells, thus improving and extending the antiviral potency and spectrum of the drugs against retro- and herpesvirus strains.
The cosalane pharmacophore has been extended by the attachment of two additional substituted benzoic acid rings through amide and methylene linkers. The resulting compounds display significant antiviral activity when tested in vitro for inhibition of the cytopathic effects of HIV-1RF in CEM-SS cells and HIV-1IIIB in MT-4 cells. The compound containing the methylene linker also shows moderate activity versus HIV-2ROD in MT-4 cells. Because cosalane and related compounds containing extended pharmacophores inhibit the binding of gp120 to CD4, the presently described new compounds are assumed to act by a similar mechanism. A hypothetical model is proposed for the binding of the methylene-linked compound to CD4.
