Synthesis and antiviral activity of novel exomethylene cyclopropyl nucleosides

Novel cyclopropyl nucleosides were synthesized as potential antiviral agents. The key intermediate 5, prepared from Feist's acid 1 was condensed with purine derivatives by the SN2 type reaction. All the synthesized compounds were evaluated for antiviral activity.     

Novel bicyclic sugar modified nucleosides: synthesis, conformational analysis and antiviral evaluation

Methodology previously described by us was applied to the formation of novel conformationally restrained bicyclic sugar modified nucleosides, with introduction of an oxazole and a thiocarbamate ring at the 2('),3(')-positions of the ribonucleosides. Two novel alkyl derivatives of 2('),3(')-dideoxy-2('),3(')-oxazole-beta-d-uridine and a novel uridine 2('),3(')-thiocarbamate were successfully synthesised. Conformational evaluation of all the synthesised compounds was conducted using the theoretical potential energy calculation via the macromodel v.6.0 molecular modelling programme. The conformationally restrained nucleosides described were evaluated against a wide range of DNA and RNA viruses. None of the compounds showed specific antiviral effects at subtoxic concentrations.     

4'-C-modified nucleosides: synthesis and antiviral properties

The synthetic methods for 4'-C-modified nucleosides as well as structure activity relationship of obtained compounds towards hepatitis C virus are reviewed.     

Novel imidazo[1,2-c]pyrimidine base-modified nucleosides: synthesis and antiviral evaluation

The preparation of a series of novel 6-(beta-D-ribofuranosyl)-2-alkyl/aryl-6H-imidazo[1,2-c]pyrimidin-5-one nucleosides and the 2-nitrile nucleosides, 6-(beta-D-ribofuranosyl)-5-oxo-5,6-dihydro-imidazo[1,2-c]pyrimidine-2-carbonitrile and 2R and 2S isomers of 6-(beta-D-ribofuranosyl)-5-oxo-2,3,5,6-tetrahydro-imidazo[1,2-c]pyrimidine-2-carbonitrile, is described using two synthetic approaches. The nucleoside mimetics described were evaluated against a wide range of viral types and strains in cell culture. With the exception of one nucleoside, which displayed anti-CMV activity at toxic concentrations, none of the compounds showed antiviral activity most likely due to a lack of substrate recognition by viral and/or cellular nucleoside kinases.     

5-substituted arabinofuranosyluracil nucleosides: synthesis and antiviral properties

A number of 5-alkyl (ethyl, propyl, isopropyl, butyl) analogues of araU, their alpha-anomers and N3-isomers have been synthesized by a number of different procedures, based on the catalytic condensation of the appropriate 5-alkyl-2,4-bis-(trimethylsilyloxy)-pyrimidine with 2,3,5-tri-O-benzyl-alpha-D-arabinofuranosyl chloride. The resulting protected nucleosides were deblocked by a new procedure based on the use of BF3 X Et2O in C2H5SH. The chloromercuri derivative of araU, on reaction with allyl chloride in the presence of Li2PdCl4, gave the 5-allyl derivative, which was catalytically reduced to the corresponding 5-propyl analogue. The antiviral activities of these compounds have been evaluated. 5-Allyl-araU showed moderate specific activity (MIC 20 micrograms/ml) against herpes simplex type 1 virus in PRK cell cultures. Structure-activity relationships are discussed for the 5-alkyl deoxy- and arabino- uracil nucleoside series.     

3-Trifluoromethylpyrazolones derived nucleosides: Synthesis and antiviral evaluation

Dengue (DENV) viral infection is a global public health problem that infrequently develops life threatening diseases such as dengue hemorrhagic fever (DFS) and dengue shock syndrome (DSS). Middle East respiratory syndrome coronavirus (MERS-CoV) is a highly pathogenic human corona virus with 38% fatality rate of infected patients. A series of 4-arylhydrazono-5-trifluoromethyl-pyrazolones, their ribofuranosyl, and 5′-deoxyribofuranosyl nucleosides were synthesized, geometry optimized using Density functional theory (DFT), and evaluated for their antiviral activity. 2-Nitrophenylhydrazonopyra-zolone derivative 5 showed significant activity against MERS-CoV (EC₅₀ = 4.6?μM). The nucleoside analog 8 showed moderate activity against DENV-2 (EC₅₀ = 10?μM), while the activity was abolished with the corresponding 5′-deoxyribonucleoside analogs. The identified hits in this study set this category of compounds for further future optimizations.     

New approaches to the synthesis of antiviral nucleosides.

There is a pressing, worldwide need for new antiviral agents. The chemical synthesis of novel nucleosides for chemotherapeutic screening usually involves multistage processes which can be time consuming. The application of enzymatic methods for the synthesis and modification of antiviral nucleosides shows great promise because of the simplicity and high specificity of enzymatic reactions.     

Synthesis and antiviral activities of enantiomeric 1-[2-(hydroxymethyl) cyclopropyl] methyl nucleosides

Cyclopropyl carbocyclic nucleosides have been synthesized from the key intermediate 2 which was converted to the mesylated cyclopropyl methyl alcohol 3. Condensation of compound 3 with various purine and pyrimidine bases gave the desired nucleosides. All synthesized nucleosides were evaluated for antiviral activity and cellular toxicity. Among them adenine 22 and guanine 23 derivatives showed moderate antiviral activity against HIV-1 and HBV. None of the other compounds showed any significant antiviral activities against HIV-1, HBV, HSV-1 and HSV-2 in vitro up to 100 microM.     

Concise synthesis and antiviral activity of novel unsaturated acyclic pyrimidine nucleosides

Novel acyclic nucleoside analogues were designed and synthesized as open-chain analogues of neplanocin A. The coupling of the allylic bromide with pyrimidine bases using cesium carbonate afforded a series of novel acyclic nucleosides. The synthesized compounds 15-22 were evaluated for their antiviral activity against various viruses such as HIV, HSV-1, HSV-2, and HCMV.     

Synthesis and antiviral evaluation of novel 5'-norcarboacyclic phosphonic acid nucleosides

This article describes a very simple route for synthesizing a novel 5'-norcarboacyclic nucleotides. The condensation of the mesylates 17 and 18 with the natural nucleosidic bases (A,U,T,C) under standard nucleophilic substitution (K2CO3, 18-Crown-6, DMF) and deprotection afforded the target nucleotide analogues 27-34. In addition, these compounds were evaluated for their antiviral properties against various viruses.     

Synthesis and antiviral evaluation of novel 4'-hydroxymethyl branched apiosyl nucleosides

Novel 4'-hydroxymethyl branched apiosyl nucleosides were synthesized in this study. The introduction of a hydroxymethyl group in the 4'-position was accomplished by a [3,3]-sigmatropic rearrangement. Apiosyl sugar moiety was constructed by sequential ozonolysis and reductions. The natural bases (uracil, thymine, cytosine, and adenine) were efficiently coupled by a classical glycosyl condensation procedure (persilyated base and TMSOTf). The antiviral activities of the synthesized compounds were evaluated against HIV-1, HSV-1, HSV-2, and HCMV. Compound 18 displayed moderate anti-HCMV activity (EC50 = 20.1 microg/mL) without exhibiting any cytotoxicity up to 100 microM.     

Isonucleosides: design and synthesis of new isomeric nucleosides with antiviral potential

Isonucleosides discovered in our laboratory have been found to have interesting antiviral activity. The design, development of methodology, and stereochemical synthesis of new isonucleosides of anti-HCV interest are described. Antiviral results are cited.     

Synthesis and evaluation of antiviral activity of higher homologues of xylo-carbocyclic nucleosides

New carbocyclic nucleosides with purine (compounds 3a and 3b), and 8-azapurine (compounds 3c and 3d) as base were prepared and assayed for in vitro activity.     

Synthesis and anti-HCMV activity of novel cyclopropyl phosphonic acid nucleosides

A simple synthetic route for novel acyclic phosphonate nucleosides is described. The characteristic cyclopropyl moiety 8 was constructed employing the Simmons-Smith reaction as key step starting from simple acyclic 2-butene-1,4-diol. The condensation of the mesylate 11 with natural nucleosidic bases (A,C,T,U) under nucleophilic substitution conditions (K2CO3, 18-Crown-6, DMF) and hydrolysis afforded the target nucleosides 16, 17, 18, and 19. In addition, the antiviral evaluations against various viruses were performed.     

Synthesis and anti-HCMV activity of novel cyclopropyl phosphonic acid nucleosides

A simple synthetic route for novel acyclic phosphonate nucleosides is described. The characteristic cyclopropyl moiety 8 was constructed employing the Simmons-Smith reaction as key step starting from simple acyclic 2-butene-1,4-diol. The condensation of the mesylate 11 with natural nucleosidic bases (A,C,T,U) under nucleophilic substitution conditions (K₂CO₃, 18-Crown-6, DMF) and hydrolysis afforded the target nucleosides 16, 17, 18, and 19. In addition, the antiviral evaluations against various viruses were performed.     

Phosphoralaninate pronucleotides of pyrimidine methylenecyclopropane analogues of nucleosides: synthesis and antiviral activity

The Z- and E-thymine and cytosine pronucleotides 3d, 4d, 3e, and 4e of methylenecyclopropane nucleosides analogues were synthesized, evaluated for their antiviral activity against human cytomegalovirus (HCMV), herpes simplex virus 1 and 2 (HSV-1 and HSV-2), varicella zoster virus (VZV), Epstein-Barr virus (EBV), human immunodeficiency virus type 1 (HSV-1), and hepatitis B virus (HBV) and their potency was compared with the parent compounds 1d, 2d, 1e, and 2e. Prodrugs 3d and 4d were obtained by phosphorylation of parent analogues 1d or 2d with reagent 8. A similar phosphorylation of N4-benzoylcytosine methylenecyclopropanes 9a and 9b gave intermediates 11a and 11b. Deprotection with hydrazine in pyridine-acetic acid gave pronucleotides 3e and 4e. The Z-cytosine analogue 3e was active against HCMV and EBV The cytosine E-isomer 4e was moderately effective against EBV.     

Squarate-based carbocyclic nucleosides: Syntheses,computational analyses and anticancer/antiviral evaluation

Squaric acid and its derivatives are versatile synthons and have demonstrated applications in medicinal chemistry, notably as non-classical bioisosteric replacements for functional groups such as carboxylic acids, alpha-amino acids, urea, guanidine, peptide bonds and phosphate/pyrophosphate linkages. Surprisingly, no reports have appeared concerning its possible application as a nucleobase substitute in nucleosides. A preliminary investigation of such an application is reported herein. 3-Amino-4-((1R,4S)-4-(hydroxymethyl)cyclopent-2-en-1-yl)amino-cyclobut-3-ene-1,2-dione, 3-((1R,4S)-4-(hydroxymethyl)cyclopent-2-en-1-yl)amino-4-methoxycyclobut-3-ene-1,2-dione, and 3-hydroxy-4-((1R,4S)-4-(hydroxymethyl)cyclopent-2-en-1-yl)amino-cyclobut-3-ene-1,2-dione sodium salt were synthesized. Computational analyses of their structures and preliminary antitumor and antiviral screening results are reported.     

Enantioselective synthesis and biological evaluation of 5-o-carboranyl pyrimidine nucleosides

Base-modified carborane-containing nucleosides such as 5-o-carboranyl-2'-deoxyuridine (CDU) when combined with neutrons have potential for the treatment of certain malignancies. Lack of toxicity in various cells, high accumulation in cancer cells and intracellular phosphorylation are desirable characteristics for modified nucleosides used in boron neutron capture therapy (BNCT) for brain tumors and other malignancies. The aim of this work was to synthesize the two beta-enantiomers of several 5-o-carboranyl-containing nucleosides. These derivatives may possess favorable properties such as high lipophilicity, high transportability, the ability to be phosphorylated, and resistance to catabolism. Beta-isomers of 2',3'-dihydroxynucleosides and analogues containing a heteroatom in the sugar moiety were also synthesized. Carboranyl pyrimidine nucleosides were prepared either from the parent beta-D-nucleoside, beta-L-nucleoside, or by a coupling reaction. The dioxolane derivative 7 was prepared by a coupling reaction between protected 5-o-carboranyluracil (8, CU) and the corresponding protected heterocycle. Specific catalysts were used during the N-glycosylation process to favor the formation of the beta-isomer. Biological evaluation of these new chiral 5-o-carboranyl pyrimidine derivatives indicated that most of these compounds have low toxicity in a variety of normal and malignant cells and achieved high cellular levels in a lymphoblastoid cell line. Increasing the number of hydroxyl groups on the sugar moiety decreased the cellular accumulation and serum binding to different extents. Five compounds were identified for further biological evaluation as potential agents for BNCT.     

New anti-HIV derivatives: synthesis and antiviral evaluation

A small focused library of 18 compounds incorporating the motif 1,3-(N,N'-dibenzyl)diamino-2-propanol has been synthesized, using adapted synthetic methodologies. These series of compounds were evaluated for their in vitro anti-HIV activity on infected MT4 cells (syncytium formation observation). Some of the new synthesized compounds show potent anti-HIV activities. EC50 values for compounds (31, 40, 34, 37 and 46) range from 0.1 to 1 microM. In order to determine at which level these new derivatives interfere with the HIV replicative cycle, inhibition assays on recombinant HIV protease and HIV integrase have been performed. None of the compounds were found active on these two enzymatic targets. Experiments are in progress in order to identify their biological target within the HIV replicative cycle.