Imidazothiadiazine dioxides: synthesis and antiviral activity.

A new series of imidazothiadiazine dioxides, including the first acyclonucleosides derived from this heterocycle moiety, has been synthesized. A wide-spectrum antiviral screening was performed. Some of the N-1 benzyl imidazothiadiazines and the new acyclonucleosides showed interesting anti-CMV or anti-HIV activity. These structures could be considered as new lead compounds for antiviral drug research.     

Metabolism of pyrimidine L-nucleosides.

The intraperitoneal application of L-nucleosides (L-Cyd, L-Urd, L-dThd) to mice results in distribution of these compounds into tissues of the organism and their gradual excretion in the unchanged form. The residual level has been observed with L-ribonucleosides only and contains in addition to the L-nucleoside its 5'-phosphate. The phosphorylation in vivo is catalyzed by nucleoside-kinase and utilizes ATP as the phosphate donor while glycerol 1-phosphate and creatine phosphate are inactive. The L-cytidine derivatives are in vivo deaminated to the derivatives of L-uridine. On the other hand, when L-uridine is applied in vivo, derivatives of L-cytidine are obtained on the level of both the nucleoside and 5'-ribonucleotide.     

Synthesis and antiviral activity of novel fluorinated 2',3'-dideoxynucleosides

A series of 5-(trifluoroethoxymethyl)-2',3'-dideoxyuridines and 5-[bis(trifluoroethoxy)-methyl]-2',3'-dideoxyuridines have been prepared and screened for antiviral activity. The conformations of these compounds are discussed on the bases of NOE studies and the MO calculations. Modelling and NOE studies suggest both syn- and anti conformations for these 5-(2,2,2-trifluoroethoxymethyl)- and 5-[bis(2,2,2-trifluoroethoxy)-methyl]- derivatives. The NOE parameters are also suggested to be more attributable to the nature of the fluorine atom than to structural or conformational changes. Compounds 17, 26 and 30 showed some activity in anti-HIV-1 and anti-HIV-2 assays, but the compounds were devoid of activity against HSV and human rhinovirus. The compounds tested exhibited low cytotoxicity and were inactive against a bank of cancer cells in vitro.     

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.     

Quinoline tricyclic derivatives. Design, synthesis and evaluation of the antiviral activity of three new classes of RNA-dependent RNA polymerase inhibitors

In this study three new classes of linear N-tricyclic compounds, derived by condensation of the quinoline nucleus with 1,2,3-triazole, imidazole or pyrazine, were synthesized, obtaining triazolo[4,5-g]quinolines, imidazo[4,5-g]quinolines and pyrido[2,3-g]quinoxalines, respectively. Title compounds were tested in cell-based assays for cytotoxicity and antiviral activity against RNA viruses representative of the three genera of the Flaviviridae family, that is BVDV (Pestivirus), YFV (Flavivirus) and HCV (Hepacivirus). Quinoline derivatives were also tested against representatives of other RNA virus families containing single-stranded, either positive-sense (ssRNA(+)) or negative-sense (RNA(-)), and double-stranded genomes (dsRNA), as well as against representatives of two DNA virus families. Some quinolines showed moderate, although selective activity against CVB-5, Reo-1 and RSV. However, derivatives belonging to all classes showed activity against BVDV. Among the most potent were the bis-triazoloquinoline 1m, the imidazoquinolines 2e and 2h, and the pyridoquinoxalines 4h, 4j and 5n (EC(50) range 1-5 μM). When tested in a replicon assay, compound 2h was the sole derivative to also display anti-HCV activity (EC(50)=3.1 μM). In enzyme assays, 1m, 2h, 5m and 5n proved to be potent inhibitors of the BVDV RNA-dependent RNA polymerase (RdRp), while only 2h also inhibited the recombinant HCV enzyme.     

Antimicrobial and cytotoxic arylazoenamines. Part III: antiviral activity of selected classes of arylazoenamines

Eighty-five arylazoenamines, characterized by different types of aryl and basic moieties, have been synthesized and evaluated in cell-based assays for cytotoxicity and antiviral activity against a panel of ten RNA and DNA viruses. The most commonly affected viruses were, in decreasing order, CVB-2, RSV, BVDV, YFV, and Sb-1; the remaining viruses were either not affected (HIV-1, VSV, and VV) or susceptible only to a very few compounds (Reo-1 and HSV-1). Thirty-five compounds exhibited high activity, with EC(50) in the range 0.8-10 microM, and other 28 compounds had EC(50) between 11 and 30 microM, thus indicating that the arylazoenamine molecular pattern is an interesting novel pharmacophore for antiviral agents against ssRNA viruses. Moreover, some compounds (as 28, 32, 42, and 53) appear of high interest, being devoid of toxicity on the human MT-4 cells (CC(50)>100 microM). A ligand-based computational approach was employed to identify highly predictive pharmacophore models for the most frequently affected viruses CVB-2, RSV, and BVDV. These models should allow the design of second generation of more potent inhibitors of these human and veterinary pathogens.     

New fluorinated carbocyclic nucleosides: synthesis and bioactivity

Novel fluorinated carbocyclic nucleosides, (+-)-3'-deoxy-3'-fluoroaristeromycin and (+-)-2',3'-dideoxy-3'-fluoroaristeromycin have been synthesized. The antitumor activities of these compounds were studied.     

"Mixed inhibitors" of HIV-reverse transcriptase: synthesis and antiviral activity.

Some "AZT-HEPT" and "ddC-HEPT" conjugates were designed, synthesized and evaluated for their anti-HIV activity.     

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.     

The synthesis and antiviral activity of some 4'-thio-2'-deoxynucleoside analogues.

A practical 7-step synthesis of benzyl 3,5-di-O-benzyl-2-deoxy-1,4-dithio-D-erythro-pentofuranoside is described and the product has been used in the synthesis of some 4'-thio-2'-deoxynucleosides. These novel nucleoside analogues have potentially useful biological activity and are resistant to phosphorolysis.     

Understanding the mode of action of L-nucleosides as antiviral agents: a molecular modeling approach

Computer modeling studies have been performed on the several pairs of D- and L-nucleoside inhibitors with the HIV-1 RT model. Additionally, clinically important M184V mutation, which confers the viral resistance against 3TC and FTC, were studied by the same modeling system.     

Design,synthesis and evaluation of antiproliferative activity of fluorinated betulinic acid

Betulinic acid (BA), a pentacyclic triterpenoid, exhibits broad spectrum antiproliferative activity, but generally with only modest potency. To improve BA’s pharmacological properties, fluorine was introduced as a single atom at C-2, creating two diastereomers, or in a trifluoromethyl group at C-3. We evaluated the impact of these groups on antiproliferative activity against five human tumor cell lines. A racemic 2-F-BA (compound 6) showed significantly improved antiproliferative activity, while each diastereomer exhibited similar effects. We also demonstrated that 2-F-BA is a topoisomerase (Topo) I and IIα dual inhibitor in cell-based and cell-free assays. A hypothetical mode of binding to the Topo I-DNA suggested a difference between the hydrogen bonding of BA and 2-F-BA to DNA, which may account for the difference in bioactivity against Topo I.     

Enantioselective synthesis and antiviral activity of purine and pyrimidine cyclopentenyl C-nucleosides

The enantiomerically pure carbocyclic purine and pyrimidine C-nucleosides 1-4 were synthesized via the key intermediate, 2,3-(isopropylidenedioxy)-4-(trityloxymethyl)-4-cyclopenten-1-ol (5), which was prepared from d-ribose in eight steps. Synthesized compounds were evaluated as potential antiviral agents against HIV, SARSCoV, Punta Toro, West Nile, and Cowpox viruses. However, only 9-deazaneplanocin A (1) exhibited moderate anti-HIV activity.     

Molecular design,synthesis and anticoagulant activity evaluation of fluorinated dabigatran analogues

In the present study, a series of unreported fluorinated dabigatran analogues, which were based on the structural scaffold of dabigatran, were designed by computer-aided simulation. Fifteen fluorinated dabigatran analogues were screened and synthesized. All target compounds were characterized by ¹H NMR, ¹³C NMR, ¹⁹F NMR and HRMS. According to the preliminary screening results of inhibition ratio, eleven analogues (inhibition ratio >90%) were evaluated for antithrombin activity in vitro (IC₅₀). The test results expressed that all the analogues showed effective inhibitory activities against thrombin. Especially, compounds 8f, 8k and 8o, with IC₅₀ values of 1.81, 3.21 and 2.16 nM, respectively, showed remarkable anticoagulant activities which were in the range of reference drug dabigatran (IC₅₀ = 1.23 nM). Moreover, compounds 8k and 8o were developed to investigate their anticoagulant activities in vivo. In those part, compound 8o exhibited a fairly strong inhibitory action for arteriovenous thrombosis with inhibition ratio of 84.66%, which was comparable with that of dabigatran (85.07%). Docking simulations demonstrated that these compounds could act as candidates for further development of novel anticoagulant drugs.     

Synthesis and antiviral evaluation of fluorinated acyclo-nucleosides and their phosphoramidates

A novel series of tetrafluoro and hexafluoro acyclic nucleosides and their phosphoramidates were successfully prepared from commercially available 2,2,3,3-tetrafluoro-1,4-butanediol and 2,2,3,3,4,4-hexafluoro-1,5-pentanediol in four to six steps. Their ability to block HIV, HCV, HSV-1, and HBV replication along with their cytotoxicity toward HepG2, human lymphocyte, CEM, and Vero cells was assessed.     

Modified cyclobutane carbonucleosides: synthesis and evaluation of their antiviral activity

The synthesis of some 9-(2-cyclobutylethyl)guanine derivatives and analogous carbonucleosides from 1S-alpha-pinene is here presented. None of them showed detectable selectivity when assayed in the performed anti-viral tests.     

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.     

The enzymatic synthesis of antiviral agents.

The majority of potential antiviral agents which are currently undergoing clinical trials are inhibitors of the replication of nucleic acids. The most common class of these inhibitors are nucleoside analogues and the elucidation of synthetic routes to these compounds has been of interest for many years as many are anticancer agents. One synthetic development has been the application of bio-transformations to nucleoside syntheses. This topic has been reviewed recently (Shirae et al., 1991) but this review is not widely available. In the present review, the application of biotechnology to the synthesis of antiviral agents including those which are not nucleoside analogues will be discussed. Enzymatic syntheses of nucleosides can be simpler and quicker than syntheses carried out by chemical methods. The most useful enzymes are those found in catabolic pathways. Nucleoside phosphorylases and N-deoxyribosyltransferases have both been widely used for nucleoside synthesis catalysing the transfer of sugar residues from a donor nucleoside to a heterocyclic base. Enzymatic methods have also been applied to the resolution of racemic mixtures and adenosine deaminase is a convenient catalyst for the hydrolysis of amino groups on purines and purine analogues. Regioselective deprotection of nucleoside esters has been achieved with lipases and these enzymes have also been applied to the synthesis of esters of sugar-like alkaloids. The latter have potential as inhibitors of the replication of HIV. Esterases have also been used in combined chemical and enzymatic syntheses of organophosphorus antiviral agents.     

New neplanocin analogues. Synthesis and antiviral activity of 6'-modified neplanocin A derivatives

Novel neplanocin A analogues modified at the 6'-position, i.e. 6'-deoxy derivatives (2, 3, 5, 6, 14), 6'-O-methylneplanocin A (10) and 6'-C-methylneplanocin A (16a and 16b) were synthesized and evaluated for their antiviral activity in a wide variety of virus systems. Compound 16a (TJ-13025) surpassed neplanocin A both in antiviral potency and selectivity.