Synthesis of Nucleoside Analogues with Potential Antiviral Activity against Negative Strand RNA Virus Targets

1989 ◽  
Author(s):  
Richard T. Walker
Keyword(s):  
Antiviral Activity ◽  
Rna Virus ◽  
Nucleoside Analogues ◽  
Negative Strand

scholarly journals Synthesis and Antiviral Evaluation of Nucleoside Analogues Bearing One Pyrimidine Moiety and Two D-Ribofuranosyl Residues

Molecules ◽  
2021 ◽  
Vol 26 (12) ◽  
pp. 3678
Author(s):  
Olga V. Andreeva ◽  
Bulat F. Garifullin ◽  
Vladimir V. Zarubaev ◽  
Alexander V. Slita ◽  
Iana L. Yesaulkova ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Antiviral Activity ◽  
Theoretical Calculations ◽  
Nucleoside Analogs ◽  
Coxsackievirus B3 ◽  
Nucleoside Analogues ◽  
Moderate Activity ◽  
Coat Proteins ◽  
Influenza Virus A ◽  
Ic50 Values

A series of 1,2,3-triazolyl nucleoside analogues in which 1,2,3-triazol-4-yl-β-d-ribofuranosyl fragments are attached via polymethylene linkers to both nitrogen atoms of the heterocycle moiety (uracil, 6-methyluracil, thymine, quinazoline-2,4-dione, alloxazine) or to the C-5 and N-3 atoms of the 6-methyluracil moiety was synthesized. All compounds synthesized were evaluated for antiviral activity against influenza virus A/PR/8/34/(H1N1) and coxsackievirus B3. Antiviral assays revealed three compounds, 2i, 5i, 11c, which showed moderate activity against influenza virus A H1N1 with IC50 values of 57.5 µM, 24.3 µM, and 29.2 µM, respectively. In the first two nucleoside analogues, 1,2,3-triazol-4-yl-β-d-ribofuranosyl fragments are attached via butylene linkers to N-1 and N-3 atoms of the heterocycle moiety (6-methyluracil and alloxazine, respectively). In nucleoside analogue 11c, two 1,2,3-triazol-4-yl-2′,3′,5′-tri-O-acetyl-β-d-ribofuranose fragments are attached via propylene linkers to the C-5 and N-3 atoms of the 6-methyluracil moiety. Almost all synthesized 1,2,3-triazolyl nucleoside analogues showed no antiviral activity against the coxsackie B3 virus. Two exceptions are 1,2,3-triazolyl nucleoside analogs 2f and 5f, in which 1,2,3-triazol-4-yl-2′,3′,5′-tri-O-acetyl-β-d-ribofuranose fragments are attached to the C-5 and N-3 atoms of the heterocycle moiety (6-methyluracil and alloxazine respectively). These compounds exhibited high antiviral potency against the coxsackie B3 virus with IC50 values of 12.4 and 11.3 µM, respectively, although both were inactive against influenza virus A H1N1. According to theoretical calculations, the antiviral activity of the 1,2,3-triazolyl nucleoside analogues 2i, 5i, and 11c against the H1N1 (A/PR/8/34) influenza virus can be explained by their influence on the functioning of the polymerase acidic protein (PA) of RNA-dependent RNA polymerase (RdRp). As to the antiviral activity of nucleoside analogs 2f and 5f against coxsackievirus B3, it can be explained by their interaction with the coat proteins VP1 and VP2.

ChemInform Abstract: Unsaturated and Carbocyclic Nucleoside Analogues: Synthesis, Antitumor, and Antiviral Activity.

ChemInform ◽  
2010 ◽  
Vol 22 (24) ◽  
pp. no-no
Author(s):  
S. PHADTARE ◽  
D. KESSEL ◽  
T. H. CORBETT ◽  
H. E. RENIS ◽  
B. A. COURT ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Nucleoside Analogues ◽  
Carbocyclic Nucleoside ◽  
Carbocyclic Nucleoside Analogues

scholarly journals Probing the Effects of Pyrimidine Functional Group Switches on Acyclic Fleximer Analogues for Antiviral Activity

Molecules ◽  
2019 ◽  
Vol 24 (17) ◽  
pp. 3184 ◽  
Author(s):  
Mary K. Yates ◽  
Payel Chatterjee ◽  
Mike Flint ◽  
Yafet Arefeayne ◽  
Damjan Makuc ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Ebola Virus ◽  
Functional Group ◽  
Yellow Fever Virus ◽  
Nucleoside Analogues ◽  
Antiviral Resistance ◽  
Protecting Group ◽  
Enzyme Binding ◽  
Potential Development ◽  
Sar Study

Due to their ability to inhibit viral DNA or RNA replication, nucleoside analogues have been used for decades as potent antiviral therapeutics. However, one of the major limitations of nucleoside analogues is the development of antiviral resistance. In that regard, flexible nucleoside analogues known as “fleximers” have garnered attention over the years due to their ability to survey different amino acids in enzyme binding sites, thus overcoming the potential development of antiviral resistance. Acyclic fleximers have previously demonstrated antiviral activity against numerous viruses including Middle East Respiratory Syndrome coronavirus (MERS-CoV), Ebola virus (EBOV), and, most recently, flaviviruses such as Dengue (DENV) and Yellow Fever Virus (YFV). Due to these interesting results, a Structure Activity Relationship (SAR) study was pursued in order to analyze the effect of the pyrimidine functional group and acyl protecting group on antiviral activity, cytotoxicity, and conformation. The results of those studies are presented herein.

scholarly journals Design and Synthesis of Antiviral Iminoribitol C-Nucleosides

2021 ◽  
Author(s):  
◽  
Ye Li
Keyword(s):  
Antiviral Activity ◽  
Rna Polymerase ◽  
Nucleoside Analogue ◽  
Rna Viruses ◽  
Active Form ◽  
Building Blocks ◽  
The Body ◽  
Nucleoside Analogues ◽  
Federal Drug Administration ◽  
Pharmacologically Active

<p>Infections caused by RNA viruses, such as Ebola and Zika, continue to exist worldwide as significant public health problems. In response to the urgent need for safer and more efficacious treatment options to treat infections caused by RNA viruses, the pharmaceutical and biotechnology industries have devoted significant efforts over the last two decades to discovering and developing new antiviral agents. One such antiviral, Sofosbuvir®, was approved by the US Federal Drug Administration (FDA) in 2014 and has revolutionized the treatment of Hepatitis-C. Sofosbuvir® was the second largest selling drug in the world in 2016 and in just twenty-one months Gilead reported sales worth $26.6 billion USD.The strategy of using nucleoside analogues to inhibit viral RNA dependent RNA polymerase(RdRp)has been pursued since the 1970s, and exemplified bythe discovery and development of ribavirin. The natural substrates of RNA polymerases are nucleoside triphosphates and often the efficacy of nucleoside analogues as antivirals are dependent on their ability to be converted by the host or virus to mono-, di-, and ultimately tri-phosphate analogues which block the active site of RNA polymerase as an analogue of the substrate causing chain termination. Recently Biocryst Pharmaceuticals (Biocryst) described the anti-viral properties of Immucillin-A (Galidesivir), an iminoribitol based nucleoside analogue, which was found to have broad spectrum antiviral activity especially against RNA viruses including Ebola. Researchers at the Ferrier Research Institute (Ferrier) have synthesizedan analogue of Immucillin-A, 8-aza-Immucillin-A (AIA) which shows comparable activityto Immucillin-A, in anti-viral screens against Ebola, and this antiviral activity forms part of a US patent application. The Ferrier is keen to further exemplify this compound class through the synthesis of analogues of both Immucillin-A and AIA as well as improve the overall synthesis of the lead compound AIA.Included as part of this study is the synthesis of pro-drugs of these iminoribitol based nucleoside analogues. Prodrugs are metabolized inside the body and are often converted to the corresponding pharmacologically active form. In general, prodrug strategies have improved the bioavailability and efficacy of many drugs. In particular, prodrugs strategies involving nucleoside analogue antivirals, which target RNA polymerase, have been particularly effective as they ensure conversion to the monophosphate in vivo. Conversion to the 5’-monophosphate form of a nucleoside analogue is the rate limiting step to the inhibition of the RNA polymerase –prior to its conversion to the triphosphateanalogue. The prodrug is effectively a protected monophosphate, and is then readily converted to monophosphate by the host and then onto the di-and tri-phosphate by kinases in both the host and virus. ProTide prodrugs, such as Sofosbuvir® provide a verified strategy for improving anti-viral activity and hence our desire to synthesize pro-drugs of all our iminoribitol based nucleoside analogues. This research thesis also involved repeating the known synthesis of the Immucillins, in particular, Immucillin-H (Forodesine), which requires in excess of 20 linear synthetic steps to make. The linear synthetic route to Immucillin-H was used instead of the more convenient convergent method developed by the Ferrier as several key synthetic intermediates in this progress were utilized in the attempted synthesis of some of the planned nucleoside analogues of AIA. As part of this work the candidate learned aspects of scaling up chemical reactions andthe critical analysis of both reaction hazards and reagent compatibilities at scale. Where possible and given the number of synthetic steps involved the candidate was also interested in improving the yields of the building blocks involved in the synthesis of the Immucillins with limited success.</p>

Zidovudine and Didanosine Combination Therapy in Children With Human Immunodeficiency Virus Infection

PEDIATRICS ◽  
1994 ◽  
Vol 93 (2) ◽  
pp. 316-322 ◽  
Author(s):  
Robert N. Husson ◽  
Brigitta U. Mueller ◽  
Maureen Farley ◽  
Linda L. Lewis ◽  
Frank M. Balis ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Combination Therapy ◽  
Antiviral Activity ◽  
Hiv Infection ◽  
Geometric Mean ◽  
Single Agent ◽  
Nucleoside Analogues ◽  
Hematologic Toxicity ◽  
Immunodeficiency Virus

Objective. Zidovudine and didanosine are both beneficial for the treatment of human immunodeficiency virus (HIV) infection in children. Because disease progression and toxicity often limit their long-term use as single agents, new approaches to using nucleoside analogues are necessary to improve current antiretroviral therapy. Design. We conducted a phase I-II study to evaluate the tolerance, pharmacokinetics, and antiviral activity of the combination of zidovudine and didanosine in children with HIV infection. Sixty-eight children who were either previously untreated or who had manifested hematologic toxicity on full-dose zidovudine were enrolled. Eight dose combinations were studied in the previously untreated children, with doses of zidovudine ranging from 90 to 180 mg/m2 every 6 hours and doses of didanosine ranging from 90 to 180 mg/m2 every 12 hours. Results. Fifty-four previously untreated HIV-infected children were enrolled in this part of the study, of whom 49 remained in the study for a minimum of 24 weeks. For children with previous zidovudine-related hematologic toxicity, three dose levels with zidovudine at 60 mg/m2 every 6 hours orally and didanosine ranging from 90 to 180 mg/m2 every 12 hours orally were used. A total of 14 children were enrolled in this part of the study, and 12 remained on therapy for at least 24 weeks. No evidence of new or enhanced toxicity was observed in either group. After 24 weeks, the median CD4 cell count for all patients increased from 331 to 556 cells/mm3 (P = .01). For the previously untreated group, the median increase in CD4 counts was from 386 to 726 cells/mm3 (P = .003). The median p24 antigen concentration (in those with a detectable level at baseline) decreased from 95 to &lt;31 pg/mL (P &lt; .001). The geometric mean titer of HIV in plasma decreased from 83.1 to 2.7 tissue culture infectious doses/mL (P = .001). Conclusions. The combination of zidovudine and didanosine was well-tolerated at doses as high as those used in single agent therapy. Potent in vivo antiviral activity was observed. Combination therapy with nucleoside analogues may be an important approach to optimizing the use of these agents in the treatment of HIV infection.

Engineered Resistance to Tomato Spotted Wilt Virus, a Negative-Strand RNA Virus

1993 ◽  
pp. 386-386
Author(s):  
Jan J. L. Gielen ◽  
Peter de Haan ◽  
Mart Q. J. M. van Grinsven ◽  
Rob Goldbach ◽  
André W. Schram
Keyword(s):  
Tomato Spotted Wilt Virus ◽  
Rna Virus ◽  
Negative Strand ◽  
Tomato Spotted Wilt ◽  
Engineered Resistance ◽  
Wilt Virus
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