Design, synthesis, and broad spectrum antiviral activity of 1-.beta.-D-ribofuranosyl-1,2,4-triazole-3-carboxamide and related nucleosides

Witkowski, J. T.; Robins, Roland K.; Sidwell, Robert W.; Simon, Lionel N.

doi:10.1021/jm00281a014

Cited by 463 publications

(228 citation statements)

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“…In addition, such an agent must inhibit a step in the process of virus replication that is common to a wide variety of RNA and DNA viruses (1). The synthesis and broad spectrum antiviral activity of 1-i3-D-ribofuranosyl-1,2,4-triazole-3-carboxamide (I, Virazole) have recently been reported (1,2).…”

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confidence: 99%

Mechanism of Action of 1-β-D-Ribofuranosyl-1,2,4-Triazole-3-Carboxamide (Virazole), A New Broad-Spectrum Antiviral Agent

Streeter¹,

Witkowski²,

Khare³

et al. 1973

Proc. Natl. Acad. Sci. U.S.A.

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442

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The antiviral activity of the synthetic nucleoside, Virazole (1-io-D-ribofuranosyl-1,2,4-triazole-3-carboxamide), against measles virus in Vero cell cultures was substantially reversed by xanthosine, guanosine, and to a slightly lesser extent by inosine. Virazole 5'-phosphate was subsequently found to be a potent competitive inhibitor of inosine 5'-phosphate dehydrogenase (IMP: NAD + oxidoreductase, EC 1.2.1.14) isolated from Escherichia coli (Km = 1.8 X 10-' M) with a Ki of 2.7 X 10-7 M.Guanosine 5'-phosphate (GMP) was a competitive inhibitor of this enzyme with a Ki of 7.7 X 106 M. Virazole 5'-phosphate was similarly active against IMP dehydrogenase isolated from Ehrlich ascites tumor cells, with a Ki of 2.5 X 10-7 M. The Km for this enzyme was 1.8 X 10-6 M, and the Ki for GMP was 2.2 X 10-4 M. These results suggest that the antiviral activity of Virazole might be due to the inhibition of GMP biosynthesis in the infected cell at the step involving the conversion of IMP to xanthosine 5'-phosphate. This inhibition would consequently result in inhibition of the synthesis of vital viral nucleic acid.The synthesis and development of a broad spectrum antiviral agent has been a challenging task because of the intimate association of virus replication and biochemical processes of the host cell. In addition, such an agent must inhibit a step in the process of virus replication that is common to a wide variety of RNA and DNA viruses (1). The synthesis and broad spectrum antiviral activity of 1-i3-D-ribofuranosyl-1,2,4-triazole-3-carboxamide (I, Virazole) have recently been reported (1,2).

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confidence: 99%

Mechanism of Action of 1-β-D-Ribofuranosyl-1,2,4-Triazole-3-Carboxamide (Virazole), A New Broad-Spectrum Antiviral Agent

Streeter¹,

Witkowski²,

Khare³

et al. 1973

Proc. Natl. Acad. Sci. U.S.A.

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442

259

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“…Tetrazoles as a group of heterocyclic compounds are reported to possess a broad spectrum of biological activities such as antibacterial, 1 antifungal, 2 antiviral, [3][4][5] analgesic, 6,7 anti-inflammatory, [8][9][10] antiulcer 11 and antihypertensive 12 activities. Also, 5-substituted-1H-tetrazoles can function as lipophilic spacers and carboxylic acid surrogates, 13 specialty explosives 14,15 and information recording systems in materials 16 ligands, and precursors of a variety of nitrogen containing heterocycles in coordination chemistry.…”

Section: Introductionmentioning

confidence: 99%

“…22 The "click" chemistry approach utilizing zinc catalysis in aqueous solution is a magnificent improvement over latter methods, 23,24 but occasionally still requires the tedious and time-consuming removal of zinc salts from the acidic products. Stoichiometric amounts of inorganic salts and metal complexes 25 as catalysts, use of TMSN 3 and TBAF 26 instead of metal salts under solvent-free conditions in micellar media and ionic liquids, and use of various catalysts [27][28][29][30][31] such as BF 3 .OEt 2 , 21 Pd(OAc) 2 /ZnBr 2 , 27 Yb(OTf) 3 , 28 Zn(OTf) 3 , 29 AlCl 3,30 and Pd (PPh 3 ) 4 31 were also employed for the same purpose. However, a drawback of these homogeneous catalytic processes lies in the tedious separation and recovery of the catalysts.…”

Section: Introductionmentioning

confidence: 99%

A novel approach for the synthesis of 5-substituted-1H-tetrazoles

Akhlaghinia¹,

Rezazadeh²

2012

J. Braz. Chem. Soc.

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Uma série de 1H-tetrazóis-5-substituídos (RCN 4 H) foi sintetizada pela reação de cicloadição de diferentes aril e alquil nitrilas com azida de sódio em DMSO, usando CuSO 4 •5H 2 O como catalisador. Uma grande variedade de aril nitrilas sofreu cicloadição [3+2], obtendo-se os correspondentes tetrazóis sob condições reacionais brandas. O catalisador utilizado é obtido facilmente e ambientalmente correto. Tempos de reação curtos, bons a excelentes rendimentos, processo seguro e simples tornam este método uma contribuição atrativa e útil à presente síntese orgânica de 1H-tetrazóis-5-substituídos.A series of 5-substituted-1H-tetrazoles (RCN 4 H) have been synthesized by cycloaddition reaction of different aryl and alkyl nitriles with sodium azide in DMSO using CuSO 4 •5H 2 O as catalyst. A wide variety of aryl nitriles underwent [3+2] cycloaddition to afford tetrazoles under mild reaction conditions in good to excellent yields. The catalyst used is readily available and environmentally friendly. Short reaction times, good to excellent yields, safe process and simple workup make this method an attractive and useful contribution to present organic synthesis of 5-substituted-1H-tetrazoles.Keywords: 5-substituted-1H-tetrazole, arylnitriles, sodium azide, CuSO 4 •5H 2 O, cycloaddition reaction IntroductionThe chemistry of heterocyclic compounds has been an interesting field of study for a long time. Tetrazoles as a group of heterocyclic compounds are reported to possess a broad spectrum of biological activities such as antibacterial, 1 antifungal, 2 antiviral, 3-5 analgesic, 6,7 anti-inflammatory, [8][9][10] [41][42][43][44][45][46][47][48] were commonly used to improve the catalytic abilities of montmorillonites. These methods require a large excess of sodium azide, longer reaction time, and expensive metals. Moreover, the cycloaddition is too slow A Novel Approach for the Synthesis of 5-Substituted-1H-tetrazoles J. Braz. Chem. Soc. 2198 to be synthetically useful except when strong electronwithdrawing groups activate the nitrile compounds.Today's stringent environmental and legislative concerns demand for the green methods that reduce the use of toxic and corrosive reagents and stop the formation of inorganic wastes. 49 However, it has been also observed that the catalysts employed are not always eco-friendly and because of this, serious environmental pollution often results. Therefore, in the area of green synthesis, the development of environmentally friendly alternatives is desirable for the synthesis of tetrazoles. 50 Recently, we have studied the application of cupric sulfate pentahydrate in the trimethylsilylation of alcohols and phenols, 51 and perceived that cupric sulfate pentahydrate as a mild Lewis acid, which is readily available, might be a useful catalyst for the synthesis of 5-substituted-1H-tetrazoles. In this paper we report a new process for the synthesis of 5-substituted 1-H-tetrazoles using cupric sulfate pentahydrate as a safe, environmentally benign, and inexpensive catalyst. ExperimentalThe p...

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“…Ribavirin (1-beta-D-ribofuranosyl1,2,4-triazole-3-carboxamide), which was first synthesized in 1970s [18], is a drug that has been used in the treatment of HPS and HFRS [2,6]. This antiviral has broad spectrum action, acting in vitro and in vivo against the genetic material of various viruses.…”

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confidence: 99%

“…Accordingly, several mechanisms for the action this compound have been suggested [18]: (1) the induction of mutations into the viral genetic material leading to fatal errors in viral replication, as shown in Hantaan virus; (2) inhibition of viral mRNA capping; (3) direct inhibition of RNA-dependent RNA viral polymerase, resulting in a delay in the initiation and elongation phases of mRNA transcript; (4) inhibition of IMP dehydrogenase, an enzyme important in the synthesis of GTP; (5) and partial suppression of cytokines through the inhibition of RANTES mRNA in Andes virus infections [8].…”

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confidence: 99%

Effectiveness of the ribavirin in treatment of hantavirus infections in the Americas and Eurasia: a meta-analysis

et al. 2014

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Hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS) are transmitted to humans through infection with the old-and new-world hantaviruses, respectively. Together these diseases affect tens of thousands of people every year, and no specific treatment is available. To investigate whether ribavirin treatment for hantaviruses infections decreases disease severity, we conducted a meta-analysis involving human and animal studies. After defining the research protocol and criteria for inclusion/exclusion, we identified seven studies. We found that in groups with HPS who were treated with ribavirin, there was no significant reduction in mortality (RR 0.99, 95 % CI 0.60-1.61, I 2 = 0 %). On the other hand, for animal group with HPS-like disease, there was significant increase in survival (RR 0.05, 95 % CI 0.01-0.34, I 2 = 0 %). For animal group infected with the old-world hantaviruses, treated with ribavirin, there was a statistically significant increase in survival (RR 0.56, 95 % CI 0.42-0.76, I 2 = 64 %). Similarly, for humans with HFRS treated, there was increase in survival (RR 0.28, 95 % CI 0.08-1), although only a study exist. Our metaanalysis provides data that should be interpreted with caution, partly due to the limited number of studies available. Additionally, the results of the application of ribavirin in the population with HPS could not be determined, particularly in patients in the end stage of this disease.

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Design, synthesis, and broad spectrum antiviral activity of 1-.beta.-D-ribofuranosyl-1,2,4-triazole-3-carboxamide and related nucleosides

Cited by 463 publications

References 0 publications

Mechanism of Action of 1-β-D-Ribofuranosyl-1,2,4-Triazole-3-Carboxamide (Virazole), A New Broad-Spectrum Antiviral Agent

Mechanism of Action of 1-β-D-Ribofuranosyl-1,2,4-Triazole-3-Carboxamide (Virazole), A New Broad-Spectrum Antiviral Agent

A novel approach for the synthesis of 5-substituted-1H-tetrazoles

Effectiveness of the ribavirin in treatment of hantavirus infections in the Americas and Eurasia: a meta-analysis

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