A pyrimidine–pyrazolone nucleoside chimera with potent in vitro anti-orthopoxvirus activity

Fan, Xuesen; Zhang, Xinying; Zhou, Longhu; Keith, Kathy A.; Kern, Earl R.; Torrence, Paul F.

doi:10.1016/j.bmcl.2006.03.043

Cited by 71 publications

(33 citation statements)

References 24 publications

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“…Recently, a new series of deoxyuridine analogs with large substituents at the 5 position were described that retained activity against both VV and CV (21)(22)(23)(24). Here, we report that the compounds exhibit an unexpected TK dependence in orthopoxviruses.…”

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confidence: 85%

Selective Phosphorylation of Antiviral Drugs by Vaccinia Virus Thymidine Kinase

Prichard¹,

Keith²,

Johnson³

et al. 2007

Antimicrob Agents Chemother

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The antiviral activity of a new series of thymidine analogs was determined against vaccinia virus (VV), cowpox virus (CV), herpes simplex virus, and varicella-zoster virus. Several compounds were identified that had good activity against each of the viruses, including a set of novel 5-substituted deoxyuridine analogs. To investigate the possibility that these drugs might be phosphorylated preferentially by the viral thymidine kinase (TK) homologs, the antiviral activities of these compounds were also assessed using TK-deficient strains of some of these viruses. Some of these compounds were shown to be much less effective in the absence of a functional TK gene in CV, which was unexpected given the high degree of amino acid identity between this enzyme and its cellular homolog. This unanticipated result suggested that the CV TK was important in the mechanism of action of these compounds and also that it might phosphorylate a wider variety of substrates than other type II enzymes. To confirm these data, we expressed the VV TK and human TK1 in bacteria and isolated the purified enzymes. Enzymatic assays demonstrated that the viral TK could efficiently phosphorylate many of these compounds, whereas most of the compounds were very poor substrates for the cellular kinase, TK1. Thus, the specific phosphorylation of these compounds by the viral kinase may be sufficient to explain the TK dependence. This unexpected result suggests that selective phosphorylation by the viral kinase may be a promising new approach in the discovery of highly selective inhibitors of orthopoxvirus replication.

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confidence: 85%

Selective Phosphorylation of Antiviral Drugs by Vaccinia Virus Thymidine Kinase

Prichard¹,

Keith²,

Johnson³

et al. 2007

Antimicrob Agents Chemother

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“…Therefore, the identification of new compounds for the treatment of tuberculosis is an important under taking in medicinal chemistry research. 1,3,4-Thiadiazole derivatives have received much attention due o their versatile biological activities as antibacterial (3)(4)(5), antitubercular (6-10), antifungal (11), antiviral (12,13), anticancer (3,(14)(15)(16)(17), antiproliferative (18), antiinflammatory, analgesic and antipyretic (19). Pyrazolinones have also shown various biological activities (20)(21)(22).…”

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confidence: 99%

The synthesis and antitubercular activity of substituted hydrazone,2-pyrazoline-5-one and 2-isoxazoline-5-one derivatives possessing 1,3,4-thiadiazole moiety

Oral¹

2012

mpj

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“…3 One drug, cidofovir (Vistide), licensed to treat cytomegalovirus (CMV) retinitis in HIV-infected patients, is available through a special protocol (Investigational New Drug, IND) We have pursued a chemistry-driven strategy for the discovery of lead molecules with antiorthopoxvirus activity. 16,17 Our approach to new orthopoxvirus antivirals has been guided by the following considerations: (a) since the "privileged" 18,19 structure of nucleosides has led to a variety of efficacious antiviral agents, 20 the nucleoside scaffold is an excellent point of departure in the search for new antiviral drugs; (b) other privileged 18,19 molecular scaffolds exist that have spawned a significant number of drugs and other biologically active agents, and these also can be used to discover molecular "masterkeys"; 21 (c) 5-formyl-2′-deoxyuridine is a neglected but powerful synthon for the generation of novel nucleoside structures that can be employed in multicomponent reactions [22][23][24][25] (MCR) to generate chemical diversity.In this study, a modified benzofuran-nucleoside chimera was generated in a MCR originating with 5-formyl-2′-deoxyuridine. [26][27][28] Benzofuran congeners form the nucleus of many biological active molecules.…”

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confidence: 99%

“…16,17 Our approach to new orthopoxvirus antivirals has been guided by the following considerations: (a) since the "privileged" 18,19 structure of nucleosides has led to a variety of efficacious antiviral agents, 20 the nucleoside scaffold is an excellent point of departure in the search for new antiviral drugs; (b) other privileged 18,19 molecular scaffolds exist that have spawned a significant number of drugs and other biologically active agents, and these also can be used to discover molecular "masterkeys"; 21 (c) 5-formyl-2′-deoxyuridine is a neglected but powerful synthon for the generation of novel nucleoside structures that can be employed in multicomponent reactions [22][23][24][25] (MCR) to generate chemical diversity.…”

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Toward Orthopoxvirus Countermeasures: A Novel Heteromorphic Nucleoside of Unusual Structure

et al. 2006

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Two privileged drug scaffolds have been hybridized to create the novel heteromorphic nucleoside 5-(2-amino-3-cyano-5-oxo-5,6,7,8-tetrahydro-4H-chromen-4-yl)-1-(2-deoxypentofuranosyl)pyrimidine-2,4-(1H,3H)-dione (2). Compound 2 inhibited the replication of two orthopoxviruses, vaccinia virus (VV) (EC 50 = 4.6 ± 2.0 μM), and cowpox virus (CV) (EC 50 = 2.0 ± 0.3 μM). Compound 2 exhibited reduced activity against a thymidine kinase (TK) negative strain of CV, implying a requirement for 5′-monophosphorylation for antiorthopoxvirus activity. Compound 2 was efficiently phosphorylated by VV TK, establishing that VV TK is more promiscuous than previously believed.Smallpox, although declared eradicated as a natural disease in 1983 by the World Health Organization, now stands as the most potentially devastating of all bioterrorist threats. 1,2 It is presently the policy of the U.S. Government to provide two FDA-approved drugs for the treatment of smallpox and to have two others in the pipeline, ideally with different modes of action. 3 One drug, cidofovir (Vistide), licensed to treat cytomegalovirus (CMV) retinitis in HIV-infected patients, is available through a special protocol (Investigational New Drug, IND) We have pursued a chemistry-driven strategy for the discovery of lead molecules with antiorthopoxvirus activity. 16,17 Our approach to new orthopoxvirus antivirals has been guided by the following considerations: (a) since the "privileged" 18,19 structure of nucleosides has led to a variety of efficacious antiviral agents, 20 the nucleoside scaffold is an excellent point of departure in the search for new antiviral drugs; (b) other privileged 18,19 molecular scaffolds exist that have spawned a significant number of drugs and other biologically active agents, and these also can be used to discover molecular "masterkeys"; 21 (c) 5-formyl-2′-deoxyuridine is a neglected but powerful synthon for the generation of novel nucleoside structures that can be employed in multicomponent reactions [22][23][24][25] (MCR) to generate chemical diversity.In this study, a modified benzofuran-nucleoside chimera was generated in a MCR originating with 5-formyl-2′-deoxyuridine. [26][27][28] Benzofuran congeners form the nucleus of many biological active molecules. [29][30][31][32] Singh et al. 33 gained entry to these fused pyrans by reactions of 1,3-oxazinanes and oxazolidines with various carbon nucleophiles. We adapted this to the reaction of 5-formyl-2′-deoxyuridine with malononitrile and 1,3-cyclohexanedione to obtain a novel nucleoside. The synthesis was carried out using 5-formyl-2′-deoxyuridine 26-28 in a multicomponent reaction with malononitrile and 1,3-cyclohexanedione in EtOH to give 5-(2-amino-3-cyano-5-oxo-5,6,7,8-tetrahydro-4H-chromen-4-yl)-1-(2-deoxypentofuranosyl)pyrimidine-2,4(1H,3H)-dione (2) (Scheme 1).Compound 2 was obtained as a 1:1 diastereomeric mixture arising from the generation of a chiral carbon at position 4 of the chromone ring.The antiviral activities of 2 (Table 1) were determined in human fores...

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A pyrimidine–pyrazolone nucleoside chimera with potent in vitro anti-orthopoxvirus activity

Cited by 71 publications

References 24 publications

Selective Phosphorylation of Antiviral Drugs by Vaccinia Virus Thymidine Kinase

Selective Phosphorylation of Antiviral Drugs by Vaccinia Virus Thymidine Kinase

The synthesis and antitubercular activity of substituted hydrazone,2-pyrazoline-5-one and 2-isoxazoline-5-one derivatives possessing 1,3,4-thiadiazole moiety

Toward Orthopoxvirus Countermeasures: A Novel Heteromorphic Nucleoside of Unusual Structure

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