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ABSTRACT: A practical and efficient synthesis of pyrazolo[1,5-c]quinazolines and 5,6-dihydro- pyrazolo[1,5-c]quinazolines, including several spiro compounds, through copper-catalyzed tandem reaction of 5-(2-bromoaryl)-1H-pyrazoles with carbonyl compounds and aqueous ammonia under air has been developed. Compared with literature methods toward pyrazolo[1,5-c]quinazoline derivatives, the synthetic method reported in this paper has the advantages of readily available and inexpensive starting materials and reagents, broad scope of substrates, and mild reaction conditions.
The Journal of Organic Chemistry 03/2013; · 4.45 Impact Factor
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ABSTRACT: A highly efficient synthesis of diversely substituted 2H-pyran-2-ones and indenes through Brønsted acid promoted tandem reaction of the readily obtainable 3-hydroxyhexa-4,5-allenic esters under extremely mild conditions has been developed.
Chemical Communications 02/2012; 48(25):3121-3. · 6.17 Impact Factor
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ABSTRACT: As a part of an ongoing medicinal chemistry, we report here the synthesis and structure evaluation of 1-(2-deoxy-3,5-di-O-acetylpentofuranosyl)-5-[(3-methyl-5-oxo-1-phenyl-4,5-dihydro-4H-pyrazol-4-ylidene) pyrimidine-2,4(1H,3H)-dione 5 and 5-[bis(3-methyl-5-oxo-1-phenyl-4,5-dihydro-4H-pyrazol-4-yl)methyl-1-(2-deoxy-3,5-di-O-acetylpentofuranosyl)pyrimidine-2,4(1H,3H)-dione 6 derived from 3',5'-di-O-acetyl-5-formyl-2'-deoxy-β-L-uridine 1. Base hydrolysis of compounds 1 and 6 furnished their deacetylated analogues in good yields, whereas hydrolysis of 5 was troublesome. Structural features of these molecules are discussed by NMR spectra analyses and density functional theory quantum chemical calculations. The newly synthesized L-analogues show no significant activity against vaccinia and cowpox viruses.
Nucleosides Nucleotides & Nucleic Acids 01/2012; 31(1):42-54. · 0.90 Impact Factor
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ABSTRACT: One-pot double Michael addition/intramolecular aldol reaction/decarboxylation of 1,2-allenic ketones with cyanoacetate offers an efficient and convenient approach to highly functionalized benzenes. With 2-substituted cyanoacetates, the reaction proceeds via a different tandem process to afford α,β-unsaturated nitriles effectively.
Organic Letters 08/2011; 13(19):5024-7. · 5.86 Impact Factor
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ABSTRACT: A novel, rapid, and efficient synthesis of bicyclic pyrimidine nucleosides and benzopyran-4-ones through oxidation of homopropargyl alcohols and subsequent isomerization, intramolecular addition of enol to allenic ketone has been developed. This methodology provides an efficient and promising approach to the structurally and pharmaceutically interesting pyrano[2,3-d]pyrimidine-2,5-dione nucleoside and benzopyran-4-one derivatives.
The Journal of Organic Chemistry 02/2011; 76(3):982-5. · 4.45 Impact Factor
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ABSTRACT: A novel and highly efficient one-pot three-component synthesis of alpha-aminophosphonates under neat condition was developed. By employing this method, hybrid compounds of aminophosphonate with pyrimidine nucleosides were synthesized in good to excellent yields starting from 5-formyl-2'-deoxyuridine, aniline and dimethyl phosphite. The antiviral and antileishmanial activities of these novel hybrid compounds were also studied but none were found to be active.
Nucleosides Nucleotides & Nucleic Acids 08/2010; 29(8):616-27. · 0.90 Impact Factor
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ABSTRACT: A highly practical and efficient preparation of pyrano[3,2-c]pyridone and pyrano[4,3-b]pyran derivatives was developed via an ionic liquid mediated and promoted multi-component reaction of aldehyde (1), 4-hydroxy-pyridin-2(1H)-one or 4-hydroxy-2-pyranone (2), and malononitrile (3). As an application, a series of pyrimidine nucleoside-pyrano[3,2-c]pyridone or pyrano[4,3-b]pyran hybrids were efficiently obtained. These hybrid compounds were evaluated as potential antiviral and antileishmanial agents and showed encouraging biological activities.
Bioorganic & medicinal chemistry letters 02/2010; 20(3):809-13. · 2.65 Impact Factor
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ABSTRACT: Without any catalyst, 2,3-disubstituted-1,3-thiazolidin-4-one derivatives were synthesized efficiently via the three-component reaction of aldehyde, amine and mercaptoacetic acid in [bmim][PF(6)]. The whole procedure is simple and straightforward and no aqueous work-up is needed. By employing this protocol, a series of novel pyrimidine nucleoside-thiazolidin-4-one hybrids were prepared and their preliminary antiparasitic activities were also studied and reported.
Bioorganic & medicinal chemistry letters 09/2009; 19(22):6280-3. · 2.65 Impact Factor
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ABSTRACT: The utilisation of an ionic liquid-[bmim][BF4] as both reaction medium and promoter for the reaction between aldehyde and 4-hydroxy-6-methylpyran-2-one is described. Without any added catalyst, this reaction was realised efficiently to give arylbispyranylmethane derivatives in high yields. Alternatively, when this reaction was carried out in the presence of acetic anhydride, fused pyran derivatives were obtained. These two novel procedures have advantages such as an environmentally benign nature, high efficiency, simple operation process and mild reaction conditions. As an application, these procedures were used in the preparation of novel 5-substituted pyrimidine nucleoside derivatives with potential antiviral activities.
Journal of Chemical Research 07/2009; 2009(8):473-477. · 0.04 Impact Factor
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ABSTRACT: The utilization of an ionic liquid, [bmim][BF(4)] as both reaction medium and promoter for a multi-component reaction of aldehyde (1) and 5-amino-3-methyl-1-phenylpyrazole (2) with Meldrum acid (3) or dimedone (5) is studied. From this reaction, pyrazolo[3,4-b]pyridinone (4) and pyrazolo[3,4-b]quinolinone (6) derivatives were prepared in high yields. This novel procedure showed such advantages as environmentally benign nature, enhanced efficiency, simple operation process, and mild reaction conditions. As an application, the procedure was successfully used in the preparation of a set of pyrimidine nucleoside-pyrazolo[3,4-b]pyridine and pyrazolo[3,4-b]quinolinone hybrids with potential biological activities.
Molecular Diversity 07/2009; 14(1):159-67. · 3.15 Impact Factor
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ABSTRACT: One-pot multi-component reactions of aldehydes, cyanothioacetamide and malononitrile promoted by ionic liquid proved to be an efficient way for the synthesis of thiopyran derivatives. Without any added catalyst, both aromatic and aliphatic aldehydes participated in this reaction smoothly. As an application of this method, a pyrimidine nucleoside-thiopyran chimera with potential biological activities was obtained in high yield from 5-formyl-2'-deoxyuridine. In addition, the ionic liquid used can be easily recovered and effectively reused for at least 5 times.
Molecular Diversity 01/2009; 13(1):57-61. · 3.15 Impact Factor
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ABSTRACT: An unexpected multicomponent reaction of cyanothioacetamide with aromatic aldehydes and aminopyrazole under MWI was found and reported. It turned out to be an efficient and simple procedure for the preparation of pyrazolo[3,4-b]pyridine derivatives. The structure of the product was characterized by IR, MS, 1H and 13C NMR, COSY and NOESY spectroscopy, X-ray crystallographic analysis, and by comparison with the authentic sample prepared with the known procedure. © 2008 Wiley Periodicals, Inc. Heteroatom Chem 19:694–699, 2008; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/hc.20497
Heteroatom Chemistry 10/2008; 19(7):694 - 699. · 1.24 Impact Factor
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ABSTRACT: One-pot reaction of aromatic aldehydes, cyanothioacetamide and malononitrile under microwave irradiation proved to be an efficient way for the synthesis of 2,6-diamino-4-aryl-4H-thiopyran-3,5-dicarbonitriles without any added catalyst.
Journal of Chemical Research 11/2007; 2007(12):693-695. · 0.04 Impact Factor
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ABSTRACT: To develop an understanding of the structure-activity relationships for the inhibition of orthopoxviruses by nucleoside analogues, a variety of novel chemical entities were synthesized. These included a series of pyrimidine 5-hypermodified acyclic nucleoside analogues based upon recently discovered new leads, and some previously unknown "double-headed" or "abbreviated" nucleosides. None of the synthetic products possessed significant activity against two representative orthopoxviruses; namely, vaccinia virus and cowpox virus. They were also devoid of significant activity against a battery of other DNA and RNA viruses. So far as the results with the orthopoxviruses and herpes viruses, the results may point to the necessity for nucleoside analogues 5'-phosphorylation for antiviral efficacy.
Bioorganic Chemistry 07/2007; 35(3):221-32. · 1.21 Impact Factor
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Mark N Prichard,
Kathy A Keith,
Mary P Johnson,
Emma A Harden,
Alexis McBrayer,
Ming Luo,
Shihong Qiu,
Debasish Chattopadhyay, Xuesen Fan,
Paul F Torrence,
Earl R Kern
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ABSTRACT: 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.
Antimicrobial Agents and Chemotherapy 06/2007; 51(5):1795-803. · 4.84 Impact Factor
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ABSTRACT: 5-Formyl-2'-deoxyuridine-3',5'-diacetate was converted to a small library of 5-substituted pyrimidine nucleoside N-acylamino acid amides by means of a Ugi multicomponent reaction. The reaction allowed introduction of various substituents at the acyl moiety, at the amino acid alpha-amide group, and at the amino acid carboxyl function. Evaluation of these novel 5-substituted nucleosides against vaccinia virus and cowpox virus provided one compound with discernable activity against cowpox virus but five- to eightfold less active than the Cidofovir standard. More promising activity was seen for the inhibition of Leishmania donovani promastigotes. Several synthetic products showed antileishmanial activity in the 10(-5)M range. When compared to earlier studies demonstrating anti-orthopoxviral and antileishmanial activity of 5-substituted pyrimidine nucleosides, these results imply that the 5-(N-acylamino acid amide)-derivatized pyrimidine nucleosides may possess more steric bulk, greater hydrophobicity, and more flexibility than is compatible with these particular biological activities.
Bioorganic Chemistry 05/2007; 35(2):121-36. · 1.21 Impact Factor
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ABSTRACT: The following structurally diverse 5-substituted-2'-deoxyuridine nucleosides displayed potent in vitro antileishmanial activity: 5-formyl, 5-(2,2,-dicyanovinyl)-, 5-(2-cyano-2-ethoxycarbonylvinyl), 5-(2-cyano-2-methoxycarbonylvinyl)-, 5-(2-amino-3-cyano-5-oxo-5,6,7,8-tetrahydro-4H-chromen-4-yl)- and related congeners, and the 5-(3-methyl-5-oxo-1-phenyl-4,5-dihydro-4H-pyrazol-4-ylidene) group.
Bioorganic & Medicinal Chemistry Letters 11/2006; 16(19):5047-51. · 2.55 Impact Factor
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ABSTRACT: The nucleoside 5-formyl-2'-deoxyuridine has been used as a starting point for the generation of novel 5-substituted pyrimidine nucleosides that are shown to possess significant antiviral activity against two representative orthopoxviruses, namely vaccinia virus and cowpox virus.
Antiviral Research 10/2006; 71(2-3):201-5. · 4.30 Impact Factor
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ABSTRACT: 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 microM), and cowpox virus (CV) (EC(50) = 2.0 +/- 0.3 microM). 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.
Journal of Medicinal Chemistry 08/2006; 49(14):4052-4. · 5.25 Impact Factor
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ABSTRACT: Synthetic hybridization of two privileged drug scaffolds, pyrazolone on the one hand and pyrimidine nucleoside on the other, resulted in the generation of two novel 5-substituted pyrimidine nucleosides with potent in vitro antiviral activity against two representative orthopoxviruses, vaccinia virus and cowpox virus.
Bioorganic & Medicinal Chemistry Letters 07/2006; 16(12):3224-8. · 2.55 Impact Factor
