The Heterocyclic Antiviral Agents

  • Baoan Song
  • Linhong Jin
  • Song Yang
  • Pinaki S. Bhadury


In conclusion, a series of novel pyrazole derivatives were synthesized by the treatment of 1-substituted phenyl-3-methyl-5-substituted phenylthio-4-pyrazolaldoximes 4.3 with acyl chloride. Their structures were verified by spectroscopic data. The results of bioassay showed that these title compounds exhibited weak to good anti-TMV bioactivity. Title compounds 4.4l, 4.4m showed better biological activity than their structurally related analogues 4.4a-4.4k and 4.4n Preliminary studies showed that treatment by compound 4.4l can significantly enhance disease resistance of tobacco and also show that the compound 4.4l is structurally related to TMV by exhibiting a higher affinity for TMV CP. So, the action mechanism of curative effect by the compound 4.4l was mainly attributed to the induced disease resistance against tobacco while the action mechanism of inactivation effect was caused by its affinity towards TMV CP. More detailed studies on mechanistic aspects are currently underway.


Antiviral Activity Title Compound Tobacco Mosaic Virus Antiviral Agent Tobacco Leaf 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Boyne M, Stratton C, Johnson F, et al. High affinity inhibitors with activity against drug-resistant strains of mycobacterium tuberculosis. Chem. Biol 2006, 1(1), 43–53.Google Scholar
  2. 2.
    Vicentini C B, Guccione S, Giurato L, et al. Pyrazole derivatives as photosynthetic electron transport inhibitors: new leads and structure-activity relationship. J. Agric. Food Chem 2005, 53, 3848–3855.CrossRefGoogle Scholar
  3. 3.
    Waldrep TW, Beck JR, Lynch MP, et al. Synthesis and herbicidal activity of l-aryl-5-halo and l-aryl-5-(trifluoromethyl)-lH-pyrazole-4-carboxamides. J. Agric. Food Chem 1990, 38(2), 541–544.CrossRefGoogle Scholar
  4. 4.
    Pevarello P, Brasca M G, Amici R, et al. 3-Aminopyrazole inhibitors of CDK2/Cyclin a as antitumor agents.l.lead finding. J. Med.Chem 2004, 47(13), 3367–3380.CrossRefGoogle Scholar
  5. 5.
    Baraldi P G, Balboni G, Pavani M G, et al. Design, synthesis, DNA binding, and biological evaluation of water-soluble hybrid molecule containing two pyrazole analogues of the alkylating cyclopropyl-pyrroloindole (CPI) subunit of the antitumor agent CC-1065 and polypyrrol minor groove binders. J.Med.Chem 2001, 44(16), 2536–2543.CrossRefGoogle Scholar
  6. 6.
    Fancelli D, Moll J, Varasi M, et al. 1,4,5,6-Tetrahydropyrrolo[3,4-c]pyrazoles: identification of a potent aurora kinase inhibitor with a favorable antitumor kinase inhibition profile. J. Med. Chem 2006, 49(24), 7247–7251.CrossRefGoogle Scholar
  7. 7.
    Ranatunge R R, Augustyniak M, Bandarage U K, et al. Synthesis and selective cyclooxy genase-2 inhibitory activity of a series of novel, nitric oxide donor-containing pyrazoles. J.Med.Chem 2004, 47(9), 2180–2193.CrossRefGoogle Scholar
  8. 8.
    Goel A, Madan A K. Structure-activity atudy on antiinflammatory pyrazole carboxylic acid hydrazide analogs using molecular connectivity indices. J. Chem. Inf. Comput. Sci 1995, 35(3), 510–514.Google Scholar
  9. 9.
    Hansen A J. Antiviral chemicals for plant disease control. Critical Reviews in Plant. Critical Reviews in Plant Sciences 1989, 8, 45–88.CrossRefGoogle Scholar
  10. 10.
    Milosevic N, Slusarenko A J. Active oxygen metabolism and lignification in the hypersensitive response in bean. Phys. Plant Path, 1996, 49, 143–158.CrossRefGoogle Scholar
  11. 11.
    Wang Y C, Hu D W, Zhang Z G, et al. Purification and immuno-cytoiocalization of a novel elicitor inducing SAR in plants from Phytophthora boehmeriae. Phys. and Mol. Plant Path 2003, 63, 223–232.CrossRefGoogle Scholar
  12. 12.
    Sticher L, Mauch-Mani B, Metraux, J.P. Systemic acquired resistance. Annu.Rev.Phytopathol 1997, 35, 235–270.CrossRefGoogle Scholar
  13. 13.
    Malamy J, Carr J P, Klessig D F, et al. Salicylic acid-a likely endogenous signal in the resistance response of tobacco to viral infection. Science 1990, 250, 1002–1004.CrossRefGoogle Scholar
  14. 14.
    Hahlbrock K, Scheel D. Physiology and molecular biology of phenylpropanoid metabolism. Annu.Rev.Plant.Physiol.Plant Mol.Biol 1989, 40, 347–369.CrossRefGoogle Scholar
  15. 15.
    Rusmussen J B, Hammersschmidt R, Zook M N. Systemic induction of salicylic acid accumulation in cucumber after inoculation with Pseudomonas syringae pv syringae. Plant Physiol 1991, 97, 1342–1347.CrossRefGoogle Scholar
  16. 16.
    Van Loon L C. Pathogen es is-related Proteins. Plant Mol. Biol 1985, 4, 111–116.CrossRefGoogle Scholar
  17. 17.
    Tornero P, Gadea J, Conejero V. Two PR-1 Genes from Tomato are differentially regulated and reveal a novel mode of expression for a pathogenesis-related gene during hypersensitive response and development. Mol. Plant.Mcrobe Interact 1997, 10, 624–634.CrossRefGoogle Scholar
  18. 18.
    Xi Z, Zhang R Y, Yu Z H, et al. Selective interaction between tylophorine B and bulged DNA. Bioorg. Med. Chem. Lett 2005, 15(10), 2673–2677.CrossRefGoogle Scholar
  19. 19.
    Jin G Y, Cao C Y, Li L T, et al. Synthesis and biological activities of substituted pyrazolo [4,5-e][l,3] thiazine derivative. Chin. J. Pestic. Sci 1999, 1, 15–19.Google Scholar
  20. 20.
    Li Z G Preparation of organic intermediates. Chemical Industry Press, Beijing, 2001, pp.8, 152,445.Google Scholar
  21. 21.
    Xu K X. Handbook of materials and intermediates of fine organic chemical industry Chemical Industry Press, Beijing, 1998, 4–39.Google Scholar
  22. 22.
    a)Xiao H Q, Ouyang G P, Sun X D, et al. Synthesis of pyrazole oxime esters. Chin. J. Syn. Chem 2005, 13(6), 600–602; b)Ouyang G P. Ph.D. Dissertation, Guizhou University, Guiyang, China, 2008.Google Scholar
  23. 23.
    Wilson A J. International table for X-ray crystallography, Vol.C, Kluwer Academic Publishers. Dordrecht: Tables (pp. 500–502) and (pp.219-222). 1992.Google Scholar
  24. 24.
    Sheldrick GM. SHELXTL, V 5.1, Software Reference Manual, Bruker AXS, Inc., Madison, Wisconsin, USA, 1997.Google Scholar
  25. 25.
    Sheldrick G M. in Program for empirical absorption correction of area detector data; University of Göttingen: Germany, 1996.Google Scholar
  26. 26.
    Gooding G V Jr, Hebert T T. A simple technique for purification of tobacco mosaic virus in large quantities. Phytopathology 1967, 57(11), 1285–1286.Google Scholar
  27. 27.
    Li S Z, Wang D M, Jiao S M. in Pesticide Experiment Methods-Fungicide Sector; Li S Z, Ed.; Agricuture Press of China: Beijing, 1991, 93–94.Google Scholar
  28. 28.
    He Z P. in A Guide to Experiments of Chemical control for Crops; He, Z.P, Ed.; Beijing Agricultural University Press: Beijing, 1933, 30–31.Google Scholar
  29. 29.
    Polle A, Otter T, Seifert F. Apoplastic Peroxidases and Lignificatio n in Needles of Norway Spruce. Plant Physiol1994, 106, 53–60.Google Scholar
  30. 30.
    Beauchamp C, Fridovich J. Superoxide dismutase. Improved assay and an assay applicable to acrylamide gels. J. Anal. Biochem1971, 444, 276–278.CrossRefGoogle Scholar
  31. 31.
    Yamakawa H, Kamada H, Satoh M, et al. Spermine is a salicylate-independent endogenous inducer for both tobacco acidic pathogen es is-related proteins and resistance against tobacco mosaic virus infection. Plant Physiol1998, 118, 1213–1222.CrossRefGoogle Scholar
  32. 32.
    Anand A, Zhou T, Trick H N, et al. Greenhouse and field testing of transgenic wheat plants stably expressing genes for thaumatin-like protein, chitinase and glucanase against Fusarium graminearum. J. Exp. Botany2003, 54, 1101–1111.CrossRefGoogle Scholar
  33. 33.
    Mohamed F, Lydia F, Masumi I, et al. Exprès s ion of potential defense responses of Asian and European pears to infection with Venturianashicola. Physiol. Mole. Plant Path 2004, 64, 319–330.CrossRefGoogle Scholar
  34. 34.
    Yuan J S, Reed A, Chen F, et al. Statistical analysis of real-time PCR data. BMCBioinform 2006, 7, 85.Google Scholar
  35. 35.
    Chen GZ. Fluorescence analytical method. Beijing: Science Press, 1990, 122.Google Scholar
  36. 36.
    The National Center for Biotechnology Information (NCBI). Protein AAD20291.Google Scholar
  37. 37.
    Fraenkel-Conrat H, Williams RC. Reconstitution of active tobacco mosaic virus from its inactive protein and nucleic acid components. Proc. Natl. Acad. USA, 1955, 41, 690.CrossRefGoogle Scholar
  38. 38.
    Liu X H, Cui P, Song B A, et al. Synthesis, structure and antibacterial activity of novel 1-(5-substituted-3-substituted-4, 5-dihydropyrazol-l-yl)ethanone oxime ester derivatives. Bioorg. &.Med.Chem 2008, 16, 4075–4082.CrossRefGoogle Scholar
  39. 39.
    Velaparthi S, Brunsteiner M, Uddin R, et al. 5-tert-Butyl-N-pyrazol-4-yl-4, 5, 6,7-tetrahydrobenzo [d]isoxazole-3-carboxamide derivatives as novel potent inhibitors of Mycobacterium tuberculosis Pantothenate synthetase: initiating a quest for new antitubercular drugs. J. Med. Chem 2008, 51, 1999–2002.CrossRefGoogle Scholar
  40. 40.
    Magedov IV, Manpadi M, Van slambrouck S, et al. Discovery and investigation of antiproliferative and apoptosis-inducing properties of new heterocyclic podophyllotoxin analogues accessible by a one-step multicomponent synthesis. J. Med. Chem 2007, 50, 5183–5192.CrossRefGoogle Scholar
  41. 41.
    Rovnyak G C, Millonig R C, Schwartz J, et al. Synthesis and antiinflammatory activity of hexahydrothiopyrano [4, 3-c]pyrazoles and related analogs. J. Med. Chem1982, 25, 1482–1488.CrossRefGoogle Scholar
  42. 42.
    Wächter G A, Hartmann R W, Sergejew T, et al. Tetrahydronaphthalenes: influence of heterocyclic substituents on inhibition of steroidogenic enzymes P450 arom and P450 17. J. Med. Chem 1996, 39, 834–841.CrossRefGoogle Scholar
  43. 43.
    Colliot F, Kukorowski K, Hawkins A, et al. Fipronil: a new soil and foliar broad spectrum insecticide. Brighton Crop Prot. Conf. Pests Dis 1992, 1, 29–34.Google Scholar
  44. 44.
    Chen H S, Li Z, Han M, et al. Synthesis and fungicidal activity against Rhizoctonia solani of 2-alkyl(alkylthio)-5-pyrazolyl-l,3,4-oxadiazoles (Thiadiazoles). J. Agric. Food. Chem 2000, 48, 5312–5315.CrossRefGoogle Scholar
  45. 45.
    Vicentini C B, Romagnoli C, Andreotti E, et al. Synthetic pyrazole derivatives as growth inhibitors of some phyto-pathogenic fungi. J. Agric. Food Chem 2007, 55(25), 10331–10338.CrossRefGoogle Scholar
  46. 46.
    Vicentini C B, Mares D, Tartari A, et al. Synthesis of pyrazole derivatives and their evaluation as photosynthetic electron transport inhibitors. J. Agric. Food Chem2004, 52, 1898–1906.CrossRefGoogle Scholar
  47. 47.
    Waldrep T W, Beck J R, Lynch M P, et al. Synthesis and herbicidal activity of l-aryl-5-halo and l-aryl-5-(trifluoromethyl)-lH-pyrazole-4-carboxamides. J. Agric. Food Chem 1990, 38, 541–544.CrossRefGoogle Scholar
  48. 48.
    Clark, R.D. ynthesis and QSAR of herbicidal 3-pyrazoryl a, a, a-trifluorotolyl ethers. JAgric.Food Chem 1996, 44, 3643–3652.CrossRefGoogle Scholar
  49. 49.
    Li Y, Zhang H Q, Liu J, et al. Stereoselective synthesis and antifungal activities of (E)-α-(methoxyimino) benzeneacetate derivatives containing 1, 3, 5-substituted pyrazole ring. J. Agric. Food. Chem 2006, 54, 3636–3640.CrossRefGoogle Scholar
  50. 50.
    Huang R Q, Song J, Feng L. Synthesis and bioactivity of 1, 3, 5-substituted pyrazol-4-methylene cyclopropane carboxylate. Chem J. Chin Univer 1996, 17, 1089–1091.Google Scholar
  51. 51.
    Liu Y, Ren J, Jin G Y Synthesis and biological activities of 1-phenyl (methyl)-3-methyl-5-(4,6-dimethyl-2-thio)pyrimidyl-4-pyrazolyl oxime ethers (esters). Chin. J. Pestic. Sci 2001, 3, 12–16.Google Scholar
  52. 52.
    Minakata S, Hamada T, Komatsu M, et al. Synthesis and biological activity of 1H-pyrrolo [2,3-b] pyridine derivatives: correlation between inhibitory activity against the fungus causing rice blast and ionization potential. J. Agric. Food Chem 1997, 45, 2345–2348.CrossRefGoogle Scholar
  53. 53.
    Cui P, Liu X H, Zhi L P, et al. Synthesis and biological activity of novel 5-aryl-N-pyrazole oxime ester derivatives. Chin J. Appl Chem2008, 25(7), 820–824.Google Scholar
  54. 54.
    Song B A, Zhang H P, Wang H, et al. Synthesis and antiviral activity of novel chiral cyanoacrylate derivatives. J. Agric.Food Chem 2005, 53, 7886–7891.CrossRefGoogle Scholar
  55. 55.
    Bartroli J, Turmo E, Alguero M, et al. New azole antifungals. 3. Synthesis and antifungal activity of 3-substituted-4(3 H)-quin azo lin ones. J. Med. Chem 1998, 48, 1869–1882.CrossRefGoogle Scholar
  56. 56.
    El-Sharief A M Sh, Ammar Y A, Zahran M A, et al. Aminoacids in the synthesis of heterocyclic systems: The synthesis of triazinoquinazolinones, triazepinoquinazolinones and triazocinoquinazolinones of potential biological interest. Molecules 2001, 6, 267–278.CrossRefGoogle Scholar
  57. 57.
    Purohit D M, Bhuva V R, Shah V H. Synthesis of 5-arylaminosulpho-N-acetyl-anthranilic acid, 6-arylaminosulpho-2-methyl-3-amino/3-N-chloroaceta mido /3-N-arylamino acetamido-4-(3H)-quinazolones as potential anti-HIV, anticancer and antimicrobial agents. Chemistry (Rqjkot, India), 2003, 1(4), 233–245.Google Scholar
  58. 58.
    Murav’eva K M, Arkhangel’skaya N V, Shchukina M N, et al. Synthesis and tuberculostatic activity of aminoquinazolines. Khimiko-Farmatsevticheskii Zhurnal 1971, 5(6), 25–27.Google Scholar
  59. 59.
    Abdel-Hamid S G. Synthesis of some new heterocyclic systems bearing 2-phenyl-6-iodo-4(3i/)-quinazolinon-3-yl moiety as antibacterial agents. J. Indian Chem. Soc 1997, 74, 613–618.Google Scholar
  60. 60.
    Barker A J. Quinazoline derivatives and their use as anti-cancer agents. Eur Pat, 635498, 1995; Chem. Abstr 1995, 122, 214099.Google Scholar
  61. 61.
    Aziza M A, Ibrahim M K, El-Helpy A G Synthesis of novel-2-styryl-3-benzylidenimino-4(3H)-quinazo lone derivatives of expected anticonvulsant activity. Al-Azhar Pharm. Sci 1994, 14, 193–201.Google Scholar
  62. 62.
    Ergenc N, Buyuktimkin S, Capan G, et al. Quinazolinones. 19. Communication [1]: synthesis and evaluation of some CNS depressant properties of 3-2-[(5-aryl-1,3,4-oxadiazol-2-yl)amino]acetamido-2-methyl-4(3H)-quinazolin ones. Pharmazie 1991, 46(4), 290–291.Google Scholar
  63. 63.
    Bekhit A A, Khalil M A. Synthesis benzopyrazolyl derivatives of quin azo lin ones. Pharmazie 1998, 53, 539–544.Google Scholar
  64. 64.
    Hamel E, Lin C M, Plowman J, et al. Antitumor 2,3-dihy dro-2-ary 1-4 (lH)-quinazolinone derivatives. Interactions with tubulin. Biochem.Pharmacol 1996, 51, 53–59.CrossRefGoogle Scholar
  65. 65.
    Terashima K, Shimamura H, Kawase A, et al. Studies on antiulcer agents. IV: Antiulcer effects of 2-benzylthio-5, 6, 7, 8-tetrahydro-4 (3H)-quinazolinones and related compounds. Chem.Pharm.Bull 1995, 43, 2021–2023.Google Scholar
  66. 66.
    Gursoy A, Karali N. Synthesis and anticonvulsant activity of new acylthiosemicarbazides and thiazolidones. Farmaco 1995, 50, 857–866.Google Scholar
  67. 67.
    Baek D J, Park Y K, Heo H I, et al. Synthesis of 5-substituted quinazolinone derivatives and their inhibitory activity in vitro. Bioorg Med.Chem.Lett 1998, 8, 3287–3290.CrossRefGoogle Scholar
  68. 68.
    Griffin R J, Srinivasan S, Bowman K, et al. Resistance-modifying agents.5. Synthesis and biological properties of quinazolinone inhibitors of the DNA repair enzyme poly (ADP-ribose) polymerase (PARP). J.Med.Chem1998, 41, 5247–5256.Google Scholar
  69. 69.
    Balazs S, Kaiman H, Tamas K. Quinazolinone-derivatives and their use for preparation of pharmaceutical compositions having parp enzyme inhibitory effect. US Paient 20070042935, 2007.Google Scholar
  70. 70.
    Uehara M, Shimizu T, Fujioka S, et al. Synthesis and insecticidal activity of 3-amino-quinazolinone derivatives. Pesticide Science 1999, 55(3), 359–362.CrossRefGoogle Scholar
  71. 71.
    Ouyang G P, Zhang P Q, Xu G F, et al. Synthesis and Antifungal Bioactivities of 3-Alkylquinazolin-4-one Derivatives. Molecules 2006, 11, 383–392.CrossRefGoogle Scholar
  72. 72.
    Liu X, Huang R Q, Li H, et al. Synthesis and bioactivity of O-(4-quinazolinyl) hydroximic thioesters (amides). Chin. J. Appl. Chem1999, 16(2), 23–26.Google Scholar
  73. 73.
    Nanda A K, Ganguli S, Chakraborty R Antibacterial activity of some 3-(Arylideneamino)-2-phenyl quinazoline-4 (3H)- on es: synthesis and preliminary QSAR studies. Molecules 2007, 12, 2413–2426.CrossRefGoogle Scholar
  74. 74.
    Ameta U, Ojha S, Bhambi D, et al. Synthetic studies on some 3-[(5-arylidene-4-oxo-l, 3-thiazolidin-2-yliden)amino]-2-phenylquinazolin-4(3.H)-ones and their ethoxyphthalimide derivatives. Arkivoc 2006, (xiii), 83–89.Google Scholar
  75. 75.
    Desai N C, Bhatt J J, Shah B R. Synthesis of substituted quinazolone derivatives as potential anti-HIV agents. (Part III). Farmaco. 1996, 51(5), 361–366.Google Scholar
  76. 76.
    Song S Q, Zhou L G, Li D, et al. Antifungal activity of five plants from Xinjiang. Nat. Prod. Res. & Dev. 2004, 16, 157–159.Google Scholar
  77. 77.
    Faize M, Faize L, Lshizaka M, et al. Expression of potencial defense relponse of Asian and European pears to infection with Venturia nashic ola.Phgsiol Mol. Plant. Path2004, 64, 319–330.CrossRefGoogle Scholar
  78. 78.
    Ouyang G P, Cai X J, Chen Z, et al. Synthesis and antiviral activities of pyrazole derivatives containing oxime ethers moiety. J. Agric. Food. Chem2008, 56, 10160–10167.CrossRefGoogle Scholar
  79. 79.
    Ouyang G P, Chen Z, Cai X J, et al. Synthesis and antiviral activities of pyrazole derivatives containing oxime esters group. Bioorg.&.Med.Chem2008, 16, 9699–9707.CrossRefGoogle Scholar
  80. 80.
    Gao X W, Cai X J, Yai K, et al. Synthesis and antiviral bioactivities of 2-phenyl-3-(substituted-benzalamino)-4(3H)-quinazolinone derivatives. Molecules, 2007, 12, 2621–2642.CrossRefGoogle Scholar

Copyright information

© Chemical Industry Press, Beijing and Springer-Verlag Berlin Heidelberg 2010

Authors and Affiliations

  • Baoan Song
    • 1
  • Linhong Jin
    • 1
  • Song Yang
    • 1
  • Pinaki S. Bhadury
    • 1
  1. 1.Center for R&D of Fine ChemicalsGuizhou UniversityGuiyangChina

Personalised recommendations