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Synthesis and antibacterial evaluation of 6-azapyrimidines with α-methylene-γ-(4-substituted phenyl)-γ-butyrolactone pharmacophores

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Abstract

A series of 6-substituted 2-[(4-methylene-5-oxo-2-(4-substituted phenyl) tetrahydrofuran-2-yl)methyl]-1,2,4-triazine-3,5(2H,4H)-diones (5, 6) and 2,4-bis[(4-methylene-5-oxo-2-(4-substituted phenyl) tetrahydrofuran-2-yl)methyl]-1,2,4-triazine-3,5(2H,4H)-diones (9, 10) were designed, synthesized, and evaluated for antibacterial activity against Gram-positive and Gram-negative microorganisms. The synthesis of these compounds involved the Reformatsky-type reaction between ethyl α-(bromomethyl)acrylate and the proper ketones. Among these compounds, 2-[(4-methylene-5-oxo-2-phenyl tetrahydrofuran-2-yl)methyl]-1,2,4-triazine-3,5(2H,4H)-dione (5a) is the most active compound and shown the selective inhibition activity against Proteus vulgaris.

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References

  • Cavallito CJ, Haskell TH (1946) Alpha-methylene butyrolactone from Erythronium americanum. J Am Chem Soc 68:2332–2334

    Article  PubMed  CAS  Google Scholar 

  • Chen IS, Lai-Yaun IL, Duh CY, Tsai IL (1998) Cytotoxic butanolides from Litsea akoensis. Phytochemistry 49:745–750

    Article  CAS  Google Scholar 

  • Creasey WA, Fink ME, Handschumacher RE, Calabresi P (1963) Clinical and pharmacological studies with 2′,3′,5′-triacetyl-6-azauridine. Cancer Res 23:444–453

    PubMed  CAS  Google Scholar 

  • Ellison RR, Tan CT, Murphy ML, Krakoff IH (1960) Clinical investigations of 6-azathymine a thymine analog. Cancer Res 20:435–442

    PubMed  CAS  Google Scholar 

  • Falke D, Rada B (1970) 6-Azauridine as an inhibitor of the synthesis of Herpesvirus hominis. Acta Virol 14:115–123

    PubMed  CAS  Google Scholar 

  • Gaito RA, Prusoff WH (1962) Studies on the metabolism of thymine and 6-azathymine. Biochem Pharmacol 11:323–336

    Article  PubMed  CAS  Google Scholar 

  • Ghose AK, Crippen GM (1986) Atomic physicochemical parameters for 3-dimensional structure-directed quantitative structure–activity relationships. 1. Partition-coefficients as a measure of hydrophobicity. J Comput Chem 7:565–577

    Article  CAS  Google Scholar 

  • Gunther HL, Prusoff WH (1967) Effect of 6-azathymine on the isolation and properties of deoxyribonucleic acid from Streptococcus faecalis. J Bacteriol 94:2067–2068

    PubMed  CAS  Google Scholar 

  • Hoffmann HMR, Rabe J (1985) Synthesis and biological activity of alpha-methylene-gamma-butyrolactones. Angew Chem Int Ed Engl 24:94–110

    Article  Google Scholar 

  • Hwang LC, Wei DC, Han CH, Lee KH, Tzeng CC (1994) Condensed as-triazines. 4. Synthesis of 2-amino-9-benzyl-6-azapurine (3-amino-5-benzyl-5H-imidazo[4,5-e]-as-triazine). J Chem Res (S) 121. J Chem Res (M) 831–842

  • Jane DE, Hoo K, Kamboj R, Deverill M, Bleakman D, Mandelzys A (1997) Synthesis of willardiine and 6-azawillardiine analogs: pharmacological characterization on cloned homomeric human AMPA and kainate receptor subtypes. J Med Chem 40:3645–3650

    Article  PubMed  CAS  Google Scholar 

  • Kim JC, Kim JA, Park JI, Kim SH, Kim SH, Choi SK, Park WW (1997) Potential antitumor alpha-methylene-gamma-butyrolactone bearing nucleic acid bases. 2. Synthesis of 5′-methyl-5′-[2-(5-substituted uracil-1-yl)ethyl]-2′-oxo-3′-methylenetetrahydrofurans. Arch Pharm Res 20:253–258

    Article  PubMed  CAS  Google Scholar 

  • Kupchan SM, Fessler DC, Eakin MA, Giacobbe TJ (1970) Reactions of alpha methylene lactone tumor inhibitors with model biological nucleophiles. Science 168:376–378

    Article  PubMed  CAS  Google Scholar 

  • Langer SH, Connell S, Wender I (1958) Preparation and properties of trimethylsilyl ethers and related compounds. J Org Chem 23:50–58

    Article  CAS  Google Scholar 

  • Lee KH, Huang BR (2003) Three-dimensional pharmacophore mapping of certain anticancer alpha-methylene-gamma-butyrolactones. Oncol Res 13:471–478

    PubMed  Google Scholar 

  • Lee KH, Hall IH, Mar EC, Starnes CO, Elgebaly SA, Waddell TG, Hadgraft RI, Ruffner CG, Weidner I (1977) Antitumor agents. 20. Sesquiterpene antitumor agents: inhibitors of cellular metabolism. Science 196:533–536

    Article  PubMed  CAS  Google Scholar 

  • Lee KH, Rice GK, Hall IH, Amarnath V (1987) Antitumor agents. 86. Synthesis and cytotoxicity of alpha-methylene-gamma-lactone bearing purines. J Med Chem 30:586–588

    Article  PubMed  CAS  Google Scholar 

  • Lee KH, Huang BR, Chen YL, Tzeng CC (1993) Condensed as-triazine. 2. Synthesis of 7-phenyldihydro-[2,3-e]-as-triazines and tetrahydropyrazino-[2,3-e]-as-triazines. Heterocycles 36:2577–2589

    Article  CAS  Google Scholar 

  • Lee KH, Huang BR, Tzeng CC (1999) Synthesis and anticancer evaluation of certain alpha-methylene-gamma-(4-substituted phenyl)-gamma-butyrolactone bearing thymine, uracil, and 5-bromouracil. Bioorg Med Chem Lett 9:241–244

    Article  PubMed  CAS  Google Scholar 

  • Lipinski CA (2000) Drug-like properties and the causes of poor solubility and poor permeability. J Pharmacol Toxicol Methods 44:235–249

    Article  PubMed  CAS  Google Scholar 

  • Luo MZ, Liu MC, Mozdziesz DE, Lin TS, Dutschman GE, Gullen EA, Cheng YC, Sartorelli AC (2000) Synthesis and biological evaluation of L- and D-configuration 1, 3-dioxolane 5-azacytosine and 6-azathymine nucleosides. Bioorg Med Chem Lett 10:2145–2148

    Article  PubMed  CAS  Google Scholar 

  • Maiti G, Roy SC (1996) Total synthesis of (±)-methylenolactocin by radical cyclisation of an epoxide using a transition-metal radical. J Chem Soc-Perkin Trans 1:403–404

    Article  Google Scholar 

  • Mandal PK, Maiti G, Roy SC (1998) Stereoselective synthesis of polysubstituted tetrahydrofurans by radical cyclization of epoxides using a transition-metal radical source. Application to the total synthesis of (±)-methylenolactocin and (±)-protolichesterinic acid. J Org Chem 63:2829–2834

    Article  CAS  Google Scholar 

  • Miller MW, Mylari BL, Howes HL, Figdor SK, Lynch MJ, Lynch JE, Gupta SK, Chappel LR, Koch RC (1981) Anticoccidial derivatives of 6-azauracil. 4. A 1000-fold enhancement of potency by phenyl sulfide and phenyl sulfone side-chains. J Med Chem 24:1337–1342

    Article  PubMed  CAS  Google Scholar 

  • Nollet AJH, Pandit UK (1969) Unconventional nucleotide analogues. 3. 4-(N1-pyrimidyl)-2-aminobutyric acids. Tetrahedron 25:5989–5992

    Article  PubMed  CAS  Google Scholar 

  • O’Shea R, Moser HE (2008) Physicochemical properties of antibacterial compounds: implications for drug discovery. J Med Chem 51:2871–2878

    Article  PubMed  Google Scholar 

  • Payne DJ, Gwynn MN, Holmes DJ, Pompliano DL (2007) Drugs for bad bugs: confronting the challenges of antibacterial discovery. Nat Rev Drug Discov 6:29–40

    Article  PubMed  CAS  Google Scholar 

  • Prusoff WH, Welch AD (1956) Studies on the mechanism of action 6-azathymine. II. Azathymine deoxyriboside, a microbial inhibitor. J Biol Chem 218:929–939

    PubMed  CAS  Google Scholar 

  • Sanyal U, Mitra S, Pal P, Chakraborti SK (1986) New alpha-methylene gamma-lactone derivatives of substituted nucleic acid bases as potential anticancer agents. J Med Chem 29:595–599

    Article  PubMed  CAS  Google Scholar 

  • Sidwell RW, Dixon GJ, Sellers SM, Schabel FM Jr (1968) In vivo antiviral properties of biologically active compounds. II. Studies with influenza and vaccinia viruses. Appl Microbiol 16:370–392

    PubMed  CAS  Google Scholar 

  • Slob A (1973) Tulip allergens in Alstroemeria and some other liliiflorae. Phytochemistry 12:811–815

    Article  CAS  Google Scholar 

  • Spring O, Albert K, Gradmann W (1981) Annuithrin, a new biologically active germacranolide from Helianthus annuus. Phytochemistry 20:1883–1885

    Article  CAS  Google Scholar 

  • Tzeng CC, Lee KH, Wang TC, Han CH, Chen YL (2000) Synthesis and cytotoxic evaluation of a series of gamma-substituted gamma-aryloxymethyl-alpha-methylene-gamma-butyrolactones against cancer cells. Pharm Res 17:715–719

    Article  PubMed  CAS  Google Scholar 

  • van Rossum MWPC, Alberda M, van der Plas LHW (1998) Tulipaline and tuliposide in cultured explants of tulip bulb scales. Phytochemistry 49:723–729

    Article  Google Scholar 

  • Walters TR, Aur RJ, Hernandez K, Vietti T, Pinkel D (1972) 6-Azauridine in combination chemotherapy of childhood acute myelocytic leukemia. Cancer 29:1057–1060

    Article  PubMed  CAS  Google Scholar 

  • Wei DC, Hwang LC, Han CH, Lee KH, Tzeng CC (1993) Condensed as-triazine. 3. Synthesis of 2-amino-6-azapurine (3-aminoimidazo[4,5-e]-as-triazine) as a potential antitumor agent. Heterocycles 36:2733–2743

    Article  CAS  Google Scholar 

  • Wiegand I, Hilpert K, Hancock REW (2008) Agar and broth dilution methods to determine the minimal inhibitory concentration (MIC) of antimicrobial substances. Nat Protoc 3:163–175

    Article  PubMed  CAS  Google Scholar 

  • Xu J, Stevenson J (2000) Drug-like index: a new approach to measure drug-like compounds and their diversity. J Chem Inf Comput Sci 40:1177–1187

    PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We are grateful to the National Center for High-performance Computing and the Center of Resources, Research and Development of Kaohsiung Medical University for computer time and facilities the technical supports.

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Authors and Affiliations

  1. Faculty of Medicinal and Applied Chemistry, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan, ROC

    Po-Jui Huang

  2. Graduate Institute of Pharmaceutical Science, Chia Nan University of Pharmacy and Science, Tainan, 71710, Taiwan, ROC

    Kuan-Han Lee

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  1. Po-Jui Huang
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Correspondence to Kuan-Han Lee.

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Huang, PJ., Lee, KH. Synthesis and antibacterial evaluation of 6-azapyrimidines with α-methylene-γ-(4-substituted phenyl)-γ-butyrolactone pharmacophores. Med Chem Res 20, 1081–1090 (2011). https://doi.org/10.1007/s00044-010-9438-7

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  • DOI: https://doi.org/10.1007/s00044-010-9438-7

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