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Medicinal Chemistry Research

, Volume 24, Issue 1, pp 32–50 | Cite as

Synthesis, structure elucidation, and anti-inflammatory/anti-cancer/anti-bacterial activities of novel (Z)-3-adamantyl-1-aryl-prop/but-2-en-1-ones

  • Utpalparna Kalita
  • Shunan Kaping
  • Revinus Nongkynrih
  • Melboureen Sunn
  • Ivee Boiss
  • Laishram Indira Singha
  • Jai Narain VishwakarmaEmail author
Original Research

Abstract

A series of hitherto unreported (Z)-3-adamantyl-1-aryl-prop/but-2-en-1-ones (4aj) were prepared from formylated/acetylated active proton compounds (2aj) and 1-adamantanamine (3) under microwave irradiation in good to excellent yields. The structures of 4aj have been unequivocally established with the help of spectral and analytical data. All the products were found to exist in Z form which was also supported by X-ray crystallographic studies. Compounds 4aj were assessed for their biological activities by testing their anti-inflammatory, anti-cancer, and anti-bacterial properties. The compounds 4h and 4i showed highest anti-inflammatory properties, while the compounds 4a and 4g were found to be the most cytotoxic and may have anti-cancer properties. However, none of the compounds exhibited anti-bacterial activity.

Keywords

Enaminone Adamantane Anti-inflammatory activity Anti-cancer Anti-bacterial 

Notes

Acknowledgments

Authors wish to thank Rev. Fr. Dr. Stephen Mavely, Vice Chancellor, Assam Don Bosco University for providing infrastructure for the execution of this work. Authors also wish to express their gratitude to IIT, Guwahati, Tezpur University, Tezpur, B. Barooah College, Guwahati, SAIF-NEHU, Shillong and SAIF-CDRI, Lucknow for providing spectral and analytical data. Our thanks are also due to the Department of Biotechnology (DBT), Government of India for a research grant. UK, SK & RN thank DBT-GOI for research fellowships.

References

  1. Alam A, Imliwati L, Rapthap C, Singh V (2001) Liposome encapsulated tumor-associated antigens elicited humoral and cellular immune responses in mice bearing tumor. Indian J Exp Biol 39(03):201–208PubMedGoogle Scholar
  2. Al-Awadi NA, Ibrahim MR, Elnagdi MH, John E, Ibrahim YA (2012) Enaminones in a multicomponent synthesis of 4-aryldihydropyridines for potential applications in photoinducedintramolecular electron-transfer systems. Beilstein J Org Chem 8:441–447PubMedCentralPubMedCrossRefGoogle Scholar
  3. Al-Deeb OA, Al-Omar MA, El-Brollosy NR, Habib EE, Ibrahim TM, El-Emam AA (2006) Synthesis, antimicrobial and anti-inflammatory activities of novel 2[3-(1-adamantyl)-4-substituted-5-thioxo-1,2,4-trizolin-1-yl]acetic acids, 2[3-(1-adamantylamino)-5-substituted-1,2,4-trizolin-1-yl]propionic acids and related derivatives. Arzneimittelforschung 56(1):40–47PubMedGoogle Scholar
  4. Al-Mousawi SM, El-Apasery MA, Elnagdi MH (2010) Enaminones in heterocyclic synthesis: a novel route to tetrahydropyrimidines, dihydropyridines, triacylbenzenes and naphthofurans under microwave irradiation. Molecules 15:58–67CrossRefGoogle Scholar
  5. Antoniadou-Vyza E, Avramidis N, Kourounakis A, Hadjipetrou L (1999) Anti-inflammatory properties of new adamantane derivatives. Design, synthesis, and biological evaluation. Arch Pharm 331:72–78CrossRefGoogle Scholar
  6. Balzarini J, Orzeszko B, Mauri JK, Orzeszko A (2007) Synthesis and anti-HIV studies of 2-adamantyl-substituted thiazolidin-4-ones. Eur J Med Chem 42:993–1003PubMedCrossRefGoogle Scholar
  7. Bartoli G, Bosco M, Cimarelli C, Dalpozzo R, Palmieri G (1991) C-alkylation of dianions of β-(isopropylamino)-α, β-enones. Synlett 4:229–230CrossRefGoogle Scholar
  8. Busse R, Mulsch A (1990) Induction of nitric oxide synthase by cytokines in vascular smooth muscle cells. FEBS Lett 275(1, 2):87–90PubMedCrossRefGoogle Scholar
  9. Chan FCY, Potter GA, Barrie SE, Haynes BP, Rowland MG, Houghton J, Jarman M (1996) 3- and 4-Pyridylalkyl adamantine carboxylates: inhibitors of human cytochrome P45017α (17α-hydroxylase/C17,20-lyase). Potential nonsteroidal agents for the treatment of prostatic cancer. J Med Chem 39:3319–3323PubMedCrossRefGoogle Scholar
  10. Chanda K, Dutta MC, Karim E, Vishwakarma JN (2004a) An efficient, microwave assisted solvent-free synthesis of polarized enamines. J Indian Chem Soc 81(9):791–793Google Scholar
  11. Chanda K, Dutta MC, Vishwakarma JN (2004b) An efficient microwave assisted solvent-free general routes to cyclic enaminones. Indian J Chem 43B(11):2475–2477Google Scholar
  12. Dannhardt G, Bauer A, Nowe U (1997) Non-steroidal anti-inflammatory agents, part 24[1] pyrrolidinoenaminones as models to mimic arachidonic acid. Arch Pharm 330(3):74–82CrossRefGoogle Scholar
  13. Davies WL, Grunnert RR, Haff RF, Mc Grahen JW, Neumeyer EM, Paulshock M, Watts JC, Wood TR, Hermann EC, Hoffman CE (1964) Antiviral activity of 1-adamantamine (amantadine). Science 144:862–863PubMedCrossRefGoogle Scholar
  14. Devi AS, Dutta MC, Nongkhlaw R, Vishwakarma JN (2010) KHSO4 assisted Michael addition-elimination reactions of formylated acetophenones in water: a facile general green synthetic route to 3-(alkyl/aralkyl/aryl)amino-1-arylprop-2-en-1-ones. J Indian Chem Soc 87(6):739–742Google Scholar
  15. Devi AS, Helissey P, Vishwakarma JN (2011) Synthesis of novel bis-enaminones by KHSO4-assisted facile Michael addition-elimination reaction of 3-dimethylamino-1-phenylprop-2-en-1-ones with diamines in water. Green Sustain Chem 1:31–35CrossRefGoogle Scholar
  16. Devi AS, Helissey P, Nongkhlaw RL, Vishwakarma JN (2013) KHSO4-assisted Michael addition–elimination reactions of indole with 3-dimethylamino-1-phenylprop-2-en-1-ones in water: an environmentally friendly synthesis of novel 3-indolylchalcones. Synthetic commun 43:1653–1660CrossRefGoogle Scholar
  17. Dutta MC, ChandaK Karim E, Vishwakarma JN (2004) A facile route to enaminones: synthesis of 3-alkyl/aralkyl/arylamino-1-aryl prop-2-en-1-ones. Indian J Chem 43B(11):2471–2474Google Scholar
  18. El-Apasery MA, Al-Mousawi SM, Elnagdia MH (2011) Green methodologies in organic synthesis: microwave-assisted solvent- and catalyst-free synthesis of enaminones and their conversion into 1,3,5-trisubstituted benzenes as well as 3-aroyl-6-substituted pyridines. Eur J Chem 2(2):168–172CrossRefGoogle Scholar
  19. El-Emam AA, Al-Deeb OA, Al- Omar MA, Lehmann J (2004) Synthesis, antimicrobial, and anti-HIV-1 activity of certain 5-(1-adamantyl)-2-substituted thio-1,3,4-oxadiazoles and 5-(1-adamantyl)-3-substituted aminomethyl-1,3,4-oxadiazoline-2-thiones. Bioorg Med Chem 12:5107–5113PubMedCrossRefGoogle Scholar
  20. El-Emam AA, Al-Tamimi AS, Al-Omar MA, Alrashood KA, Habib EE (2013) Synthesis and antimicrobial activity of novel 5-(1-adamantyl)-2-aminomethyl-4-substituted-1,2,4-triazoline-3-thiones. Eur J Med Chem 68:96–102PubMedCrossRefGoogle Scholar
  21. El-Sehemi AG, Bondock S, Ammar YA (2013) Transformations of naproxen into pyrazole carboxamides: search for potent anti-inflammatory, analgesic and ulcerogenic agents. Med Chem Res. doi: 10.1007/s00044-013-0650-0 Google Scholar
  22. El-Sherbeny MA (2000) Synthesis, antitumor activity, and anti-HIV-1 testing of certain heterocyclic systems containing an adamantane nucleus. Arch Pharm 333:323–328CrossRefGoogle Scholar
  23. Fleck C, Franzmann E, Claes D, Rickert A, Maison W (2013) Synthesis of functionalized adamantane derivatives: (3 + 1)-scaffolds for applications in medicinal and material chemistry. Synthesis 45:1452–1461CrossRefGoogle Scholar
  24. Foster JE, Nicholson JM, Butcher R, Stables JP, Edafiogho IO, Goodwin AM, Henson MC, Smith CA, Scott KR (1999) Synthesis, characterization and anticonvulsant activity of enaminones. Part 6: synthesis of substituted vinylic benzamides as potential anticonvulsants. Bioorg Med Chem 7:2415–2425PubMedCrossRefGoogle Scholar
  25. Fytas C, Zoidis G, Tzoutzas N, Taylor MC, Fytas G, Kelly JM (2011) Novel lipophilic acetohydroxamic acid derivatives based on conformationally constrained spiro carbocyclic 2,6-diketopiperazine scaffolds with potent trypanocidal activity. J Med Chem 54:5250–5254PubMedCentralPubMedCrossRefGoogle Scholar
  26. Goku A, Dolaz M, Digrak M, Serin S (2002) The biological activity of Dyer’s Madder. Proc INCP: 255–258Google Scholar
  27. Hareng L, Lasek W, Switaj T, Sienko J, Jakubowska AB, Nowaczyk M, Kazimierczuk Z (2006) TNF-· production-enhancing activity of 2-(1-adamantylamino)-6-methylpyridine (AdAMP) in cultures of human normal and neoplastic cells. Anticancer Res 26:1209–1216PubMedGoogle Scholar
  28. Hassaneen HME (2011) Chemistry of the enaminone of 1-acetylnaphthalene under microwave irradiation using chitosan as a green catalyst. Molecules 16:609–623PubMedCrossRefGoogle Scholar
  29. Houwen B (2000) Blood film preparation and staining procedures. Lab Hematol 6(1):1–7Google Scholar
  30. Josefik F, Svobodova M, Bertolasi V, Simunek P (2013) A simple, enaminone-based approach to some bicyclic pyridazinium tetrafluoroborates. Beilstein J Org Chem 9:1463–1471PubMedCentralPubMedCrossRefGoogle Scholar
  31. Kadi AA, El-Brollosy NR, Al-Deeb OA, Habib EE, Ibrahim TM, El-Emam AA (2007) Synthesis, antimicrobial, and anti-inflammatory activities of novel 2-(1-adamantyl)-5-substituted-1,3,4-oxadiazoles and 2-(1-adamantylamino)-5-substituted-1,3,4-thiadiazoles. Eur J Med Chem 42:235–242PubMedCrossRefGoogle Scholar
  32. Li J, Yu Y, Tu MS, Jiang B, Wang SL, Tu SJ (2012) New domino heteroannulation of enaminones: synthesis of diverse fused naphthyridines. Org Biomol Chem 10(28):5361–5365PubMedCrossRefGoogle Scholar
  33. Lipson VV, Zamigajlo LL, Petrova ON (2011) Development of 11β HSD1 inhibitors for the treatment of metabolic syndrome. Ukr Bioorg Acta 9(2):3–13Google Scholar
  34. Liu Y, Zhao R, Wan JP (2013) Water-promoted synthesis of enaminones: mechanism investigation and application in multicomponent reactions. Synth Commun 43(18):2475–2483CrossRefGoogle Scholar
  35. Makarova NV, Boreko EI, Moiseev IK, Pavlova NI, Zemtsova MN, Nikolaeva SN, Vladyko GV (2001) Antiviral activity of adamantyl-containing β-aminoketones, enaminoketones, and related compounds. Pharm Chem J 35(9):480–484CrossRefGoogle Scholar
  36. Mantovani A, Germano G, Marchesi F, Locatelli M, Biswas SK (2011) Cancer-promoting tumor-associated macrophages: new vistas and open questions. Eur J Immunol 41(9):2522–2525PubMedCrossRefGoogle Scholar
  37. Maples KR, Wheeler C, Ip E, Plattner JJ, Chu D, Zhang YK, Preobrazhenskaya MN, Printsevskaya SS, Solovieva SE, Olsufyeva EN, Heine H, Lovchik J, Lyons CR (2007) Novel semisynthetic derivative of antibiotic eremomycin active against drug-resistant gram positive pathogens including Bacillus anthracis. J Med Chem 50(15):3681–3685PubMedCrossRefGoogle Scholar
  38. Michael JP, De Koning CB, Gravestock D, Hosken GD, Howard AS, Jungmann CM, Krause RWN, Parsons AS, Pelly SE, Stanbury TV (1999) Enaminones: versatile intermediates for natural product synthesis. Pure Appl Chem 71(6):979–988CrossRefGoogle Scholar
  39. Michael JP, De Koning CB, Hosken GD, Stanbury TV (2001) Reformatsky reactions with N-arylpyrrolidine-2-thiones: synthesis of tricyclic analogues of quinolone antibacterial agents. Tetrahedron 57:9635–9648CrossRefGoogle Scholar
  40. Moustafa MS, Al-Mousawi SM, Hilmy NM, Ibrahim YA, Liermann JC, Meier H, Elnagdi MH (2013) Unexpected behavior of enaminones: interesting new routes to 1,6-naphthyridines, 2-oxopyrrolidines and pyrano[4,3,2-de][1,6]naphthyridines. Molecules 18:276–286CrossRefGoogle Scholar
  41. Omar K, Geronikaki A, Zoumpoulakis P, Camoustsis C, Sokovic M, Ciric A, Glamoclija (2010) Novel 4-thiazolidinene derivatives as potential antifungal and antibacterial drugs. J Biorg Med Chem 18:426–432CrossRefGoogle Scholar
  42. Orzeszko A, Kaminska B, Starosciak BJ (2002) Synthesis and antimicrobial activity of new adamantane derivatives III. II Farmaco 57:619–624CrossRefGoogle Scholar
  43. Patel VS, Nandre KP, Ghosh S, Rao VJ, Chopade BA, Sridhar B, Bhosale SV, Bhosale SV (2013) Synthesis, crystal structure and antidiabetic activity of substituted (E)-3-(Benzo [d]thiazol-2-ylamino) phenylprop-2-en-1-one. Eur J Med Chem 59:304–309CrossRefGoogle Scholar
  44. Plumb J, Milroy R, Kaye SB (1989) Effects of the pH dependence of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide-formazan absorption on chemosensitivity determined by a novel tetrazolium-based assay. Cancer Res 49:4435–4440PubMedGoogle Scholar
  45. Prachayasittikul S, Suksrichavalit T, Isarankura-Na-Ayudhya C, Ruchirawat S, Prachayasittikul V (2008) Antimicrobial and antioxidative activities of 1-adamantyl thio derivatives of 3-substituted pyridines. EXCLI J 7:63–70Google Scholar
  46. Rees DD, Palmer RMJ, Moncada S (1989) Role of endothelium-derived nitric oxide in the regulation of blood pressure. Proc Natl Acad Sci 86(9):3375–3378PubMedCentralPubMedCrossRefGoogle Scholar
  47. Riyadh SM (2011) Enaminones as building blocks for the synthesis of substituted pyrazoles with antitumor and antimicrobial activities. Molecules 16:1834–1853PubMedCrossRefGoogle Scholar
  48. Riyadh SM, Abdelhamid IA, Al-Matar HM, Hilmy NH, Elnagdi MH (2008) Enamines as precursors to polyfunctionalheteroaromatic compounds; a decade of development. Heterocycles 75:1849–1905CrossRefGoogle Scholar
  49. Salvemini D, Misko TP, Masferrer JL, Seibert K, Currie MG, Needleman P (1993) Nitric oxide activates cyclooxygenase enzymes. Proc Natl Acad Sci 90(15):7240–7244PubMedCentralPubMedCrossRefGoogle Scholar
  50. Schleyer PVR, Williams JE, Blanchard KR (1970) The evaluation of strain in hydrocarbons. The strain adamantane and its origin. J Am Chem Soc 92:2377–2386CrossRefGoogle Scholar
  51. Shang-Chih L, Weng-Huang P, Shun-Chiah H, Yu-Ling H, Tai-Hung H, Zheng-Rung L, Yuan-Shiun C (2009) Analgesic and anti-inflammatory activities of methanol extract from Desmodium triflorum DC in mice. Am J Chin Med 37(3):573–580CrossRefGoogle Scholar
  52. Shao Y, Yao W, Liu J, Xhu K, Li Y (2012) Copper-catalyzed selective synthesis of highly substituted pyridones by the reaction of enaminones with alkynes. Synthesis 44:3301–3306CrossRefGoogle Scholar
  53. Shibata Y, Shichita M, Sasaki K, Nishimura K, Hashimoto Y, Iwasaki S (1995) N-Alkylphthalimides: structural requirement of thalidomidal action on 12-O-tetradecanoylphorbol-13-acetate-induced tumor necrosis factor alpha production by human leukemia HL-60 cells. Chem Pharm Bull 43:177PubMedCrossRefGoogle Scholar
  54. Spano R, Linari G, Marri R (1970) 1-Adamantanecarboxylic acid amide of 4-aminoantipyrine. J Med Chem 13:554PubMedCrossRefGoogle Scholar
  55. Svete J (2006) Utilisation of chiral enaminones and azomethine imines in the synthesis of functionalized pyrazoles. Arkivoc vii:35–56Google Scholar
  56. Teplov VG, Suslov VE, Zarubaev VV, Shtro AA, Karpinskaya AL, Rogachev DA, Korchagina VD, Volcho PK, Salakhutdinov FN, Kiselev IO (2013) Synthesis of new compounds combining adamantanamine and monoterpene fragments and their antiviral activity against influenza virus A(H1N1)pdm09. Lett Drug Discov Des 10:477–485CrossRefGoogle Scholar
  57. Vincent Chen HS, Lipton SA (2006) The chemical biology of clinically tolerated NMDA receptor antagonists. J Neurochem 97:1611–1626CrossRefGoogle Scholar
  58. Vishwakarma JN, Dutta MC, Chanda K, Das B, Laskar MA, Nongkhlaw RL (2009) Synthesis and anti-bacterial activities of novel 5-isonicotinoyl-1,2,3,4-tetrahydropyrimidines and bis-(5-isonicotinoyl-1,2,3,4-tetrahydropyrimidines). ARKIVOC 13:131–141CrossRefGoogle Scholar
  59. Wang JJ, Lee JY, Chen YC, Chern YT, Chi CW (2006) The antitumor effect of a novel differentiation inducer, 2, 2-Bis (4-(4-amino-3-hydroxyphenoxy) phenyl) adamantane (DPA), in combinatory therapy on human colon cancer. Int J Oncol 28:1003–1012PubMedGoogle Scholar
  60. Weinberg JB, Misukonis MA, Shami PJ, Mason SN, Sauls DL, Dittman WA, Wood ER, Smith GK, Mcdonald B, Bachus KE, Haney AF, Granger DL (1995) Human mononuclear phagocyte inducible nitric oxide synthase (iNOS): analysis of iNOS mRNA, iNOS protein, biopterin, and nitric oxide production by blood monocytes and peritoneal macrophages. Blood 86(3):1184–1195PubMedGoogle Scholar
  61. Winter CA, Risley EA, Nuss GW (1962) Carrageenin-induced edema in hind paw of the rat as an assay for antiinflammatory drugs. Proc Soc Exp Biol Med 111:544–547PubMedCrossRefGoogle Scholar
  62. Yu X, Wang L, Feng X, Bao M, Yamamoto Y (2013) Copper-catalyzed aldol-type addition of ketones to aromatic nitriles: a simple approach to enaminone synthesis. Chem Commun 49:2885–2887CrossRefGoogle Scholar
  63. Zhu S, Zhao K, Su X, Ji S (2009) Microwave-assisted synthesis of new spiro[indoline-3,4′-quinoline] derivatives via a one-pot multicomponent reaction. Synth Commun 39:1355–1366CrossRefGoogle Scholar
  64. Zoidis G, Kolocouris N, Naesens E, De Clercq E (2009) Design and synthesis of 1,2-annulated adamantine piperidines with anti-influenza virus activity. Bioorg Med Chem 17:1534–1541PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Utpalparna Kalita
    • 1
  • Shunan Kaping
    • 1
  • Revinus Nongkynrih
    • 2
  • Melboureen Sunn
    • 2
  • Ivee Boiss
    • 2
  • Laishram Indira Singha
    • 2
  • Jai Narain Vishwakarma
    • 1
    Email author
  1. 1.Organic Research Lab., Department of Chemical ScienceAssam Don Bosco UniversityGuwahatiIndia
  2. 2.Department of BiotechnologySt. Anthony’s CollegeShillongIndia

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