Abstract
1-(6-Hydroxy-2-isopropenyl-1-benzofuran-5-yl)-1-ethanone (1), isolated from the roots of Petasites hybridus L., and a series of synthetic benzoxazepine derivatives of compound 1 (2–6) were evaluated for their immunomodulatory effects. The compounds were evaluated for their effects on the respiratory burst of human whole blood and isolated human polymorphonuclear leukocytes (PMNs) using luminol- and lucigenin-based chemiluminescence (CL) assays, and their effect on chemotactic migration of PMNs was assessed using the Boyden chamber technique. Compound 1 exhibited stronger inhibition than acetylsalicylic acid (ASA) on luminol-enhanced CL of PMNs. It also inhibited PMN chemotaxis with an IC50 value comparable to that of ibuprofen. Of the compounds tested, 5 was the most effective in inhibiting luminol-enhanced CL and also strongly inhibited lucigenin-enhanced CL with IC50 values lower than that of ASA. Compound 2 was the most active in inhibiting migration of PMNs and was five times stronger than ibuprofen. The results suggest that compound 1 and its synthesized benzoxazepine derivatives, especially compounds 2 and 5, were able to modulate the innate immune response of phagocytes at different steps, emphasizing their potential as leads for the development of new immunomodulatory agents.
![](http://media.springernature.com/m312/springer-static/image/art%3A10.1007%2Fs11418-013-0805-9/MediaObjects/11418_2013_805_Fig1_HTML.gif)
![](http://media.springernature.com/m312/springer-static/image/art%3A10.1007%2Fs11418-013-0805-9/MediaObjects/11418_2013_805_Fig2_HTML.gif)
![](http://media.springernature.com/m312/springer-static/image/art%3A10.1007%2Fs11418-013-0805-9/MediaObjects/11418_2013_805_Fig3_HTML.gif)
Similar content being viewed by others
References
Beutler B (2004) Innate immunity: an overview. Mol Immunol 40:845–859
Afonso V, Champy R, Mitrovic D, Collin P, Lomri A (2007) Reactive oxygen species and superoxide dismutases: role in joint diseases. Joint Bone Spine 74:324–329
Cottineau B, Toto P, Marot C, Pipaud A, Chenault J (2002) Synthesis and hypoglycemic evaluation of substituted pyrazole-4-carboxylic acids. Bioorg Med Chem Lett 12:2105–2108
Kalkhambkar RG, Aridoss G, Kulkarni GM (2011) Synthesis and biological activities of novel ethers of quinolinone linked with coumarins. Monatshefte fur Chemie 142:305–315
Ghate M, Manohar D, Kulkarni VR, Shobha SY (2003) Kattimani synthesis of vanillin ethers from 4-(bromomethyl) coumarins as anti-inflammatory agents. Eur J Med Chem 38:297–302
Khan IA, Kulkarni MV, Sun CM (2005) One pot synthesis of oxygenated tri-heterocycles as anti-microbial agents. Eur J Med Chem 40:1168–1172
Rostom SAF, Shalaby MA, El-Demellawy MA (2003) Polysubstituted pyrazoles, part 5. Synthesis of new 1-(4-chlorophenyl)-4-hydroxy-1H-pyrazole-3-carboxylic acid hydrazide analogs and some derived ring systems. A novel class of potential antitumor and anti-HCV agents. Eur J Med Chem 38:959–974
Manna K, Agrawal YK (2009) Microwave assisted synthesis of new indophenazine 1,3,5-trisubstituted pyrazoline derivatives of benzofuran and their antimicrobial activity. Bioorg Med Chem Lett 19:2688–2692
Khaleghi F, Din LB, Charati FR, Yaacob WA, Khalilzadeh MA (2011) A new bioactive compound from the roots of Petasites hybridus. Phytochem Lett 4:254–258
Eaton J (1998) Butterbur, herbal help for migraine. Nat Pharm 2:23–24
Mauskop A (2000) Petasites hybridus: ancient medicinal plant is effective prophylactic treatment for migraine. Townsend Lett 202:104–106
Scheidegger C, Dahinden C, Wiesmann U (1998) Effects of extracts and of individual components from Petasites on prostaglandin synthesis in cultured skin fibroblasts and on leucotriene synthesis in isolated human peripheral leucocytes. Pharm Acta Helvetiae 72:376–378
Thomet OAR, Schapowal A, Heinisch IVWM, Wiesmann UN, Simon HU (2002) Anti-inflammatory activity of an extract of Petasites hybridus in allergic rhinitis. Int Immunopharmacol 2:997–1006
Berger D, Burkard W, Schaffner W (1998) Influence of Petasites hybridus on dopamine-D2 and histamine-H1 receptors. Pharm Acta Helv 72:373–375
Danesch UC (2004) Petasites hybridus (Butterbur root) extract in the treatment of asthma—an open trial. Altern Med Rev 9:54–62
Coyne WE, Cusic JW (1967) Antiinflammatory dialkylaminoalkylureas. J Med Chem 10:541–546
Jilek JO, Pomykacek J, Metysova J (1965) Neurotropic and psychotropic substances. III. Derivatives of dibenz[b,f][1,4]oxazepine. Collect Czechoslov Chem Commun 30:463–471
Schmutz J, Hunziker F, Stille G (1967) Chemical structure and pharmacological activity of a new group of tricyclic neuroleptics. XI. Heterocycles with seven atoms. Eur J Med Chem (Chim Ther) 2:424–429
Coyne WE, Cusic JW (1968) Anticonvulsant semicarbazides. J Med Chem 11:1158–1160
Fiorentino A, D’Abrosca B, Pacifico S, Cefarelli G, Uzzo P, Monaco P (2007) Natural dibenzoxazepinones from leaves of Carex distachya: structural elucidation and radical scavenging activity. Bioorg Med Chem Lett 17:636–639
Kamei K, Maeda N, Nomura K, Shibata M, Katsuragi-Ogino R, Koyama M, Nakajima M, Inoue T, Ohno T, Tatsuoka T (2006) Synthesis, SAR studies, and evaluation of 1,4-benz oxazepine derivatives as selective 5-HT1A receptor agonists with neuroprotective effect: discovery of piclozotan. Bioorg Med Chem 14:1978–1992
Lowe EW Jr, Ferrebee A, Rodriguez AL, Conn J, Meiler J (2010) 3D-QSAR CoMFA study of benzoxazepine derivatives as mGluR5 positive allosteric modulators. Bioorg Med Chem Lett 20:5922–5924
Uto Y, Ueno Y, Kiyotsuka Y, Miyazawa Y, Kurata H, Ogata T, Takagi T, Wakimoto S, Ohsumi J (2011) Discovery of novel SCD1 inhibitors: 5-alkyl-4,5-dihydro-3H-spiro[1,5-benzoxazepine-2,41-piperidine] analogs. Eur Med Chem 46:1892–1896
Khaleghi F, Din LB, Jantan I, Yaakob WA, Khalilzadeh A (2011) A facile synthesis of novel 1,4-benzoxazepine-2-one derivatives. Tetrahedron Lett 52:7182–7184
Jantan I, Harun NH, Septama AW, Murad S, Mesaik MA (2011) Inhibition of chemiluminescence and chemotactic activity of phagocytes in vitro by the extracts of selected medicinal plants. J Nat Med 65:400–405
Sacerdote P, Massi P, Panerai AE (2000) In vivo and in vitro treatment with the synthetic cannabinoid CP55,940 decreases the in vitro migration of macrophages in the rat: involvement of both CB1 and CB2 receptors. J Neuroimmunol 109:155–163
Arnhold J (2004) Properties, functions, and secretion of human myeloperoxidase. Biochemistry 69:4–9
Rathakrishnan C, Tiku ML (1993) Lucigenin-dependent chemiluminescence in articular chondrocytes. Free Radic Biol Med 15:143–149
Parij NAM, Nagy AM, Fondu P, Neve J, Parolaro D (1998) Effects on nonsteroidal anti-inflammatory drugs on the luminol- and lucigenin-amplified chemiluminescence of human neutrophils. Eur Pharmacol 352:299–305
Allen A (1986) Phagocytic leucocytic oxygen activities and chemiluminescence: a kinetic approach to analysis. In: Deluca M et al (eds) Methods in enzymology. bioluminescence and chemiluminescence, vol 133B. Academic Press, New York, pp 449–493
Spisani S, Vanzini G, Traniello S (1979) Inhibition of human leucocytes locomotion by anti-inflammatory drugs. Experientia 35:803–804
Acknowledgments
This work was supported by the Ministry of Higher Education, Malaysia, under the Fundamental Research Grant Scheme (FRGS)(grant number 03-FRGS0029-2010).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Khaleghi, F., Jantan, I., Din, L.B. et al. Immunomodulatory effects of 1-(6-hydroxy-2-isopropenyl-1-benzofuran-5-yl)-1-ethanone from Petasites hybridus and its synthesized benzoxazepine derivatives. J Nat Med 68, 351–357 (2014). https://doi.org/10.1007/s11418-013-0805-9
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11418-013-0805-9