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Synthesis and Biological Activity of Cinnamic Acids Amides

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Synthesis and Biological Activity of Cinnamic Acids Amides Section: CHEMISTRY SYNTHESIS AND BIOLOGICAL ACTIVITY OF CINNAMIC ACIDS AMIDES Tsenka Milkova a,b * , Maya Spasova c, Galya Ivanova b, Stefan Philipov b, Lubomira Nikolaeva-Glomb d, Galina Radeva c (Plenary report) aSouth-West University “Neofit Rilski” Blagoevgrad, Bulgaria b Institute of Organic Chemistry with Centre of Phytochemistry, Bulgarian Academy of Sciences, Sofia, Bulgaria cInstitute of Molecular Biology, Bulgarian Academy of Sciences, Sofia, Bulgaria d The Stephan Angeloff Institute of Microbiology, Bulgarian Academy of Sciences, Sofia, Bulgaria Abstract: Seventeen cinnamoyl-, feruloyl- and sinapoyl- amino acids amides have been synthesized using the standard methods in peptide chemistry. The antioxidant activity of six feruloyl- and three sinapoyl- amino acid amides was studied on the oxidation stability of a lipid system. Some of the synthesized compounds have been tested for their antibacterial and antiviral activity. Twenty three N-alkylcinnamoyl amides have been prepared in solution and by sonochemical and microwave activated Wittig reaction. Some of the synthesized hydroxycinnamoyl amides were tested for their antiradical activity by DPPH* tests. All sinapoyl alkylamides were more active than the feruloyl amides. The results obtained demonstrated that the amides are twice less active than the free hydroxycinnamic acids The alkaloid glaucine has been modified and connected with cinnamoyl- and hydroxycinnamoyl residue. The compounds obtained have been tested for their antiradical activity by DPPH* tests. Keywords: cinnamoyl amides, sonochemical and microwave activated Wittig reaction, glaucine, antibacterial- and antiviral activity; DPPH* test 1. INTRODUCTION The biochemical properties of polyphenolic secondary plant metabolites such esters of cinnamic acids (caffeic, ferulic, p- and o-coumaric, sinapic) attract much attention in biology and medicine. These compounds show antiviral, antibacterial, vasoactive, antiflammatory and other properties. Cinnamic acid conjugates also are commonly isolated from plant sources as the corresponding N-substituted amides. While esters of cinnamic acids occur widely in higher plants, amides of cinnamic acids seem to be rare. In order to define precisely the scope of their biological activity we synthesized a series of amides of cinnamic acids. The growing interest during the last years to naturally and synthetic amides of phenyl propenoic acids is due to the more metabolically stability of the amide group in comparison to the ester group [6]. In this paper we discuss our results in: • synthesis of cinnamoyl, feruloyl and sinapoyl- amino acids amides. • synthesis of amides of substituted cinnamic acids with aliphatic monoamines. • synthesis of cinnamoyl- and hydroxycinnamoyl amides of the alkaloid glaucine. • biological activity of the synthesized amides. 5 Faculty of Mathematics& Natural Sciences – FMNS 2007 2. RESULTS AND DISCUSSION N-substituted amides of cinnamic acids are commonly isolated from plant sources in different forms [8]. In one of them phenylpropenoic acids (basic, water soluble) are linked with aromatic amino acids (tyrosine, phenylalanine, tryptophane) [1, 3, 9]. Little is known about the biological function of the last class of compounds in nature. The formation of these amides is regarded as a protective mechanism in plants after virus infection, wounding, heavy metal ions, high temperature etc [4]. Fifteen amides have been obtained by a standard method of coupling of phenylpropanoic acids with natural and unnatural C- protected amino acids (Tab. 1). The synthesized amides 10, 12, 14 and 16 have been found in nature. The rest of cinnamoyl and hydroxycinnamoyl conjugates of amino acids are new. The antioxidant activity of six feruloyl- (7-12) and three sinapoyl- (14-16) amino acid amides on the oxidation stability of a lipid system (kinetically pure triacylglicerols of sunflower oil) during oxidation at 80 oC in bulk phase was investigated. The highest antioxidant activity was found for the compounds 10 and 14, containing the same phenylalanine rest [7, 11]. Feruloyl- and sinapoyl amides of phenylalanine showed antibacterial activity against E.coli and Bacillus subtilis . The antiviral activity was assessed by the agar-diffusion plaque-inhibition test which revealed that sinapoyl phenylalanine amide possessed moderate effect against Coxsakivirus B1 and poliovirus type 1 (Lsc-2ab). Cinnamic acid amides of phenylalanine, 3-fluorophenylalanine and tyrosine were found to possess border effect against both viruses. The second topic in this report is the synthesis of amides of substituted cinnamic acids with aliphatic monoamines. As our attempts to prepare amides of caffeic acid with aliphatic amines by the methods used in the peptide chemistry failed, we tried to find alternative ways for their synthesis. In order to obtain amides without protection of the phenolic hydroxyl groups a recently developed new method for the synthesis of esters of cinnamic acids (including caffeic acid) by sonochemical [2, 5] and microwave [10] activated Wittig reaction was applied. 6 Section: CHEMISTRY Tab. 1. Synthesized N-cinnamoyl- and N-hydroxycinnamoyl amino acid amides. O 3R NHR 1R 2R № _ 20 NR 1R2 R' R'' R''' Molecule [a] D, MeOH Yields, % Weight _ 1 NH-CH(CH 3)-COOC(CH 3)3 HHH 275.35 (-) 3.55, c=0.19 85. 0 C16 H21 NO 3 _ 2 NH-CH(CH(CH 3)2)-COOCH 3 HHH 261.32 (+) 4.96, c=0.19 13. 0 C15 H19 NO 3 _ 3 NH-CH(CH 2-CH(CH 3)2)-COOCH 3 HHH 275.35 (-) 16.35, c=0.38 14. 5 C16 H21 NO 3 _ 4 NH-CH(CH 2-C 6H5)-COOC(CH 3)3 HHH 351.45 (-) 22.00, c=0.25 71. 0 C22 H25 NO 3 _ 5 NH-CH(CH 2-C 6H4 -F-m)-COOCH 3 HHH 327.35 (-) 44.27, c=0.13 77. 1 C19 H18 NO 3F _ 6 NH-CH(CH 2-C 6H4 -OH-p)-COOCH 3 HHH 309.36 (-) 28.19, c=0.19 40. 5 C19 H19 NO 3 _ 7 NH-CH(CH 3)-COOC(CH 3)3 OCH 3 OH H 321.37 (+) 41.86, c=0.43 55. 0 C17 H23 NO 5 _ 8 NH-CH(CH(CH 3)2)-COOCH 3 OCH 3 OH H 307.35 (+) 10.00, c=0.31 41. 0 C16 H21 NO 5 _ 9 NH-CH(CH 2-CH(CH 3)2)-COOCH 3 OCH 3 OH H 321.37 (-) 5.83, c=1.00 34. 0 C17 H23 NO 5 _ 10 NH-CH(CH 2-C 6H5)-COOC(CH 3)3 OCH 3 OH H 397.47 (-) 20.83, c=0.36 45. 0 C23 H27 NO 5 _ 11 NH-CH(CH 2-C 6H4 -F-m)-COOCH 3 OCH 3 OH H 373.38 (-) 24.17, c=0.20 62. 6 C20 H20 NO 5F _ 12 NH-CH(CH 2-C 6H4 -OH-p)-COOCH 3 OCH 3 OH H 371.39 (-) 28.74, c=3.25 62. 0 C20 H21 NO 6 13 OCH 3 OH H 319.35 (-) 26.25, c=0.47 24.8 OC H N 2 5 OC H N 2 5 O O C17 H21 NO 5 _ 14 NH-CH(CH 2-C 6H5)-COOC(CH 3)3 OCH 3 OH OCH 3 427.50 (-) 11.35, c=2.42 47. 1 C24 H29 NO 6 _ 15 NH-CH(CH 2-C 6H4 -F-m)-COOCH 3 OCH 3 OH OCH 3 403.41 (-) 91.76, c=0.17 28. 9 C21 H22 NO 6F _ 16 NH-CH(CH 2-C 6H4 -OH-p)-COOCH 3 OCH 3 OH OCH 3 400.41 (-) 36.75, c=0.42 40. 5 C21 H22 NO 7 17 OCH 3 OH OCH 3 348.37 (-) 8.62, c=0.29 31. 0 OC H N 2 5 O C18 H23 NO 6 The three step synthesis of N-alkylcinnamoyl amides are summarized in the Sch. 1. 7 Faculty of Mathematics& Natural Sciences – FMNS 2007 O O i Br + NH2-R Br OH NHR O 3R ii H O 1R 3 R 2 NHR R Br + Ph PCH CONHR 1R iii 3 2 2 R 21, 23, 24, 26-36 Sch. 1. As it is shown in Tab. 2 the advantage of the microwave accelerated Wittig reaction is a short time (10 min). Some of the synthesized hydroxycinnamoyl amides were tested for their antiradical activity by DPPH* tests. All sinapoyl alkylamides are more active than the feruloyl amides. The results obtained demonstrated two times lower activity of the obtained amides than the free hydroxycinnamic acids. From the literature it is known that the alkaloid glaucine possesses radical scavenging activity. We modified the glaucine by introduction of amino group and connection of this function with cinnamoyl residue as shown in Sch. 2. Interesting biological activity could be expected for this new molecules combining two different parts, everyone of which posseses antioxidant properties. 8 Section: CHEMISTRY Reaction time Yields, % № 1 2 3 R R R R b c a b c а (h) (h) (min) 1H-NMR GC-MS E:Z E:Z _ _ 58.1 _ _ 18 (CH 2)3CH 3 H H H HBTU, (5) _ _ 64.4 _ _ 19 (CH 2)5CH 3 H H H HBTU, (5) _ _ 24.5 _ _ 20 (CH 2)6CH 3 H H H HBTU, (5) 52.6 50.0 30.1 21 (CH 2)3CH 3 OH OCH 3 H HBTU, (5) 13.00 10 _ _ 61.0 _ _ 22 (CH 2)5CH 3 OH OCH 3 H HBTU, (5) 33.7 42.9 25.9 23 (CH 2)6CH 3 OH OCH 3 H HBTU, (5) 13 10 35.7 49.3 36.4 24 (CH 2)3CH 3 OH OCH 3 OCH 3 EDC/HOBt, (22) 55.30 10 _ _ 18.3 _ _ 25 (CH 2)5CH 3 OH OCH 3 OCH 3 EDC/HOBt, (22) 38.6 69.9 23.4 26 (CH 2)6CH 3 OH OCH 3 OCH 3 EDC/HOBt, (22) 13 10 __ _ _ 48.1 5:1 3:1 27 (CH 2)3CH 3 OCH 3 OH H 10 __ _ _ 46.6 5:1 2:1 28 (CH 2)6CH 3 OCH 3 OH H 10 _ _ 37.3 68.2 7:1 4:1 29 (CH 2)3CH 3 OCH 3 OCH 3 H 55.30 10 _ 55.30 _ 41.7 87.5 7:1 4:1 30 (CH 2)6CH 3 OCH 3 OCH 3 H 10 _ _ 87.5 63.6 2.5:1 1.5:1 31 (CH 2)3CH 3 OCH 3 OCH 3 OCH 3 55.30 10 _ _ 40.0 83.9 4:1 1.5:1 32 (CH 2)6CH 3 OCH 3 OCH 3 OCH 3 13 10 __ _ _ 70.7 4:1 2:1 33 (CH 2)3CH 3 H OCH 2O 10 __ _ _ 91.7 6:1 4:1 34 (CH 2)6CH 3 H OCH 2O 10 __ _ _ 45.7 8:1 5:1 35 (CH 2)3CH 3 H OH H 10 __ 10 _ _ 64.2 20:1 11:1 36 (CH 2)6CH 3 H OH H Tab.
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