Synthesis and Biological Activity of Brominated Phenols with Lactamomethyl Moieties --- Natural Compounds Analogues

Authors: Vorobyev S.V., Starostin A.A., Vasilieva B.F., Efremenkova O.V., Primerova O.V., Koshelev V.N. Published: 17.12.2023
Published in issue: #6(111)/2023  
DOI: 10.18698/1812-3368-2023-6-134-146

Category: Chemistry | Chapter: Organic Chemistry  
Keywords: polyphenols, brominated compounds, natural compounds analogues, antibacterial activity


This paper describes the synthesis of the brominated polyphenols with lactams fragments, which are analogues of natural marine compounds, and their biological activity research. Eight target substances were obtained with good yields via bromination of pyrrolidone and caprolactam derivatives of catechol, resorcinol, pyrogallol, phloroglucinol and propyl gallate by bromine in acetic acid or dioxane dibromide. The structures of all the obtained compounds were proved using IR spectroscopy and 1H- and 13C-NMR spectrometry, and, for several compounds, by mass-spectroscopy. The composition of the target substances was confirmed using elemental analysis. For the first time it was shown that dioxane dibromide can form polybrominated aromatic derivatives, while the reaction proceeds also in ortho-position to hydroxyl groups. Results of antimicrobial activity research against various pathogenic organisms (both Gram-negative and Gram-positive, together with fungus) revealed that, among all compounds, only 1-(3,5-dibromo-2,4-dihydroxyben-zyl)pyrrolidin-2-one displayed antibacterial activity against Staphylococcus epidermidis INA 01254 with minimum inhibitory concentration equals to 16 µg/ml

Please cite this article as:

Vorobyev S.V., Starostin A.A., Vasilieva B.F., et al. Synthesis and biological activity of brominated phenols with lactamomethyl moieties --- natural compounds analogues. Herald of the Bauman Moscow State Technical University, Series Natural Sciences, 2023, no. 6 (111), pp. 134--146. DOI: https://doi.org/10.18698/1812-3368-2023-6-134-146


[1] Xu X., Song F., Fan X., et al. A novel bromophenol from marine red alga Symphyocladia latiuscula. Chem. Nat. Compd., 2009, vol. 45, no. 6, pp. 811--813. DOI: https://doi.org/10.1007/s10600-010-9501-0

[2] Etahiri S., El Kouria A.K., Bultel-Ponce V., et al. Antibacterial bromophenol from the marine red alga Pterosiphonia complanata. Nat. Prod. Commun., 2007, vol. 2, no. 7, pp. 749--752. DOI: https://doi.org/10.1177/1934578x0700200708

[3] Choi J.S., Park H.J., Jung H.A., et al. A cyclohexanonyl bromophenol from the red alga Symphyocladia latiuscula. J. Nat. Prod., 2000, vol. 63, iss. 12, pp. 1705--1706. DOI: https://doi.org/10.1021/np0002278

[4] Li K., Li X.-M., Gloer J.B., et al. Isolation, characterization, and antioxidant activity of bromophenols of the marine red alga Rhodomela confervoides. J. Agric. Food Chem., 2011, vol. 59, iss. 18, pp. 9916--9921. DOI: https://doi.org/10.1021/jf2022447

[5] Lee J.-H., Park S.E., Hossain M.A., et al. 2,3,6-Tribromo-4,5-dihydroxybenzyl Methyl Ether Induces Growth inhibition and apoptosis in MCF-7 human breast cancer cells. Arch. Pharm. Res., 2007, vol. 30, no. 9, pp. 1132--1137. DOI: https://doi.org/10.1007/bf02980248

[6] Liu M., Zhang W., Wei J., et al. Marine bromophenol bis(2,3-dibromo-4,5-dihydro-xybenzyl) ether, induces mitochondrial apoptosis in K562 cells and inhibits topoisomerase I in vitro. Toxicol. Lett., 2012, vol. 211, iss. 2, pp. 126--134. DOI: https://doi.org/10.1016/j.toxlet.2012.03.771

[7] Rajasulochana P., Krishnamoorthy P., Dhamotharan R. Isolation, identification of bromophenol compound and antibacterial activity of Kappaphycus sp. Int. J. Pharm. Biol. Sci., 2012, vol. 3, pp. 173--186.

[8] Xu X., Yin L., Gao J., et al. Antifungal bromophenols from marine red alga Symphyocladia latiuscula. Chem. Biodivers., 2014, vol. 45, iss. 45, pp. 807--811. DOI: https://doi.org/10.1002/chin.201445230

[9] Oh K.-B., Lee J.H., Chung S.-C., et al. Antimicrobial activities of the bromophenols from the red alga Odonthalia corymbifera and some synthetic derivatives. Bioorg. Med. Chem. Lett., 2008, vol. 18, no. 1, pp. 104--108. DOI: https://doi.org/10.1016/j.bmcl.2007.11.003

[10] Ilyasov I.R., Beloborodov V.L., Selivanova I.A., et al. ABTS/PP decolorization assay of antioxidant capacity reaction pathways. Int. J. Mol. Sci., 2020, vol. 21, iss. 3, art. 1131. DOI: https://doi.org/10.3390/ijms21031131

[11] Kicklighter C., Kubanek J., Hay M. Do brominated natural products defend marine worms from consumers? Some do, most don’t. Limnol. Oceanogr., 2004, vol. 49, iss. 2, pp. 430--441. DOI: https://doi.org/10.4319/lo.2004.49.2.0430

[12] Negrebetsky V., Vorobyev S., Kramarova E., et al. Lactamomethyl derivatives of diphenols: synthesis, structure, and potential biological activity. Russ. Chem. Bull., 2018, vol. 67, no. 8, pp. 1518--1529. DOI: https://doi.org/10.1007/s11172-018-2250-0

[13] Vorobyev S.V., Primerova O.V., Ivanova L.V., et al. Facile synthesis of phenolic derivatives, containig lactamomethyl substituents. Izvestiya vysshikh uchebnykh zavedenii. Khimiya i khimicheskaya tekhnologiya [ChemChemTech], 2019, vol. 62, no. 10, pp. 40--48 (in Russ.). DOI: https://doi.org/10.6060/ivkkt.20196210.5930

[14] Singh I.P., Bharate S.B. Phloroglucinol compounds of natural origin. Nat. Prod. Rep., 2006, vol. 23, iss. 4, pp. 558--591. DOI: https://doi.org/10.1039/b600518g

[15] Chen M., Shao C.-L., Fu X.-M., et al. Bioactive indole alkaloids and phenyl ether derivatives from a marine-derived Aspergillus sp. fungus. J. Nat. Prod., 2013, vol. 76, iss. 4, pp. 547--553. DOI: https://doi.org/10.1021/np300707x

[16] Taslimi P., Aslan H.E., Demir Y., et al. Diarylmethanon, bromophenol and diarylmethane compounds: discovery of potent aldose reductase, α-amylase and α-glycosidase inhibitors as new therapeutic approach in diabetes and functional hyperglycemia. Int. J. Biol. Macromol., 2018, vol. 119, pp. 857--863. DOI: https://doi.org/10.1016/j.ijbiomac.2018.08.004

[17] Oztaskin N., Taslimi P., Maras A., et al. Novel antioxidant bromophenols with acetylcholinesterase, butyrylcholinesterase and carbonic anhydrase inhibitory actions. Bioorg. Chem., 2017, vol. 74, pp. 104--114. DOI: https://doi.org/10.1016/j.bioorg.2017.07.010

[18] Rezai M., Bayrak C., Taslimi P., et al. The first synthesis and antioxidant and anticholinergic activities of 1-(4,5-dihydroxybenzyl) pyrrolidin-2-one derivative bromophenols including natural products. Turk. J. Chem., 2018, vol. 42, no. 3, pp. 808--825. DOI: https://doi.org/10.3906/kim-1709-34

[19] Bellucci G., Bianchini R., Chiappe C., et al. Reversibility of bromonium ion formation and its effect on olefin reactivity in electrophilic bromination. New evidence from the 5H-dibenz[b,f]azepine system. J. Am. Chem. Soc., 1988, vol. 110, iss. 2, pp. 546--552. DOI: https://doi.org/10.1021/ja00210a039

[20] Caldwell S.T., Petersson H.M., Farrugia L.J., et al. Isotopic labelling of quercetin 3-glucoside. Tetrahedron, 2006, vol. 62, iss. 31, pp. 7257--7265. DOI: https://doi.org/10.1016/j.tet.2006.05.046

[21] Wischang D., Radlow M., Hartung J. Vanadate-dependent bromoperoxidases from Ascophyllum nodosum in the synthesis of brominated phenols and pyrroles. Dalton Trans., 2013, vol. 42, iss. 33, pp. 11926--11940. DOI: https://doi.org/10.1039/c3dt51582f

[22] Nath J., Chaudhuri M.K. Boric acid catalyzed bromination of a variety of organic substrates: an eco-friendly and practical protocol. Green Chem. Lett. Rev., 2008, vol. 1, iss. 4, pp. 223--230. DOI: https://doi.org/10.1080/17518250902758887

[23] Chaudhuri S.K., Roy S., Bhar S. Dioxane dibromide mediated bromination of substituted coumarins under solvent-free conditions. Beilstein J. Org. Chem., 2012, vol. 8, no. 1, pp. 323--329. DOI: https://doi.org/10.3762/bjoc.8.35

[24] Korsakova I.Y., Safonova O., Ageeva O., et al. Adamantylphenols. II. Synthesis and antiviral activity of brominated hydroquinones and quinones containing an adamantyl substituent. Pharm. Chem. J., 1982, vol. 16, no. 2, pp. 127--130. DOI: https://doi.org/10.1007/bf00762033

[25] Chaudhuri S.K., Roy S., Saha M., et al. Regioselective aromatic electrophilic bromination with dioxane dibromide under solvent‐free conditions. Synth. Commun., 2007, vol. 37, no. 4, pp. 579--583. DOI: https://doi.org/10.1080/00397910601055081

[26] Kikushima K., Moriuchi T., Hirao T. Vanadium-catalyzed oxidative bromination promoted by Bronsted acid or Lewis acid. Tetrahedron, 2010, vol. 66, iss. 34, pp. 6906--6911. DOI: https://doi.org/10.1016/j.tet.2010.06.042

[27] Boruah J.J., Das S.P., Borah R., et al. Polymer-anchored peroxo compounds of molybdenum and tungsten as efficient and versatile catalysts for mild oxidative bromination. Polyhedron, 2013, vol. 52, pp. 246--254. DOI: https://doi.org/10.1016/j.poly.2012.09.036

[28] Wiegand I., Hilpert K., Hancock R.E. Agar and broth dilution methods to determine the minimal inhibitory concentration (MIC) of antimicrobial substances. Nat. Protoc., 2008, vol. 3, no. 2, pp. 163--175. DOI: https://doi.org/10.1038/nprot.2007.521

[29] Shvedov V., Safonova O., Korsakova I.Ya., et al. Synthesis and antiviral activity of halogenated adamantylphenols. Pharm. Chem. J., 1980, vol. 14, no. 2, pp. 127--130. DOI: https://doi.org/10.1007/bf00765913

[30] Brewster C., Harris J. Some halogen derivatives of acyl and alkyl resorcinols.J. Am. Chem. Soc., 1930, vol. 52, iss. 12, pp. 4866--4872. DOI: https://doi.org/10.1021/ja01375a031

[31] Li K., Li X.-M., Gloer J.B., et al. New nitrogen-containing bromophenols from the marine red alga Rhodomela confervoides and their radical scavenging activity. Food Chem., 2012, vol. 135, no. 3, pp. 868--872. DOI: https://doi.org/10.1016/j.foodchem.2012.05.117

[32] Qin S.-G., Tian H.-Y., Wei J., et al. 3-bromo-4,5-dihydroxybenzaldehyde protects against myocardial ischemia and reperfusion injury through the Akt-PGC1α-Sirt3 pathway. Front. Pharmacol., 2018, vol. 9, art. 722. DOI: https://doi.org/10.3389/fphar.2018.00722

[33] Akyeva A.Y., Kansuzyan A.V., Vukich K.S., et al. Remote stereoelectronic effects in pyrrolidone- and caprolactam-substituted phenols: discrepancies in antioxidant properties evaluated by electrochemical oxidation and h-atom transfer reactivity. J. Org. Chem., 2022, vol. 87, iss. 8, pp. 5371--5384. DOI: https://doi.org/10.1021/acs.joc.2c00207

[34] Khandazhinskaya A.L., Alexandrova L.A., Matyugina E.S., et al. Novel 5’-norcarbo-cyclic pyrimidine derivatives as antibacterial agents. Molecules, 2018, vol. 23, iss. 12, art. 3069. DOI: https://doi.org/10.3390/molecules23123069