Naringenin, Helichrysin A: Characterization, isolation, molecular docking studies and enzyme inhibitory profiles for carbonic anhydrase, acetylcholinesterase, and α-glycosidase

Year 2025, Volume: 29 Issue: 3, 1198 - 1208, 04.06.2025

Leyla Güven , Adem Ertürk , İlhami Gülçin

https://doi.org/10.12991/jrespharm.1694383

https://izlik.org/JA24XE94FY

Abstract

In the current study, Naringenin and Helichrysin A purified and characterized from Helichrysum plicatum subsp. pseudoplicatum. The inhibitory effects of isolated Naringenin and Helichrysin A were tested against human carbonic anhydrase I (hCA I) and II isoenzymes (hCA II), α-glycosidase (α-gly) and acetylcholinesterase (AChE). Naringenin and Helichrysin A’s Ki values were found to respectively 51.99±2.78 and 75.75±13.66 nM against hCA I, 36.16±2.02 and 96.81±12.46 nM against hCA II, 0.74±0.04 and 1.27±0.16 nM against AChE, 8.34±1.61 and 9.58±1.90 nM against α-gly. As a result, the inhibitory effects of the isolated compounds against each metabolic enzyme examined were demonstrated. Moreover, in the molecular docking study of Helichrysin A, it was observed that the three enzymes had the lowest binding free energy and maximum binding affinity. Helichrysin A and Naringenin show promise as treatments for conditions including epilepsy, leukemia, diabetes mellitus, glaucoma, and Alzheimer's disease.

Keywords

Enzyme inhibition , Helichrysin A , Molecular docking , Naringenin

References

• [1] Erbaş S, Erdoğan Ü, Mutlucan M. The Scent compounds of immortelle ecotypes (Helichrysum italicum (Roth) G. Don.) grown in Türkiye and its new products (absolute and concrete). S Afr J Bot. 2023; 158: 301-311. https://doi.org/10.1016/j.sajb.2023.05.029
• [2] Albayrak S, Aksoy A, Sagdic O, Hamzaoglu E. Compositions, antioxidant and antimicrobial activities of Helichrysum (Asteraceae) species collected from Turkey. Food Chem. 2010; 119 (1): 114-122. https://doi.org/10.1016/j.foodchem.2009.06.003
• [3] Vural A. Gold and silver content of plant Helichrysum arenarium, popularly known as the golden flower, growing in Gümüşhane, NE Turkey. Acta Phys Pol A. 2017; 132 (3): 978-980. https://doi.org/10.12693/APhysPolA.132.978
• [4] Antunes Viegas D, Palmeira-de-Oliveira A, Salgueiro L, Martinez-de-Oliveira J, Palmeira-de-Oliveira R. Helichrysum italicum: From traditional use to scientific data. J Ethnopharmacol. 2014; 151 (1): 54-65. https://doi.org/10.1016/j.jep.2013.11.005
• [5] Pljevljakušić D, Bigović D, Janković T, Jelačić S, Šavikin K. Sandy everlasting (Helichrysum arenarium (L.) Moench): Botanical, chemical and biological properties. Front Plant Sci. 2018; 9: 1123. https://doi.org/10.3389/fpls.2018.01123
• [6] Akaberi M, Sahebkar A, Azizi N, Emami SA. Everlasting flowers: Phytochemistry and pharmacology of the genus Helichrysum. Ind Crops Prod. 2019; 138. https://doi.org/10.1016/j.indcrop.2019.111471
• [7] Maksimovic S, Tadic V, Skala D, Zizovic I. Separation of phytochemicals from Helichrysum italicum: An analysis of different isolation techniques and biological activity of prepared extracts. Phytochemistry. 2017; 138: 9-28. https://doi.org/10.1016/j.phytochem.2017.01.001
• [8] Süntar I, Küpeli Akkol E, Keles H, Yesilada E, Sarker SD. Exploration of the wound healing potential of Helichrysum graveolens (Bieb.) Sweet: Isolation of apigenin as an active component. J Ethnopharmacol. 2013; 149 (1): 103-110. https://doi.org/10.1016/j.jep.2013.06.006
• [9] Sarfaraj Hussain M, Azam F, Ahmed Eldarrat H, Haque A, Khalid M, Zaheen Hassan M, et al. Structural, functional, molecular, and biological evaluation of novel triterpenoids isolated from Helichrysum stoechas (L.) Moench. Collected from Mediterranean Sea bank: Misurata- Libya. Arab J Chem. 2022; 15 (6): 103818. https://doi.org/10.1016/j.arabjc.2022.103818
• [10] Nono HW, Donfack Nanfack AR, Tchegnitegni BT, Njanpa Ngansop CA, Mafodong Dongmo FL, Awouafack MD, Fekam Boyom F, Ndjakou BL, Stammler HG, Neumann B, Sewald N, Ngouela SA. Foetidumins A-D, and other chemical constituents from Helichrysum foetidum (L.) Moench (Asteraceae) with antiparasite activity. Phytochemistry. 2023;210:113672. https://doi.org/10.1016/j.phytochem.2023.113672
• [11] Akinfenwa AO, Sagbo IJ, Makhaba M, Mabusela WT, Hussein AA. Helichrysum genus and compound activities in the management of diabetes mellitus. Plants. 2022; 11 (10): 1386. https:// doi.org/10.3390/plants11101386
• [12] Les F, Venditti A, Cásedas G, Frezza C, Guiso M, Sciubba F, Serafini M, Bianco A, Valero MS, Lopez V. Everlasting flower (Helichrysum stoechas Moench) as a potential source of bioactive molecules with antiproliferative, antioxidant, antidiabetic and neuroprotective properties. Ind Crops Prod. 2017; 108: 295-302. https://doi.org/10.1016/j.indcrop.2017.06.043
• [13] Arifah FH, Nugroho AE, Rohman A, Sujarwo W. A review of medicinal plants for the treatment of diabetes mellitus: The case of Indonesia. S Afr J Bot. 2022; 149: 537-558. https://doi.org/10.1016/j.sajb.2022.06.042
• [14] Taslimi P, Akıncıoglu H, Gülçin İ. Synephrine and phenylephrine act as α-amylase, α-glycosidase, acetylcholinesterase, butyrylcholinesterase, and carbonic anhydrase enzymes inhibitors. J Biochem Mol Tox. 2017; 31 (11): e21973. https://doi.org/10.1002/jbt.21973
• [15] Ozden EM, Bingol Z, Mutlu M, Karagecili H, Köksal E, Goren AC, Alwasel SH, Gulcin I. Antioxidant, antiglaucoma, anticholinergic, and antidiabetic effects of kiwifruit (Actinidia deliciosa) oil: Metabolite profile analysis using LC-HR/MS, GC/MS and GC-FID. Life. 2023; 13 (9): 1939. https://doi.org/10.3390/life13091939
• [16] He Z, King GL. Microvascular complications of diabetes. Endocrinol Metab Clin. 2004; 33 (1): 215-238. https://doi.org/10.1016/j.ecl.2003.12.003 [17] Bailey CJ. Metformin: Historical overview. Diabetologia. 2017; 60 (9): 1566-1576. https://doi.org/10.1007/s00125-017-4318-z
• [18] Taqui R, Debnath M, Ahmed S, Ghosh A. Advances on plant extracts and phytocompounds with acetylcholinesterase inhibition activity for possible treatment of Alzheimer's disease. Phytomedicine Plus. 2022; 2 (1): 100184. https://doi.org/10.1016/j.phyplu.2021.100184
• [19] Taslimi P, Köksal E, Gören AC, Bursal E, Aras A, Kılıç Ö, Alwasel S, Gülçin I. Anti-Alzheimer, antidiabetic and antioxidant potential of Satureja cuneifolia and analysis of its phenolic contents by LC-MS/MS. Arab J Chem. 2020; 13 (3): 4528-4537. https://doi.org/10.1016/j.arabjc.2019.10.002
• [20] Durmaz L, Karagecili H, Gulcin İ. Evaluation of carbonic anhydrase, acetylcholinesterase, butyrylcholinesterase, and α-glycosidase inhibition effects and antioxidant activity of baicalin hydrate. Life. 2023; 13 (11): 2136. https://doi.org/10.3390/life13112136
• [21] Kucukoglu K, Gul HI, Taslimi P, Gulcin I, Supuran CT. Investigation of inhibitory properties of some hydrazone compounds on hCA I, hCA II and AChE enzymes. Bioorg Chem. 2019; 86: 316-321. https://doi.org/10.1016/j.bioorg.2019.02.008
• [22] Karageçili H, İzol E, Kireçci E, Gülçin İ. Antioxidant, antidiabetic, antiglaucoma, and anticholinergic effects of Tayfi grape (Vitis vinifera): A phytochemical screening by LC-MS/MS analysis. Open Chem. 2023; 21 (1). https://doi.org/10.1515/chem-2023-0120
• [23] Taslimi P, Gulçin İ. Antioxidant and anticholinergic properties of olivetol. J Food Biochem. 2018; 42 (3): e12516. https://doi.org/10.1111/jfbc.12516
• [24] Turkan F, Cetin A, Taslimi P, Karaman M, Gulçin İ. Synthesis, biological evaluation and molecular docking of novel pyrazole derivatives as potent carbonic anhydrase and acetylcholinesterase inhibitors. Bioorg Chem. 2019; 86: 420-427. https://doi.org/10.1016/j.bioorg.2019.02.013
• [25] Tokalı FS, Taslimi P, Tuzun B, Karakuş A, Sadeghian N, Gulçin İ. Novel quinazolinone derivatives: potential synthetic analogs for the treatment of glaucoma, alzheimer's disease and diabetes mellitus. Chem Biodivers. 2023; 20 (10): e202301134. https://doi.org/10.1002/cbdv.202301134
• [26] Olsen HT, Stafford GI, van Staden J, Christensen SB, Jäger AK. Isolation of the MAO-inhibitor naringenin from Mentha aquatica L. J Ethnopharmacol. 2008; 117 (3): 500-502. https://doi.org/10.1016/j.jep.2008.02.015
• [27] Maltese F, Erkelens C, Kooy Fvd, Choi YH, Verpoorte R. Identification of natural epimeric flavanone glycosides by NMR spectroscopy. Food Chem. 2009; 116 (2): 575-579. https://doi.org/10.1016/j.foodchem.2009.03.023
• [28] Salehi B, Fokou PVT, Sharifi-Rad M, Zucca P, Pezzani R, Martins N, Shaifi-Rad J. The therapeutic potential of naringenin: a review of clinical trials. Pharmaceuticals. 2019; 12 (1): 11. https://doi.org/10.3390/ph12010011
• [29] Zeng W, Jin L, Zhang F, Zhang C, Liang W. Naringenin as a potential immunomodulator in therapeutics. Pharmacol Res. 2018; 135: 122-126. https://doi.org/10.1016/j.phrs.2018.08.002
• [30] Jung HA, Park JJ, Min BS, Jung HJ, Islam MN, Choi JS. Inhibition of advanced glycation endproducts formation by Korean thistle, Cirsium maackii. Asian Pac J Trop Med. 2015; 8 (1): 1-5. https://doi.org/10.1016/S1995-7645(14)60178-4
• [31] Kiziltas H, Bingol Z, Goren AC, Pinar SM, Ortaakarsu AB, Alwasel SH, Gülçin I. Comprehensive metabolic profiling of Acantholimon caryophyllaceum using LC–HRMS and evaluation of antioxidant activities, enzyme inhibition properties and molecular docking studies. S Afr J Bot. 2022; 151: 743-755. https://doi.org/10.1016/j.sajb.2022.10.048
• [32] Durmaz L, Kiziltas H, Guven L, Karagecili H, Alwasel S, Gulcin İ. Antioxidant, antidiabetic, anticholinergic, and antiglaucoma effects of magnofluorine. Molecules. 2022; 27 (18): 5902. https://doi.org/10.3390/molecules27185902
• [33] Şentürk M, Gülçin İ, Beydemir Ş, Küfrevioğlu Öİ, Supuran CT. In vitro inhibition of human carbonic anhydrase i and ii isozymes with natural phenolic compounds. Chem Biol Drug Des. 2011; 77 (6): 494-499. https://doi.org/10.1111/j.1747-0285.2011.01104.x
• [34] Aydin T. Secondary metabolites of Helichrysum plicatum DC. subsp. plicatum flowers as strong carbonic anhydrase, cholinesterase and α-glycosidase inhibitors. Z Naturforsch C 2020; 75 (5-6): 153-159. https://doi.org/10.1515/znc-2020-0026
• [35] Liu MY, Zeng F, Shen Y, Wang YY, Zhang N, Geng F. Bioguided isolation and structure identification of acetylcholinesterase enzyme inhibitors from Drynariae rhizome. J Anal Metod Chem. 2020; 2971841. https://doi.org/10.1155/2020/2971841.
• [36] Acet T, Ozcan K, Zengin G. An assessment of phenolic profiles, fatty acid compositions, and biological activities of two Helichrysum species: H. plicatum and H. chionophilum. J Food Biochem. 2020; 44 (2): e13128. https://doi.org/10.1111/jfbc.13128
• [37] Meng XY, Zhang HX, Mezei M, Cui M. Molecular docking: A powerful approach for structure-based drug discovery. Curr Comput Aided Drug Des. 2011; 7 (2): 146-157. https://doi.org/10.2174/157340911795677602
• [38] Hata H, Phuoc Tran D, Marzouk Sobeh M, Kitao A. Binding free energy of protein/ligand complexes calculated using dissociation Parallel Cascade Selection Molecular Dynamics and Markov state model. Biophys Physicobiol 2021; 18: 305-316. https://doi.org/10.2142/biophysico.bppb-v18.037
• [39] Lolak N, Akocak S, Türkeş C, Taslimi P, Işık M, Beydemir Ş, Gülçin I, Durgun M. Synthesis, characterization, inhibition effects, and molecular docking studies as acetylcholinesterase, α-glycosidase, and carbonic anhydrase inhibitors of novel benzenesulfonamides incorporating 1,3,5-triazine structural motifs. Bioorg Chem. 2020; 100: 103897. https://doi.org/10.1016/j.bioorg.2020.103897
• [40] Ellman GL, Courtney KD, Andres V, Featherstone RM. A new and rapid colorimetric determination of acetylcholinesterase activity. Biochem Pharmacol. 1961; 7 (2): 88-95. https://doi.org/10.1016/0006-2952(61)90145-9
• [41] Sezer Senol F, Orhan IE, Ozgen U, Renda G, Bulut G, Guven L, Karaoğlan ES, Sevindik HG, Skalicka-Wozniak K, Koca Çalışkan U, Şekeroğlu N. Memory-vitalizing effect of twenty-five medicinal and edible plants and their isolated compounds. S Afr J Bot. 2016; 102: 102-109. https://doi.org/10.1016/j.sajb.2015.07.011
• [42] Tao Y, Zhang Y, Cheng Y, Wang Y. Rapid screening and identification of α-glucosidase inhibitors from mulberry leaves using enzyme-immobilized magnetic beads coupled with HPLC/MS and NMR. Biomed Chrom. 2013; 27 (2): 148-155. https://doi.org/10.1002/bmc.2761
• [43] Şenol H, Çelik Turgut G, Şen A, Sağlamtaş R, Tuncay S, Gülçin İ, Topçu G. Synthesis of nitrogen-containing oleanolic acid derivatives as carbonic anhydrase and acetylcholinesterase inhibitors. Med Chem Res. 2023; 32 (4): 694-704. https://doi.org/10.1007/s00044-023-03031-z
• [44] Özaslan MS, Sağlamtaş R, Demir Y, Genç Y, Saraçoğlu İ, Gülçin İ. Isolation of some phenolic compounds from Plantago subulata l. and determination of their antidiabetic, anticholinesterase, antiepileptic and antioxidant activity. Chem Biodivers. 2022; 19 (8): e202200280. https://doi.org/10.1002/cbdv.202200280
• [45] Arabaci B, Gulcin I, Alwasel S. Capsaicin: a potent inhibitor of carbonic anhydrase isoenzymes. Molecules. 2014; 19 (7): 10103-10114. https://doi.org/10.3390/molecules190710103
• [46] Gulçin İ, Abbasova M, Taslimi P, Huyut Z, Safarova L, Sujayev A, Farzaliyev V, Beydemir Ş, Alwasel SH, Supuran CT. Synthesis and biological evaluation of aminomethyl and alkoxymethyl derivatives as carbonic anhydrase, acetylcholinesterase and butyrylcholinesterase inhibitors. J Enzyme Inhib Med Chem. 2017; 32 (1): 1174-1182. https://doi.org/10.1080/14756366.2017.1368019
• [47] Gök Y, Taslimi P, Şen B, Bal S, Aktaş A, Aygün M, Sadeghi M, Gülçin I. Design, synthesis, characterization, crystal structure, in silico studies, and inhibitory properties of the PEPPSI type Pd(II)NHC complexes bearing chloro/fluorobenzyl group. Bioorg Chem. 2023; 135: 106513. https://doi.org/10.1016/j.bioorg.2023.106513