Synthesis of N-phenethyl-p-methoxycinnamamide and N-morpholinyl-p-methoxycinnamamide, In Vitro and In Silico Study as α-Glucosidase Inhibitor

https://doi.org/10.22146/ijc.76802

Herlina Rasyid(1*), Firdaus Firdaus(2), Syadza Firdausiah(3), Nunuk Hariani Soekamto(4), Seniwati Seniwati(5), Riska Mardiyanti(6), Reynaldi Reynaldi(7), Andi Eka Sri Rahayu(8), Wahyu Dita Saputri(9)

(1) Department of Chemistry, Faculty of Mathematics and Natural Sciences, Hasanuddin University, Jl. Perintis Kemerdekaan km 10, Makassar 90245, South Sulawesi, Indonesia
(2) Department of Chemistry, Faculty of Mathematics and Natural Sciences, Hasanuddin University, Jl. Perintis Kemerdekaan km 10, Makassar 90245, South Sulawesi, Indonesia
(3) Department of Chemistry, Faculty of Mathematics and Natural Sciences, Hasanuddin University, Jl. Perintis Kemerdekaan km 10, Makassar 90245, South Sulawesi, Indonesia
(4) Department of Chemistry, Faculty of Mathematics and Natural Sciences, Hasanuddin University, Jl. Perintis Kemerdekaan km 10, Makassar 90245, South Sulawesi, Indonesia
(5) Department of Chemistry, Faculty of Mathematics and Natural Sciences, Hasanuddin University, Jl. Perintis Kemerdekaan km 10, Makassar 90245, South Sulawesi, Indonesia
(6) Department of Chemistry, Faculty of Mathematics and Natural Sciences, Hasanuddin University, Jl. Perintis Kemerdekaan km 10, Makassar 90245, South Sulawesi, Indonesia
(7) Department of Chemistry, Faculty of Mathematics and Natural Sciences, Hasanuddin University, Jl. Perintis Kemerdekaan km 10, Makassar 90245, South Sulawesi, Indonesia
(8) Department of Chemistry, Faculty of Mathematics and Natural Sciences, Hasanuddin University, Jl. Perintis Kemerdekaan km 10, Makassar 90245, South Sulawesi, Indonesia
(9) Research Center for Quantum Physics, National Research and Innovation Agency (BRIN), Habibie Science and Technology Complex (Puspiptek), Serpong 15314, South Tangerang, Indonesia
(*) Corresponding Author

Abstract


Aromatic ginger (Kaempferia galanga L.) is one of the natural sources containing ethyl-p-methoxycinnamate, which is known to have beneficial activity, especially as an α-glucosidase inhibitor. This study aims to convert ethyl-p-methoxycinnamate into amide form as N-phenethyl-p-methoxycinnamamide (4a) and N-morpholinyl-p-methoxycinnamamide (4b) through some synthetic ways then tested their activity as an α-glucosidase inhibitor. The FTIR spectra of 4a present a short single peak at 3269.34 cm−1 that belongs to the N-H group, while spectra of 4b show no absorption band between 3200–3400 cm−1 due to its tertiary amide structure. Spectroscopy analysis through 1H- and 13C-NMR exhibits the successful synthesis of both compounds. Bioactivity test results show that compound 4b has better activity than 4a. In molecular dynamics simulation, the binding energy of compounds 4a and 4b reveal that both compounds have a similar binding energy of about -98980.8 and -97696.7 kJ mol−1, respectively.


Keywords


aromatic ginger (Kaempferia galanga L.); cinnamamide derivatives; α-glucosidase inhibitor; molecular docking; MD simulation

Full Text:

Full Text PDF


References

[1] Hakim, A., Andayani, Y., and Rahayuan D.R., 2018, Isolation of ethyl-p-methoxy cinnamate from Kaemferia galanga L, J. Phys.: Conf. Ser., 1095 (1), 012039.

[2] Singh, S., Sahoo, S., Sahoo, B.C., Kar, B., Dash, M., Nayak, S., and Kar, B., 2022, Derivatives of cinnamic acid esters and terpenic diversity in volatiles of thirty-six sand ginger (Kaempferia galanga L.) accessions of Eastern India revealing quality chemovars, Molecules, 27 (3), 1116.

[3] Wisetsai, A., Schevenels, F.T., Kanokmedhakul, S., Kanokmedhakul, K., Boonmak, J., Youngme, S., Suebrasri, T., and Lekphrom, R., 2021, Isopimarane-type diterpenoids from the rhizomes of Kaempferia galanga L. and their biological activities, Nat. Prod. Res., 1–10.

[4] Elshamy, A.I., Mohamed, T.A., Swapana, N., Ahmed, R.F., Yoneyama, T., Paré, P.W., Noji, M., Hegazy, M.E.F., and Umeyama, A., 2021, Two new diterpenoids from kencur (Kaempferia galanga): Structure elucidation and chemosystematic significance, Phytochem. Lett., 44, 185–189.

[5] Raina, A.P., and Abraham, Z., 2016, Chemical profiling of essential oil of Kaempferia galanga L. germplasm from India, J. Essent. Oil Res., 28 (1), 29–34.

[6] Firdaus, F., Soekamto, N.H., Seniwati, S., Firdausiah, S., Rasyid, H., Bahja, B., and Islam, M.F., 2021, Phenethyl p-coumarate and N-Phenethyl-p-coumaramide: Synthesis, characterization. docking studies, and anticancer activity through P388 cell, Sains Malays., 51 (4), 1085–1097.

[7] Firdaus, F., Seniwati, S., Alamsyah, N., and Paramita, S., 2019, Synthesis and activity of N-(o-tolyl)caffeamide and N-(o-tolyl)-p-coumaramide against P388 leukemia murine cells, J. Phys.: Conf. Ser., 1341, 032005.

[8] Zenta, F., Soekamto, N.H., Dali, S., Firdausiah, S., Rasyid, H., Bahriah, B., Agustan, A., and Tahir, D., 2022, Development trans-N-benzyl hydroxyl cinnamamide based compounds from cinnamic acids and characteristics anticancer potency, J. Iran. Chem. Soc., 19, 2845–2853.

[9] Umar, M.I., Asmawi, M.Z., Sadikun, A., Atangwho, I.J., Yam, M.F., Altaf, R., and Ahmed, A., 2012, Bioactivity-guided isolation of ethyl-p-methoxycinnamate, an anti-inflammatory constituent, from Kaempferia galanga L. extracts, Molecules, 17 (7), 8720–8734.

[10] Komala, I., Supandi, S., Nurhasni, N., Betha, O.S., Putri, E., Mufidah, S., Awaludin, M.F., Fahmi, M., Reza, M., and Indriyani, N.P., 2018, Structure-activity relationship study on the ethyl p-methoxycinnamate as an anti-inflammatory agent, Indones. J. Chem., 18 (1), 60–65.

[11] Lakshmanan, D., Werngren, J., Jose, L., Suja, K.P., Nair, M.S., Varma, R.L., Mundayoor, S., Hoffner, S., and Kumar, R.A., 2011, Ethyl p-methoxycinnamate isolated from a traditional anti-tuberculosis medicinal herb inhibits drug resistant strains of Mycobacterium tuberculosis in vitro, Fitoterapia, 82 (5), 757–761.

[12] Ichwan, S.J.A., Husin, A., Suriyah, W.H., Lestari, W., Omar, M.N., and Kasmuri, A.R., 2019, Anti-neoplastic potential of ethyl-p-methoxycinnamate of Kaempferia galanga on oral cancer cell lines, Mater. Today: Proc., 16, 2115–2121.

[13] Guzman, J.D., 2014, Natural cinnamic acids, synthetic derivatives and hybrids with antimicrobial activity, Molecules, 19 (12), 19292–19349.

[14] Chowdhury, M.Z., Al Mahmud, Z., Ali, M.S., and Bachar, S.C., 2014, Phytochemical and pharmacological investigations of rhizome extracts of Kaempferia galanga, Int. J. Pharmacogn., 1 (3), 185–192.

[15] Sudatri, N.W., Wirasiti, N., Gde Bidura, I.G.N., and Suartini, N.M., 2019, Anti-diabetic and anti-cholesterol activity of Kaempferia galanga L. herbal medicine rhizome in albino rats, Int. J. Fauna Biol. Stud., 6 (5), 13–17.

[16] Adisakwattana, S., Roengsamran, S., Hsu, W.H., and Yibchok-Anun, S., 2005, Mechanisms of antihyperglycemic effect of p-methoxycinnamic acid in normal and streptozotocin-induced diabetic rats, Life Sci., 78 (4), 406–412.

[17] Adisakwattana, S., Sompong, W., Meeprom, A., Ngamukote, S., and Yibchok-anun, S., 2012, Cinnamic acid and its derivatives inhibit fructose-mediated protein glycation, Int. J. Mol. Sci., 13 (2), 1778–1789.

[18] Ernawati, T., Radji, M., Hanafi, M., Mun’im, A., and Yanuar, A., 2017, Cinnamic acid derivatives as α-glucosidase inhibitor agents, Indones. J. Chem., 17 (1), 151–160.

[19] Ernawati, T., Mun’im, A., Hanafi, M., and Yanuar, A., 2020, Synthesis of cinnamamide derivatives and their α-glucosidase inhibitory activities, Sains Malays., 49 (2), 315–322.

[20] Song, Y.H., Kim, D.W., Curtis-Long, M.J., Park, C., Son, M., Kim, J.Y., Yuk, H.J., Lee, K.W., and Park, K.H., 2016, Cinnamic acid amides from Tribulus terrestris displaying uncompetitive α-glucosidase inhibition, Eur. J. Med. Chem., 114, 201–208.

[21] Guerreiro, L.R., Carreiro, E.P., Fernandes, L., Cardote, T.A.F., Moreira, R., Caldeira, A.T., Guedes, R.C., and Burke, A.J., 2013, Five-membered iminocyclitol α-glucosidase inhibitors: Synthetic, biological screening and in silico studies, Bioorg. Med. Chem., 21 (7), 1911–1917.

[22] Khan, K.M., Rahim, F., Wadood, A., Kosar, N., Taha, M., Lalani, S., Khan, A., Fakhri, M.I., Junaid, M., Rehman, W., Khan, M., Perveen, S., Sajid, M., and Choudhary, M.I., 2014, Synthesis and molecular docking studies of potent α-glucosidase inhibitors based on biscoumarin skeleton, Eur. J. Med. Chem., 81, 245–252.

[23] Rahim, F., Zaman, K., Taha, M., Ullah, H., Ghufran, M., Wadood, A., Rehman, W., Uddin, N., Shah, S.A.A., Sajid, M., Nawaz, F., and Khan, K.M., 2020, Synthesis, in vitro alpha-glucosidase inhibitory potential of benzimidazole bearing bis-Schiff bases and their molecular docking study, Bioorg. Chem., 94, 103394.

[24] Rahman, N., Muhammad, I., Nayab, G.E., Khan, H., Aschner, M., Filosa, R., and Daglia, M., 2019, Molecular docking of isolated alkaloids for possible α-glucosidase inhibition, Biomolecules, 9 (10), 544.

[25] Mollica, A., Zengin, G., Durdagi, S., Ekhteiari Salmas, R., Macedonio, G., Stefanucci, A., Dimmito, M.P., and Novellino, E., 2019, Combinatorial peptide library screening for discovery of diverse α-glucosidase inhibitors using molecular dynamics simulations and binary QSAR models, J. Biomol. Struct. Dyn., 37 (3), 726–740.

[26] Azimi, F., Ghasemi, J.B., Azizian, H., Najafi, M., Faramarzi, M.A., Saghaei, L., Sadeghi-aliabadi, H., Larijani, B., Hassanzadeh, F., and Mahdavi, M., 2021, Design and synthesis of novel pyrazole-phenyl semicarbazone derivatives as potential α-glucosidase inhibitor: Kinetics and molecular dynamics simulation study, Int. J. Biol. Macromol., 166, 1082–1095.

[27] Kim, Y.M., Wang, M.H., and Rhee, H.I., 2004, A novel α-glucosidase inhibitor from pine bark, Carbohydr. Res., 339 (3), 715–717.

[28] Waterhouse, A., Bertoni, M., Bienert, S., Studer, G., Tauriello, G., Gumienny, R., Heer, F.T., de Beer, T.A.P., Rempfer, C., Bordoli, L., Lepore, R., and Schwede, T., 2018, SWISS-MODEL: Homology modelling of protein structures and complexes, Nucleic Acids Res., 46 (W1), W296–W303.

[29] Wang, G., Peng, Z., Wang, J., Li, X., and Li, J., 2017, Synthesis, in vitro evaluation and molecular docking studies of novel triazine-triazole derivatives as potential α-glucosidase inhibitors, Eur. J. Med. Chem., 125, 423–429.

[30] Morris, G.M., Huey, R., Lindstrom, W., Sanner, M.F., Belew, R.K., Goodsell, D.S., and Olson, A.J., 2009, AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility, J. Comput. Chem., 30 (16), 2785–2791.

[31] Pettersen, E.F., Goddard, T.D., Huang, C.C., Couch, G.S., Greenblatt, D.M., Meng, E., and Ferrin, T.E., 2004, UCSF Chimera – A visualization system for exploratory research and analysis, J. Comput. Chem., 25 (13), 1605–1612.

[32] Morris, G.M., Goodsell, D.S., Halliday, R.S., Huey, R., Hart, W.E., Belew, R.K., and Olson, A.J., 1998, Automated docking using a Lamarckian genetic algorithm and an empirical binding free energy function, J. Comput. Chem., 19 (14), 1639–1662.

[33] BIOVIA, 2019, Discovery Studio Visualizer, Dassault Systèmes, San Diego.

[34] Land, H., and Humble, M.S., 2018, YASARA: A tool to obtain structural guidance in biocatalytic investigations, Methods Mol. Biol., 1685, 43–67.

[35] Wang, J., Wolf, R.M., Caldwell, J.W., Kollman, P.A., and Case, D.A., 2004, Development and testing of a general AMBER force field, J. Comput. Chem., 25 (9), 1157–1174.

[36] Dash, R., Ali, M.C., Dash, N., Azad, M.A.K., Zahid Hosen, S.M., Hannan, M.A., and Moon, I.S., 2019, Structural and dynamic characterizations highlight the deleterious role of SULT1A1 R213H polymorphism in substrate binding, Int. J. Mol. Sci., 20 (24), 6256.

[37] Mark, P., and Nilsson, L., 2001, Structure and dynamics of the TIP3P, SPC, and SPC/E water models at 298 K, J. Phys. Chem. A, 105 (43), 9954–9960.

[38] Umar, M.I., Asmawi, M.Z., Sadikun, A., Majid, A.M.S.A., Al-Suede, F.S.R., Hassan, L.E.A., Altaf, R., and Ahamed, M.B.K., 2014, Ethyl-p-methoxycinnamate isolated from Kaempferia galanga inhibits inflammation by suppressing interleukin-1, tumor necrosis factor-α, and angiogenesis by blocking endothelial functions, Clinics, 69 (2), 134–144.

[39] El-Gogary, T.M., and Soliman, M.S., 2001, Ab-Initio molecular geometry and normal coordinate analysis of pyrrolidine molecule, Spectrochim. Acta, Part A, 57 (13), 2647–2657.

[40] Firdaus, F., Soekamto, N.H., Firdausiah, S., Rasyid, H., Asmi, N., and Waleulu, M., 2021, Novel hydroxycinnamamide from morpholine and pyrrolidine: Synthesis, characterization, docking study, and anticancer activity against P388 leukemia murine cells, J. Appl. Pharm. Sci., 11 (01), 40–48.

[41] Firdaus, F., Husain, D.R., Naid, T., Seniwati, S., Soekamto, N.H., Sumarna, S., and Islam, M.F., 2017, Synthesis of piperidine and morpholine amides of ferulic acid and their bioactivity against P-388 leukemia cells, Int. J. ChemTech. Res., 10 (1), 27–33.

[42] Ernawati, T., Mun’im, A., Hanafi, M., and Yanuar, A., 2017, Design of cinnamic acid derivatives and molecular docking toward human-neutral a-glucosidase by using homology modeling, Orient. J. Chem., 33 (5), 2249–2256.

[43] Yamamoto, E., Akimoto, T., Mitsutake, A., and Metzler, R., 2021, Universal relation between instantaneous diffusivity and radius of gyration of proteins in aqueous solution, Phys. Rev. Lett., 126 (12), 128101.

[44] Miller, B.R., Mcgee, T.D., Swails, J.M., Homeyer, N., Gohlke, H., and Roitberg, A.E., 2012, MMPBSA.py: An efficient program for end-state free energy calculations, J. Chem. Theory Comput., 8 (9), 3314–3321.



DOI: https://doi.org/10.22146/ijc.76802

Article Metrics

Abstract views : 2301 | views : 1484


Copyright (c) 2022 Indonesian Journal of Chemistry

Creative Commons License
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.

 


Indonesian Journal of Chemistry (ISSN 1411-9420 /e-ISSN 2460-1578) - Chemistry Department, Universitas Gadjah Mada, Indonesia.

Web
Analytics View The Statistics of Indones. J. Chem.