Sains Malaysiana 49(2)(2020): 315-322

http://dx.doi.org/10.17576/jsm-2020-4902-09

Synthesis of Cinnamamide Derivatives and Their α-Glucosidase Inhibitory Activities

(Sintesis Terbitan Sinamamida dan Aktiviti Rencatan α-Glucosidase)

TENI ERNAWATI¹*, ABDUL MUN'IM², MUHAMAD HANAFI¹ & ARRY YANUAR²

¹Research Center for Chemistry, Indonesian Institute of Sciences (LIPI), Kawasan Puspiptek, Serpong Tangerang Selatan, Banten 15314, Indonesia

²Faculty of Pharmacy, Universitas Indonesia, Depok 16242, Indonesia

Diserahkan: 5 September 2019/Diterima: 7 November 2019

ABSTRACT

Chemically, methyl trans-cinnamate offers treatment at the three main reactive sites such as substitution at the phenyl ring, addition at the α,β-unsaturation, and substitution at the carboxylic methyl ester functionality. We focus our research to the amide and related derivatives of cinnamates because of their lesser known attributes towards antidiabetic activities. In this research, we modify methyl trans-cinnamate by amidating the carboxylic methyl ester functionality using several amines introduced in functional groups of methyl trans-cinnamate. A series of cinnamamide derivatives was synthesized and evaluated for α-glucosidase inhibitory effects. The structure of synthesized compounds was characterized by IR, melting point, UV, ¹H NMR, ¹³C NMR, and mass spectral analysis. All 13 cinnamamide showed higher α-glucosidase activity than the starting compound. The substitution of cinnamic acid with an amide group altered the α-glucosidase inhibitory activity. Increased bulkiness and the chain length of the amine substituents decreased the inhibitory activity. Propylcinnamamide (3c) showed the most potent inhibitory activity among all the cinnamamide derivatives, all of which act through a competitive inhibitory mechanism. These compounds may be worth exploring further.

Keywords: α-glucosidase inhibitor; cinnamamide derivative; synthesis

ABSTRAK

Secara kimia, metil trans-sinamat menawarkan rawatan pada tiga tapak reaktif utama seperti penggantian pada gelang fenil, penambahan pada ketaktepuan α,β dan penggantian pada kefungsian karbosilik metil ester. Kami memfokuskan kajian ini kepada amida dan terbitan berkaitan sinamat kerana atribut yang kurang dikenali terhadap aktiviti antidiabetis. Dalam kajian ini kami mengubah suai metil trans-sinamat dengan keamidaan kefungsian karbosilik metil ester menggunakan beberapa amina yang diperkenalkan dalam kumpulan fungsian metil trans-sinamat. Beberapa terbitan sinamamida telah disintesis dan dinilai untuk kesan rencatan α-glucosidase. Struktur sintesis sebatian telah dicirikan oleh IR, titik lebur, UV, ¹H NMR, ¹³C NMR dan analisis jisim spektrum. Kesemua 13 sinamamida menunjukkan aktiviti α-glucosidase yang tinggi berbanding sebatian pemula. Penggantian asid sinamik dengan kumpulan amida mengubah aktiviti perencatan α-glucosidase. Peningkatan berpukal dan panjang rantai bahan ganti amina mengurangkan aktiviti rencatan. Propilsinamamida (3c) menunjukkan aktiviti rencatan poten dalam kalangan terbitan sinamamida, dengan kesemuanya bertindak melalui mekanisme perencatan berpersaingan. Sebatian ini mungkin berbaloi untuk kajian lanjut.

Kata kunci: Perencat α-glucosidase; sintesis; terbitan sinamamida

RUJUKAN

Adisakwattana, S., Charoenlertkul, P. & Yibchok-anun, S. 2009. α-Glucosisade inhibitory activity of cyaniding-3-galactoside and synergitic effect with acarbose. Journal of Enzyme Inhibition and Medicinal Chemistry 24: 65-69.

Adisakwattana, S., Sookkongwaree, K., Roengsumran, S., Petsom, A., Ngamrojnavanich, N., Chavasiri, W. & Yibchok-Anun, S.D. 2004. Structure activity relationships of trans-cinnamic acid derivatives on α-glucosidase inhibition. Bioorg. Med. Chem. Lett. 14: 2893-2894.

Babu, P.S., Prabuseenivasan, S. & Ignacimuthu, S. 2007. Cinnamaldehyde a potential antidiabetic agent. Phytomedicine 14: 15-20.

Bösenberg, L.H. & van Zyl, D.G. 2008. The mechanism of action of oral antidiabetic drugs: A review of recent literature. Endocr. Metab. Diab. South Afr. 13(3): 80-88.

Carvalho, S.A., Silva, E.F., Souza, M.V.N., Lourenc, M.C.S. & Vicente, F.R. 2008. Synthesis and antimycobacterial evaluation of new trans-cinnamic acid hydrazide derivatives.  Bioorg. Med. Chem. Lett. 18: 538-544.

Davies, G. & Henrissat, B. 1995. Structures and mechanisms of glycosyl hydrolases. Structure 3: 853-858.

Fischer, P.B., Collin, M., Karlsson, G.B., James, W., Butters, T.D., Davis, S.J. & Platt, F.M. 1995. The α-glucosidase inhibitor N-Butyldeoxynojirimycin inhibits human immunodeficiency virus entry at the level of post-CD4 binding.  J. Virol. 69: 5791-5796.

Huang, D.W., Shen, S.C. & Wu, J.S.B. 2009. Effects of caffeic acid and cinnamic acid on glucose uptake in insulin-resistant mouse hepatocytes. J. Agric. Food Chem. 57: 7687-7692.

Hurth, K., Jacquier, S., Lehmann, H. & Wilcken, R. 2015. Regioselective nitration of 3-fluoro-2-substituted benzoic acids. Tetrahedron Lett. 56: 2860-2860.

Kim, Y.M., Wang, M.H. & Rhee, H.I. 2004. A novel alpha-glucosidase inhibitor from pine bark. Carbohydr. Res. 339: 715-720.

Liu, Y., Zou, L., Ma, L., Chen, W.H., Wang, B. & Xu, Z.L. 2006. Synthesis and pharmacologies activies xanthone derivatives as alpha glucosidase inhibitors. Bioorg. Med. Chem. 14: 5683-5688.

Lu, Y., Li, Y., Zhang, R., Jin, K. & Duan, C. 2013. Regioselective ortho-nitration of N -phenyl carboxamides and primary anilines using bismuth nitrate/acetic anhydride. Tetrahedron 69: 9422-9426.

Matsuura, H., Miyazaki, H. & Asakawa, C. 2004. Isolation of α-glusosidase inhibitors from hyssop (Hyssopus officinalis). Phytochemistry 65: 91-95.

Mehta, A., Zitzmann, N., Rudd, P.M. & Block, T.M. 1998. α-Glucosidase inhibitors as potential broad based anti-viral agents. FEBS Lett. 430: 17-20.

Melo, E.B. & Carvalho, I. 2006. α- and β-glucosidase inhibitors: Chemical structure and biological activity. Tetrahedron 62: 10277-10280.

Mohammed, K., Rahim, F., Wadood, A., Kosar, N., Taha, M., Lalani, S. & Perveen, S. 2014. Synthesis and molecular docking studies of potent α-glucosidase inhibitors based on biscoumarin skeleton. Eur. J. Med. Chem. 81: 245-250.

Montalbetti, C.A. & Falque, V. 2005. Amide bond formation and peptide coupling. Tetrahedron 61: 10827-10832.

Murray, K., Granner, D.K., Mayes, P. & Rodwell, V. 2003. Harper's Illustrated Biochemistry. 26th ed. Longe Medical Pub.

Narender, T., Shweta, S., Tiwari, P., Reddy, K.P., Khaliq, T., Prathipati, P. & Raj, K. 2007. Antihyperglycemic and antidyslipidemic agent from Aegle marmelos. Bioorg. Med. Chem. Lett. 17: 1808-1814.

Oxley, J.C., Smith, J.L., Moran, J.S., Canino, J.N. & Almog, J. 2008. Aromatic nitration using nitroguanidine and EGDN. Tetrahedron Lett. 49: 4449-4454.

Park, J.E., So, H.P., Jung, Y.W., Hye, S.H., Jaeho, C. & Heeseob, L. 2013. Enzymatic properties of a thermostable α-glucosidase from acidothermophilic crenarchaeon Sulfolobus tokodaii Strain 7. J. Microbiol. Biotechnol. 23(1): 56-63.

Park, H., Hwang, K.Y., Oh, H., Kim, H., Yeon, J. & Kim, K. 2008a. Discovery of novel α-glucosidase inhibitors based on the virtual screening with the homology-modeled protein structure. Bioorg. Med. Chem. 16: 284-286.

Park, J., Ko, S. & Park, H. 2008b. Toward the virtual screening of α-glucosidase inhibitors with the homology-modeled protein structure. Bull. Korean Chem. Soc. 29: 921-925.

Phuwapraisirisan, P., Puksasook, T., Jong-aramruang, J. & Kokpol, U. 2008. Phenylethyl cinnamides: A new series of α -glucosidase inhibitors from the leaves of Aegle marmelos.  Bioorg. Med. Chem. Lett. 18: 4956-4960.

Pili, R., Chang, J.A., Partis, R.A., Mueller, R.J., Chrest, F. & Passaniti, A. 1995. The alpha-glucosidase I inhibitor castanospermine alters endothelial cell glycosylation, prevents angiogenesis, and inhibits tumor growth. Cancer Res. 55: 2920-2926.

Rodrigues, J.A.R., de Oliveira Filho, A.P., Moran, P.J.S. & Custódio, R. 1999. Regioselectivity of the nitration of phenol by acetyl nitrate adsorbed on silica gel. Tetrahedron. 55(22): 6733-6738.

Van de Laar, F.A. 2008. α-Glucosidase inhibitors in the early treatment of Type 2 diabetes. Health Risk Manag. 4: 1189-1195.

*Pengarang untuk surat-menyurat; email: teni.ernawati.lipi@gmail.com