Indones. J. Chem., 2022, 22 (6), 1673 - 1683 Herlina Rasyid et al. 1673 Synthesis of N-phenethyl-p-methoxycinnamamide and N-morpholinyl-p- methoxycinnamamide, In Vitro and In Silico Study as α-Glucosidase Inhibitor Herlina Rasyid 1* , Firdaus Firdaus 1 , Syadza Firdausiah 1 , Nunuk Hariani Soekamto 1 , Seniwati Seniwati 1 , Riska Mardiyanti 1 , Reynaldi Reynaldi 1 , Andi Eka Sri Rahayu 1 , and Wahyu Dita Saputri 2 1 Department of Chemistry, Faculty of Mathematics and Natural Sciences, Hasanuddin University, Jl. Perintis Kemerdekaan km 10, Makassar 90245, South Sulawesi, Indonesia 2 Research Center for Quantum Physics, National Research and Innovation Agency (BRIN), Habibie Science and Technology Complex (Puspiptek), Serpong 15314, South Tangerang, Indonesia * Corresponding author: tel: +62-85255606583 email: herlinarasyid@unhas.ac.id Received: August 2, 2022 Accepted: October 5, 2022 DOI: 10.22146/ijc.76802 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 1 H- and 13 C-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 ■ INTRODUCTION Aromatic ginger (Kaempferia galanga L.) is one of the traditional medicine which is known to contain ethyl- p-methoxycinnamate (EPMC) [1], ethyl cinnamate [2], isopimarane-type diterpenoids [3-4]. The other chemical compounds were δ-3-carene, 1,8-cineole, borneol, and pentadecane [5]. The two most abundant compounds in the aromatic ginger essential oil were trans-ethyl-p- methoxycinnamate and trans-ethyl cinnamate [1-2,5]. Ethyl-p-methoxycinnamate and its derivatives had many benefits, including as anticancer [6-8], anti-inflammatory [9-10], anti-tuberculosis [11], anti-neoplastic [12], antimicrobe [13], and antidiabetic [14] agents. The study of K. galanga L. extract as an antidiabetic using the Gavage method every day for one month found that diabetic rats before and after treatment with K. galanga L. extract showed a significant difference in reducing the amount of blood glucose [15]. In addition, the cinnamic acid derivative compound had an antidiabetic activity which had been shown to reduce plasma glucose concentrations in diabetic rats by reducing the excessive activity of glucose-6-phosphatase, hepatic hexokinase, glucokinase, and phosphofructokinase and increasing liver glycogen in diabetic rats but did not change plasma glucose concentrations in normal rats. The antihyperglycemic effect of p-methoxy cinnamic acid worked by increasing insulin secretion and glycolysis and reducing gluconeogenesis [16] and significantly inhibited the formation of advanced glycation end products (AGEs). This result proved that cinnamic acid and its derivatives could effectively protect BSA from