Quinoliniumolate and 2H-1,2,3-Triazole Derivatives from the Stems of

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Quinoliniumolate and 2H‑1,2,3-Triazole Derivatives from the Stems of Paramignya trimera and Their α‑Glucosidase Inhibitory Activities: In Vitro and in Silico Studies Nhan T. Nguyen,*,†,‡ Phu H. Dang,† Ngoc X. T. Vu,† Tho H. Le,† and Mai T. T. Nguyen†,‡ †

Faculty of Chemistry, VNUHCM−University of Science, 227 Nguyen Van Cu Street, District 5, Ho Chi Minh City, Vietnam Cancer Research Laboratory, Vietnam National University, Ho Chi Minh City, 227 Nguyen Van Cu Street, District 5, Ho Chi Minh City, Vietnam

‡

S Supporting Information *

ABSTRACT: From a CHCl3-soluble extract of the stems of Paramignya trimera, two new alkaloids, (E)-2-(prop-1-enyl)-Nmethylquinolinium-4-olate (1) and (R)-2-ethylhexyl 2H-1,2,3triazole-4-carboxylate (2), were isolated. Their structures were elucidated based on the spectroscopic data interpretation. Compound 2 possesses α-glucosidase inhibitory activity, with an IC50 value of 137.9 μM. Molecular docking studies of 1 and 2 with human maltase-glucoamylase (MGAM) were performed for the first time; thus, the 2,3-diH+-1H-1,2,3-triazolium cation (2i) showed good interactions with both MGAM-N (2QMJ) and -C (3TOP) terminal subunits.

Paramignya trimera (Oliv.) Guillaum is a woody shrub belonging to the family Rutaceae, which is found in Thailand and Vietnam. P. trimera, local name “Xao tam phan”, is an endemic plant in South Vietnam. The roots of this plant have been used as Vietnamese traditional medicines for the treatment of diabetes.1 As part of our continuing study on the screening of medicinal plants for α-glucosidase inhibitory activity,2−7 it was also found that the CHCl3-soluble extract of the stems of P. trimera exhibited potent α-glucosidase inhibitory activity, with an IC 50 value of 94.5 μg/mL. Further phytochemical investigation of the stems of P. trimera collected from Khanh Hoa Province led to the isolation of two new alkaloids, (E)-2-(prop-1-enyl)-N-methylquinolinium-4-olate (1) and (R)-2-ethylhexyl 2H-1,2,3-triazole-4-carboxylate (2), and their α-glucosidase inhibitory activities were examined. The interactions of the active compound with human maltaseglucoamylase (MGAM) were also studied by molecular docking. The powdered stems of P. trimera was heated at reflux in MeOH. The MeOH-soluble extract was suspended in H2O and successively partitioned to yield petroleum ether-, CHCl3-, and EtOAc-soluble fractions. Further separation and purification of the CHCl3-soluble fraction led to the isolation of two new compounds, (E)-2-(prop-1-enyl)-N-methylquinolinium-4-olate (1) and (R)-2-ethylhexyl 2H-1,2,3-triazole-4-carboxylate (2). Compound 1 was isolated as a yellow, amorphous solid and showed a protonated molecular ion at m/z 200.1059, corresponding to the molecular formula C13H13NO. The 1H NMR spectrum of 1 showed signals for a 1,2-disubstituted benzene moiety [δH 8.40 (dd, J = 8.1, 1.5 Hz), 7.49 (brt, J = 7.6 Hz), 7.80 (ddd, J = 8.7, 6.9, 1.5 Hz), and 7.68 (brd, J = 8.7 Hz)], an olefinic singlet [δH 7.11 (brs)], a prop-1-enyl group © 2017 American Chemical Society and American Society of Pharmacognosy

[δH 6.59 (m), 6.58 (m), and 2.02 (d, J = 4.4 Hz)], and an Nmethyl singlet [δH 3.96 (s)] (Table 1). The 13C NMR spectrum of 1 displayed resonances for an enolate carbon (δC 174.5), six aromatic carbons (δC 141.1, 133.6, 126.3, 125.2, 124.1, 116.3), three olefinic carbons (δC 140.5, 124.4, 108.0), an imino carbon (δC 154.3), an N-methyl carbon (δC 36.7), and a methyl group (δC 19.4). These 1H and 13C NMR data of 1 closely resembled those reported for N-alkylquinolinium derivatives.8,9 The presence of the enolate group was confirmed by the absence of a hydroxy absorption (∼3419 cm−1)8 in the IR spectrum of 1 (Figure 9S, Supporting Information). The 1,2-disubstituted benzene moiety was confirmed by the 1H−1H COSY correlations between H-5, H-6, H-7, and H-8 (Figure 1). The location of the prop-1-enyl group was suggested to be at C-2 based on the HMBC correlations between N-Me/C-2/C-8a, HReceived: April 3, 2017 Published: July 20, 2017 2151

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Table 1. NMR Spectroscopic Data of Compounds 1 and 1i in CDCl3 1 position 2 3 4 4a 5 6 7 8 8a 1′ 2′ 3′ N-Me

1i

δC, type 154.3, 108.0, 174.5, 124.1, 126.3, 125.2, 133.6, 116.3, 141.1, 124.4, 140.5, 19.4, 36.7,

C CH C C CH CH CH CH C CH CH CH3 CH3

δH (J in Hz)

δH (J in Hz)

7.11, brs

6.38, s

8.40, 7.49, 7.80, 7.68,

dd (8.1, 1.5) brt (7.6) ddd (8.7, 6.9, 1.5) brd (8.7)

8.44, 7.37, 7.66, 7.49,

dd (8.0, 1.7) ddd (8.0, 7.0, 0.9) ddd (8.6, 7.0, 1.7) brd (8.6)

6.58, 6.59, 2.02, 3.96,

m m d (4.4) s

6.46, 6.37, 1.98, 3.76,

dq (15.3, 1.5) dd (15.3, 6.5) dd (6.5, 1.5) s

Table 2. NMR Spectroscopic Data of Compound 2 in CDCl3 position NH 4 5 CO 1′ 2′ 3′ 4′ 5′ 6′ Et-2′

Figure 1. Connectivities (bold lines) deduced by the COSY spectrum and significant HMBC correlations (solid arrows) observed for 1 and 2.

3/C-2/C-1′, and H-1′/C-2. Further, the keto−enolate interconversion of compound 1 occurred under condensedphase conditions, to afford compound 1i. The 1H NMR spectrum of 1i (Table 1) resembled those of (E)-2-(prop-1enyl)quinolin-4(1H)-one,10 except for the presence of an Nmethyl group at δH 3.76 (s). In the 1H NMR spectra of 1i and 1, the conspicuous differences involved the signals of the olefinic H-3 and the N-methyl group (δH 7.11 and 3.96 in 1 and δH 6.38 and 3.76 in 1i). The variations in ΔδH‑3 and ΔδN‑Me values for 1i and 1 (− 0.73 and −0.20 ppm, respectively) could be explained by the keto−enolate tautomerism at C-4, which also led to equilibration of the tertiary amine and quaternary ammonium functionalities. The (E)-prop-1-enyl group was defined based on the chemical shifts at δH 6.46 (dq, J = 15.3, 1.5 Hz), 6.37 (dd, J = 15.3, 6.5 Hz), and 1.98 (dd, J = 6.5, 1.5 Hz) in the 1H NMR spectrum of 1i. The NOESY spectrum of 1i showed the correlation between N-Me/H-8/H-1′, which suggested the location of the (E)-prop-1-enyl group at C-2. Thus, the structure of 1 was assigned as (E)-2-(prop-1-enyl)-Nmethylquinolinium-4-olate (1). Compound 2 was deduced to have the molecular formula C11H19N3O2 based on the HRFABMS ion at m/z 226.1570 [M + H]+ (calcd for C11H20N3O2, 226.1556). The 1H NMR spectrum of 2 showed signals for the overlapped CH-triazole and NH-triazole protons [δH 8.10 (2H, s)], an oxymethylene group [δH 4.26 (m)], a methine proton [δH 1.73 (hept, J = 6.2 Hz)], four methylene groups [δH 1.40 (tt, J = 5.6, 2.5 Hz), 1.34 (td, J = 6.4, 6.2, 3.4 Hz), and 1.46 (dtd, J = 13.8, 7.5, 2.7 Hz)], and two terminal methyl groups [δH 0.95 (t, J = 7.5 Hz) and 0.91 (t, J = 7.0 Hz)] (Table 2). The 13C NMR spectrum of 2 showed the presence of a carbonyl (δC 166.1), two olefinic carbons (δC 134.5, 129.6), an oxymethylene (δC 67.9), a methine (δC 39.1), four methylenes (δC 30.7, 29.1, 24.2, 23.1), and two methyls (δC 14.2, 11.2). Comparison of these data with

δC, type

δH (J in Hz) 8.10, s

134.4, 129.6, 166.1, 67.9, 39.1, 30.7, 29.1, 23.1, 14.2, 24.2, 11.2,

C CH C CH2 CH CH2 CH2 CH2 CH3 CH2 CH3

8.10, s 4.26, 1.73, 1.40, 1.33, 1.33, 0.91, 1.46, 0.95,

m hept (6.2) tt (5.6, 2.5) m m t (7.0) dtd (13.8, 7.5, 2.7) t (7.5)

those of 1,2,3-triazole and 1,2,4-triazole derivatives11 suggested the structure of 2 to be a 1,2,3-triazole-type alkaloid, as evident from the 13C NMR chemical shifts of two olefinic carbons (C-4, δC 134.5 and C-5, δC 129.6). The unsymmetrical 1,2,3-triazole moiety was a mixture of the 1H- (a or c) and 2H- (b) tautomers (Figure 2). The 2H-tautomer predominated in the

Figure 2. Tautomeric forms (a−c) of 1,2,3-triazole and their 1H NMR data17 (in ppm).

gas phase, while both the 1H- and 2H-tautomers are present in solution. In the solid state, the 1,2,3-triazoles could exist as a single tautomer or a 1:1 mixture of two tautomers depending on the nature of the C-substituent.12,13 The temperaturedependent 1H NMR studies of the 1,2,3-triazoles in CD2Cl2 and toluene-d8 at 27 °C indicated that the 2H-tautomers were predominant (80% and 97%, respectively).14−16 The 1H NMR data of the mixture of the three tautomers (a−c) showed the broadened singlets of the NH protons in the range δH 8.20− 9.25.17 The N−H signal of tautomer c resonated as a singlet at δH 8.55. The N−H signals of tautomers a and b were assigned at δH 8.20 and 9.00, respectively, but without explanation. 2152

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formations of 1ii and 2i were obtained by using the MOE suite. The docked conformation with the highest negative binding free energy value (S value) was selected to analyze the protein−ligand interactions. The comparative values for the binding free energies of the two compounds for both terminals are given in Table 3. The protonated acarbose, which was found at the binding site of the complex with human maltaseglucoamylase, was also used as the positive control in this docking study. Results from molecular docking studies revealed that 2i has good interactions with both MGAM-N (2QMJ) and -C (3TOP) terminal subunits (Figure 4). The N(2)H+ group formed a strong H-donor interaction with the ASP203 residue of the binding site in the MGAM-N protein. The N(2)H+ group interacted moderately with the ASP542 residue via an ionic bond. The aliphatic substituent of 2i showed a weak arene−H interaction with the PHE575 residue. Compound 2i showed better interactions with targeting residues of the binding site in the MGAM-C unit. It contributed a strong interaction with the ASP1157 residue by forming H-donor and ionic interactions via the N(2)H+ group. The N(3)H group has a moderate H-donor interaction with the MET1412 residue. Thus, the S values and these interactions suggested that 2i had a higher binding affinity for MGAM-C and a slightly lower binding affinity for MGAM-N.

Hence, the C−H triazole signal was used to determine the tautomeric form of 2 (Figure 2). The overlapped signal at δH 8.10 (s) in the 1H NMR spectrum of 2 belonged to a methine proton of the 2H-tautomer b due to the electron-withdrawing imino group.17 The 2-ethylhexyloxy group was defined by the HMBC correlations between H-2″/C-2′, H-1″/C-1′, H-3′/C1″, and H-4′/C-2′, its location being assigned at C(O)-4 based on the HMBC correlations between H-1′/CO and C− H triazole/CO (Figure 1). The acid-catalyzed hydrolysis reaction of 2 afforded (R)-2-ethylhexanol,18,19 which showed a 25 negative specific rotation [α]25 D −2.80 (c 0.1, CHCl3) and [α]365 −11.2 (c 0.1, CHCl3). Thus, the structure of 2 was assigned as (R)-2-ethylhexyl 2H-1,2,3-triazole-4-carboxylate. Compounds 1i and 2 were tested for their α-glucosidase (from Saccharomyces cerevisiae) inhibitory activity. Acarbose, which is used to control the blood glucose level of patients, was used as the positive control. Compound 2 was found to possess α-glucosidase inhibitory activity, with an IC50 value of 137.9 μM, and compound 1i showed no effect (IC50 > 250 μM). In molecular studies, the 1,2,3-triazolic compounds contribute to the hydrogen acceptor/donor and dipole−dipole interactions because of their strong dipole moments and are extremely stable to hydrolysis.20 Owing to the poor basicity of the 1,2,3triazole functionality, it is not protonated at physiological pH. The nonprotonated sp2-hybridized nitrogen atoms of 1,2,3triazoles may develop to an oxycarbocation-like transition state during the cleavage of the glycosidic bond catalyzed by αglucosidase.21 The quinolinium 1 could also mimic the conformation and charge of the oxycarbocation-like intermediate. Thus, the structures of 1 and 2 should be protonated to match the above mechanism prior to the docking calculations. Human maltase-glucoamylase plays a key role in the production of glucose in the human lumen and acts as a promising target for the treatment of type 2 diabetes. The amino- and hydroxycarbonyl-terminal catalytic domains of MGAM (MGAM-N and MGAM-C) carry out the same reaction but have different substrate specificities. MGAM-N catalyzes the cleavage of short α-(1→4) oligosaccharide units, while MGAM-C prefers longer substrates.22 In this work, the molecular docking studies of 1ii (a protonated form of 1) and 2i, respectively, with MGAM-N and -C proteins were carried out for the first time in order to explore their interactions and the potential mechanism of α-glucosidase inhibition. The Molecular Operating Environment 2016 (MOE 2016.0802) docking program was used to analyze the interactions. The topranked conformation of the active compound was selected based on the docking score S for further analysis of protein− ligand interactions. Owing to the presence of both the 1H- and 2H-tautomers in aqueous solution, the protonated forms of 1,2,3-triazole included 1,2-diH+, 1,3-diH+, and 2,3-diH+ cations (Figure 3). In an explicit water model, the energy minimizations of these forms led to the determination of the most stable form as 2i, a 2,3-diH+-1H-1,2,3-triazolium cation. The most stable con-

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EXPERIMENTAL SECTION

General Experimental Procedures. Optical rotations were measured on an A. Krüss Optronic P3000 polarimeter (A. Krüss Optronic GmbH, Hamburg, Germany) and a JASCO DIP-140 digital polarimeter (JASCO International Co., Ltd., Japan). The IR spectra were measured with a Shimadzu IR-408 infrared spectrometer (Shimadzu Pte., Ltd., Singapore). The NMR spectra were recorded on a Bruker Avance III 500 spectrometer (Bruker BioSpin AG, Bangkok, Thailand) with tetramethylsilane as an internal standard, and the chemical shifts are expressed in δ values. HRMS data were acquired on JEOL JMS-AX505HA (JEOL Ltd., Japan), Bruker MicrOTOF-QII (Bruker Singapore Pte., Ltd., Singapore), and Shimadzu LCMS-IT-TOF (Shimadzu Singapore Pte., Ltd., Singapore) mass spectrometers. Column chromatography was carried out using silica gel 60, 0.06−0.2 mm (Scharlau, Barcelona, Spain). Analytical and preparative TLC were carried out on precoated Kieselgel 60F254 or RP18 plates (Merck KGaA, Darmstadt, Germany). Other chemicals were of the highest grade available. Plant Material. The stems of P. trimera was collected in the Hon Heo Forest, Ninh Hoa Town, Khanh Hoa Province, Vietnam, in February 2013 and were identified by M. D. Thuong Nguyen, President of Khanh Hoa Traditional Medicine. A voucher specimen (MCE0050) has been deposited at the Division of Medicinal Chemistry, Faculty of Chemistry, University of Science, VNU-HCMC. Extraction and Isolation. The stems of P. trimera (8.0 kg) was refluxed with MeOH (20 L, 3 h × 3), and the MeOH-soluble extract (560 g) was suspended in H2O (4 L) and successively partitioned with n-hexane (2 L), CHCl3 (2 L), and EtOAc (2 L) to give n-hexane (70 g), CHCl3 (64 g), EtOAc (55 g), and aqueous (270 g) soluble fractions. The CHCl3-soluble fraction was subjected to a silica gel column (8 × 150 cm) and eluted with EtOAc−n-hexane (0:100 → 100:0) and MeOH−CHCl3 (5:95 → 20:80) mixtures, to obtain 13 major fractions (Fr.1−Fr.13). Fraction Fr.9 (8.4 g) was chromatographed over a silica gel column (5 × 80 cm) with EtOAc−n-hexane (10:90 → 100:0) mixtures, to afford six subfractions (Fr.9.1−Fr.9.6). Subfraction Fr.9.6 (1.8 g) was separated by column chromatography with EtOAc−n-hexane (10:90 → 50:50) and acetone−n-hexane (30:70 → 100:0) mixtures and then purified by preparative TLC with MeOH−CHCl3 (5:95), to yield compounds 1 (5.0 mg) and 2 (15.6 mg). (E)-2-(Prop-1-enyl)-N-methylquinolinium-4-olate (1): yellow, amorphous solid; IR νmax (KBr) 3055, 1604, 1445, 1390, 1225, 1055

Figure 3. Protonated forms of the unsymmetrical 1,2,3-triazole. 2153

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Table 3. Docking Results of 1ii, 2i, and Protonated Acarbose with Both MGAMs MGAM-N (2QMJ) compound

S values

1ii 2i acarbose-H+a

−5.16 −7.75 −10.22

a

MGAM-C (3TOP) S values

targeting residues ASP203, ASP542, MET444 ASP203, ASP542, PHE575 ASP203, ASP327, ASP443, ASP542, MET444, HIS600, THR205

−6.70 −8.45 −13.37

targeting residues ASP1157, MET1412 ASP1279, ASP1157, ASP1526, ARG1510, MET1421, HIS1584, PHE1559

Positive control.

Figure 4. 2D docking models of 1ii and 2i with both MGAM-N (2QMJ) and -C (3TOP) generated by the MOE suite. The dashed lines represent the interactions between the protein and the ligand. cm−1; 1H and 13C NMR (CDCl3, 500 MHz, see Table 1); HRESIMS m/z 200.1059 [M + H]+ (calcd for C13H14NO, 200.1070). (R)-2-Ethylhexyl 2H-1,2,3-triazole-4-carboxylate (2): white, amorphous solid; [α]25 D −13.2 (c, 0.1, CHCl3); IR νmax (KBr) 3440, 3135, 1715, 1352, 1245 cm−1; 1H and 13C NMR (CDCl3, 500 MHz, see Table 2); HRFABMS m/z 226.1570 [M + H]+ (calcd for C11H20N3O2, 226.1556). α-Glucosidase Inhibitory Assay. The α-glucosidase inhibitory activity was determined according to a previous method.7 Thus, 3 mM p-nitrophenyl-α-D-glucopyranoside (25 μL) and 0.2 U/mL αglucosidase (25 μL) in 0.01 M phosphate buffer (pH = 7.0) were added to the sample solution (625 μL) to start the reaction. Each reaction was carried out at 37 °C for 30 min and stopped by adding 0.1 M Na2CO3 (375 μL). Enzymatic activity was quantified by measuring absorbance at 401 nm. The IC50 value was defined as the concentration of an α-glucosidase inhibitor that inhibited 50% of αglucosidase activity. Acarbose was used as a positive control. Keto−Enolate Interconversion of 1. After spectroscopic measurements, a solution of 1 was evaporated to dryness. The dried

solid was stored at room temperature (∼30 °C) for 20 days, to convert completely to the quinolone 1i. After that time, the 1H NMR spectrum of 1i was recorded. Acid-Catalyzed Hydrolysis of 2. An aliquot (8 mg) of 2 was dissolved in 3 mL of methanolic HCl (5% v/v), and the mixture refluxed for 18 h. The resulting mixture was diluted with 10 mL of water. The aqueous solution was extracted with n-hexane (3 × 3 mL), and the organic phase was dried over anhydrous Na2SO4. After removal of solvent, 4 mg of (R)-2-ethylhexanol was obtained, with 25 [α]25 D −2.80 (c 0.1, CHCl3) and [α]365 −11.2 (c 0.1, CHCl3); HRESIMS m/z 131.1438 [M + H]+ (calcd for C8H19O, 131.1436). Molecular Docking Experiment. The molecular docking was carried out using the Molecular Operating Environment 2016 (MOE 2016.0802) suite.23 The structures of the compounds were built by using the Builder module in MOE. Subsequently, all compounds was solvated with H2O (margin 10 Å), and the potential energy was minimized up to 0.0001 gradient using the Amber10:EHT force field, cutoff [10,12]. The crystal structures of MGAM-N (2QMJ)24 and -C (3TOP)22 proteins were derived from the Protein Data Bank and 2154

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(14) Lunazzi, L.; Parisi, F.; Macciantelli, D. J. Chem. Soc., Perkin Trans. 2 1984, 1025−1028. (15) Albert, A.; Taylor, P. J. J. Chem. Soc., Perkin Trans. 2 1989, 1903−1905. (16) Katritzky, A. R.; Buciumas, A.-M.; Todadze, E.; Munawar, M. A.; Khelashvili, L. Heterocycles 2010, 82, 479−489. (17) Anisimova, N. A.; Berestovitskaya, V. M.; Berkova, G. A.; Makarova, N. G. Russ. J. Org. Chem. 2007, 43, 652−655. (18) Gröst, C.; Gräber, M.; Hell, M.; Berg, T. Bioorg. Med. Chem. 2013, 21, 7357−7363. (19) Xue, J.; Singh, G.; Qiang, Z.; Karim, A.; Vogt, B. D. Nanoscale 2013, 5, 7928−7935. (20) Ferreira, S. B.; Sodero, A. C. R.; Cardoso, M. F. C.; Lima, E. S.; Kaiser, C. R.; Silva, F. P.; Ferreira, V. F. J. Med. Chem. 2010, 53, 2364− 2375. (21) Borges de Melo, E.; Gomes, A. d. S.; Carvalho, I. Tetrahedron 2006, 62, 10277−10302. (22) Ren, L.; Qin, X.; Cao, X.; Wang, L.; Bai, F.; Bai, G.; Shen, Y. Protein Cell 2011, 2, 827−836. (23) Molecular Operating Environment (MOE) 2016.08, 2016.0802; Chemical Computing Group Inc., 2016. (24) Sim, L.; Quezada-Calvillo, R.; Sterchi, E. E.; Nichols, B. L.; Rose, D. R. J. Mol. Biol. 2008, 375, 782−792.

prepared by using the QuickPrep module in MOE. The binding site was determined based on the PLB (Propensity for Ligand Binding) score in the Site Finder module. Docking was performed by MOE 2016.0802, using the Rigid Receptor protocol, Triangle Matcher placement, London dG as a first rescoring, force field (Amber10:EHT) refinement, and GBVI/WSA dG as a second rescoring. Five top poses showed up based on the negative binding free energy value (S value). The best pose with the highest negative S value was selected to analyze the 2D and 3D ligand−protein interactions.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jnatprod.7b00289. Copies of spectroscopic data for 1, 1i, and 2 (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail (N. T. Nguyen): [email protected]. Tel: +84-907426-331. Fax: +84-838-353-659. ORCID

Nhan T. Nguyen: 0000-0001-5142-4573 Mai T. T. Nguyen: 0000-0001-8006-4028 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This research was supported by a grant from the Vietnam National University Ho Chi Minh City (No. A2015-18-02) to M.T.T.N.

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REFERENCES

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