Arch. Pharm. Res. DOI 10.1007/s12272-015-0614-7
RESEARCH ARTICLE
Synthesis of biscoumarin and dihydropyran derivatives as two novel classes of potential anti-bacterial derivatives Jing Li1 • Xiao-yan Xue2 • Xia Li3 • Zheng Hou2 • Xiao-hui Yang1 Di Qu2 • Ying Zhou2 • Zi-dan Zhang4 • Xiao-xing Luo2 • Jiang-tao Li1 • Ming-kai Li2
•
Received: 30 October 2014 / Accepted: 2 May 2015 The Pharmaceutical Society of Korea 2015
Abstract A series of bisoumarin (1–4) and dihydropyran (5–8) derivatives were successfully synthesized as new antibacterial agents. The molecular structures of three representative compounds 1, 5 and 7 were confirmed by single crystal X-ray diffraction study. Among these compounds tested toward Staphylococcus aureus (S. aureus ATCC 29213), methicillin-resistant S. aureus (MRSA XJ 75302), vancomycin-intermediate S. aureus (Mu50 ATCC 700699), and USA 300 (Los Angeles County clone, LAC), compounds 1 and 2 displayed the most potent antibacterial activity. Additionally, the HB energy in biscoumarins 1–4 was calculated by density functional theory (DFT) [B3LYP/6-31G*] method. Keywords DFT
Bisoumarin Dihydropyran Antibacterial
Jing Li, Xiao-yan Xue, Xia Li are contributed equally to this work. & Jiang-tao Li
[email protected] Ming-kai Li
[email protected] 1
College of Chemistry and Chemical Engineering, The Key Laboratory for Surface Engineering and Remanufacturing in Shaanxi Province, Xi’an University, Xi’an, China
2
Department of Pharmacology, School of Pharmacy, The Fourth Military Medical University, Xi’an, China
3
Department of Neurosurgery, Xijing Hospital, The Fourth Military Medical University, Xi’an, China
4
Department of Physics, School of Science, Tianjin University, Tianjin, China
Introduction Staphylococcus aureus (S. aureus) is a main pathogen responsible for a number of diseases from serious hospital infections and community acquired infections (Sandora and Goldmann 2012; Frisina et al. 2013). There is still no specific and selective antibacterial agents to kill Methicillin-resistant S. aureus (MRSA), which is the major cause of high death rate of patients in hospital because of its emergence, spread and rapid evolution (Gordon and Lowy 2008; Malani 2013). Vancomycin is the last effective antibiotic treatment option for MRSA. However, the emergence of vancomycin-resistant MRSA was reported one after another in the United States, France, Australian and this situation is more and more serious, which leads to the urgent necessity of developing new antimicrobials (Fylaktakidou et al. 2004; Murray et al. 2008). Bisoumarin and dihydropyran derivatives are two privileged scaffolds among heterocyclics and are known to possess a wide range of biological activities with interesting potential in therapeutic application besides their traditional use as anticoagulants, antifungal, anti-inflammatory agents, etc. (Hamdi et al. 2008; Gacche and Jadhav 2012). They have also shown important property as antibiotics (novobiocin and analogs), anti-AIDS agents (calanolides) and antitumor drugs (Bonsignore et al. 1993; Khan et al. 2011). The biological importance and the therapeutic action of these compounds have generated a lot of interest over the years. The preparation of biscoumarins (1–4) and dihydropyrans (5–8), which could be used as new antibacterial agents against drug-susceptive and drug resistant S. aureus in vitro, is presented in this study. Additionally, the total HB energy of compounds 1–4 was calculated by density functional theory (DFT) method (Fig. 1).
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J. Li et al.
OH HO
OH HO
O
O O
OH HO
O
O O
O
O
OH HO
O
O O
O
O
O O
O
O 1
NH2 O
3
2
4
NH2
CN
NH2
NH2
CN
O
O
CN
O
O
CN Br
O
SCH3
5
O
NO2
6
O
O
7
8
F
Fig. 1 Chemical structures of compounds 1–8
Experimental Apparatus and materials IR spectra (400–4000 cm-1) were obtained using a Brucker Equinox-55 spectrophotometer. 1H NMR spectra were obtained using a Varian Inova-400 spectrometer (at 400 MHz). Mass spectra were obtained using a micrOTOFQ II mass spectrometer. The melting points were taken on a XT-4 micro melting apparatus, and the thermometer was uncorrected. All antibiotics used were purchased from the National Institute for the Control of Pharmaceutical and Biological Products (Beijing, China). All other chemicals and solvents were of analytical grade. MRSA (XJ 75302) was isolated from cultures of sputum samples from patients in Xijing Hospital (Xi’an, China). S. aureus strain (ATCC 29213) was purchased from the Chinese National Center for Surveillance of Antimicrobial Resistance. Mu50 (ATCC 700699) and USA 300 (LAC) were purchased from MicroBiologics (MN, USA). Synthesis and characterization of compounds 1–8 Biscoumarins 1–4 were synthesized according to the methods of a previous report (Li et al. 2014). A mixture of 4-isopropylbenzaldehyde (4-tertbutylbenzaldehyde, 4-methoxybenzaldehyde or 4-ethoxybenzaldehyde) (10 mmol) and 4-hydroxycoumarin (20 mmol) was dissolved in 100 mL of EtOH. A few drops of piperidine were added, and the mixture
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was stirred for 3 h at room temperature. After the completion of reaction as determined by TLC, water was added until precipitation occurred. After filtering the precipitates, they were sequentially washed with ice-cooled water, ethanol and dried in a vacuum. 3,30 -(4-Isopropylbenzylidene)-bis-(4-hydroxycoumarin) (1): m.p. 239–240 C. IR (KBr pellet cm-1): 3040 (OH), 1660 (CO), 1550 (C=C). 1H NMR (CDCl3, d, ppm): 11.527 (s, 1H), 11.299 (s, 1H), 8.023–8.099 (q, 2H), 7.630–7.673 (m, 2H), 7.425–7.446 (d, 4H), 7.147–7.213 (q, 4H), 6.095 (s, 1H), 2.904–2.938 (t, 1H), 1.257–1.274 (d, 6H). HRMS (ESI?): m/z: calcd for [C28H22O6?Na?]: 477.1309; found: 477.1244. 3,30 -(4-Tertbutylbenzylidene)-bis-(4-hydroxycoumarin) (2): m.p. 247–248 C. IR (KBr pellet cm-1): 3045 (OH), 1666 (CO), 1559 (C=C). 1H NMR (CDCl3, d, ppm): 11.526 (s, 1H), 11.300 (s, 1H), 8.026–8.102 (q, 2H), 7.631–7.674 (m, 2H), 7.344–7.446 (m, 6H), 7.156–7.175 (d, 2H), 6.093 (s, 1H), 1.332 (s, 9H). HRMS (ESI?): m/z: calcd for [C29H24O6?Na?]: 491.1465; found: 491.1433. 3,30 -(4-Methoxybenzylidene)-bis-(4-hydroxycoumarin) (3): m.p. 232–233 C. IR (KBr pellet cm-1): 3065 (OH), 1826 (CO), 1100 (C=C). 1H NMR (CDCl3, d, ppm): 11.512 (s, 1H), 11.296 (s, 1H), 7.994–8.075 (q, 2H), 7.605–7.647 (t, 2H), 7.399–7.419 (d, 4H), 7.118–7.139 (d, 2H), 6.844–6.866 (d, 2H), 6.050 (s, 1H), 3.797 (s, 3H). HRMS (ESI?): m/z: calcd for [C26H18O7?Na?]: 465.0945; found: 465.0933. 3,30 -(4-Ethoxybenzylidene)-bis-(4-hydroxycoumarin) (4): m.p. 234–235 C. IR (KBr pellet cm-1): 3065 (OH), 1663 (CO), 1564 (C=C). 1H NMR (CDCl3, d, ppm):
Synthesis of biscoumarin and dihydropyran derivatives as two novel classes of potential anti-…
11.520 (s, 1H), 11.305 (s, 1H), 8.035–8.077 (d, 2H), 7.624–7.667 (m, 2H), 7.419–7.440 (d, 4H), 7.126–7.146 (d, 2H), 6.854–6.876 (d, 2H), 6.069 (s, 1H), 4.014–4.066 (q, 2H), 1.406–1.440 (t, 3H). HRMS (ESI?): m/z: calcd for [C27H20O7?Na?]: 479.1101; found: 479.1129. Dihydropyran derivatives (5–8) were also synthesized according to a reported procedure (Eshghi et al. 2012). A mixture of 3,5-cyclohexanedione (or 1,1-dimethyl-3,5-cyclohexanedione) (10 mmol), 4-methylsulfanylbenzaldehyde (or 4-nitrobenzaldehyde, 4-isopropylbenzaldehyde, 3-bromo-4fluorobenzaldehyde) (10 mmol), malononitrile (10 mmol) and 4-(dimethylamino)pyridine (DMAP) (1 mmol) in ethanol (100 mL) was refluxed for 2–3 h and then cooled to room temperature. After filtering the precipitates, they were sequentially washed with ice-cooled water and ethanol and then dried under a vacuum. 2-Amino-4-(4-methylsulfanylphenyl)-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (5): m.p. 224– 225 C. IR (KBr pellet cm-1): 1681 (CO), 1651 (C=C), 1214 (–O–). 1H NMR (DMSO-d6, d, ppm): 7.169–7.190 (t, 2H), 7.087–7.107 (d, 2H), 7.029 (s, 2H), 4.149 (s, 1H), 2.590–2.621 (q, 2H), 2.499–2.516 (m, 3H), 2.216–2.311 (m, 2H), 1.864–1.981 (m, 2H). HRMS (ESI?): m/z: calcd for [C17H16N2O2S?Na?]: 335.0825; found: 335.0832. 2-Amino-4-(4-nitrophenyl)-5-oxo-5,6,7,8-tetrahydro-4Hchromene-3-carbonitrile (6): m.p. 234–235 C. IR (KBr pellet cm-1): 1682 (CO), 1590 (C=C), 1209 (–O–). 1H NMR (DMSO-d6, d, ppm): 8.156–8.178 (d, 2H), 7.454–7.475 (d, 2H), 7.199 (s, 2H), 4.366 (s, 1H), 2.624–2.654 (t, 2H), 2.255–2.330 (m, 2H), 1.913–1.978 (m, 2H). HRMS (ESI?): m/z: calcd for [C16H13N3O4?Na?]: 334.0789; found: 334.0233. 2-Amino-4-(4-isopropylphenyl)-3-cyano-7,7-dimethyl5-oxo-4H-5,6,7,8-tetrahydrobenzo[b]pyran (7): m.p. 210–211 C. IR (KBr pellet cm-1): 1675 (CO), 1606 (C=C), 1213 (–O–). 1H NMR (DMSO-d6, d, ppm): 7.149–7.169 (d, 2H), 7.037–7.057 (d, 2H), 6.964 (s, 2H), 4.135 (s, 1H), 2.822–2.856 (t, 1H), 2.503–2.521 (m, 1H), 2.237–2.277 (d, 1H), 2.139 (s, 1H), 2.092 (s, 1H), 1.191 (s, 3H), 1.174 (s, 3H), 1.046 (s, 3H), 0.977 (s, 3H). HRMS (ESI?): m/z: calcd for [C21H24N2O2?Na?]: 359.1730; found: 359.1788. 2-Amino-4-(3-bromo-4-fluorophenyl)-3-cyano-7,7-dimethyl-5-oxo-4H-5,6,7,8-tetrahydrobenzo[b]pyran (8): m.p. 228–229 C. IR (KBr pellet cm-1): 1683 (CO), 1601 (C=C), 1215 (–O–). 1H NMR (DMSO-d6, d, ppm): 7.431–7.453 (q, 1H), 7.291–7.334 (t, 1H), 7.187–7.221 (m, 1H), 7.109 (s, 2H), 4.247 (s, 1H), 2.527–2.530 (d, 2H), 2.233–2.73 (d, 1H), 2.114–2.154 (d, 1H), 1.039 (s, 3H), 0.963 (s, 3H). HRMS (ESI?): m/z: calcd for [C18H16BrFN2O2?Na?]: 413.0271; found: 413.0289.
X-ray crystallography For X-ray diffraction experiments, single crystals of compounds 1, 5 and 7 were both grown from methanol. The X-ray diffraction data were collected on a Bruker SMART APEX II CCD diffractometer equipped with a graphite monochromated ˚ ) by using the x-2h scan Mo Ka radiation (k = 0.71073 A technique at room temperature. The structure was solved by direct methods using SHELXS-97 (Sheldrick 1997) and refined using the full-matrix least squares method on F2 with anisotropic thermal parameters for all non-hydrogen atoms by using SHELXL-97. Hydrogen atoms were generated geometrically. The crystal data and details concerning data collection and structure refinement are given in Table 1. Molecular illustrations were prepared using the XP package. Parameters in CIF format are available as electronic supplementary publication from Cambridge Crystallographic Data Centre. Quantum chemical calculations All calculations were carried out using the Gaussian 09 package (Frisch et al. 2009). Density functional theory (DFT) (Kohn and Sham 1965), Becke’s three-parameter hybrid function (B3LYP) (Becke 1993), and LYP correlation function (Lee et al. 1988; Miehlich et al. 1989) were used to fully optimize all the geometries on the energy surface without constraints. To obtain precise results that are in conjunction with experimental results, three basis sets, namely 6-31G*, 6-31 ? G**, and 6-311G*, were tested. Frequency calculations at the B3LYP (with basis sets 6-31G*) level of theory were carried out to confirm stationary points as minima and to obtain the zero-point energies and the thermal correlation data at 1 atm and 298 K. Minimal inhibitory concentration (MIC) assay Based on the CLSI broth microdilution method, the determination of minimum inhibitory concentrations (MICs) via microdilution assay was performed in sterilized 96-well polypropylene microtiter plates (Sigma-Aldrich) in a final volume of 200 lL. Bacteria were grown overnight in nutrient broth. Mueller-Hinton (MH) broth (100 lL) containing bacteria (5 9 105 CFU/mL) was added to 100 lL of the culture medium containing the test compound (0.12 lg/mL to 256 lg/mL in serial twofold dilutions). The plates were incubated at 37 C for 20 h in an incubator. About 50 lL of 0.2 % triphenyl tetrazolium chloride (TTC), a colorimetric indicator, was added to each well of microtiter plates and incubated at 35 C for 1.5 h. The TTC-based MIC was determined as the lowest concentration of oxacillin that showed no red color change indicating complete growth inhibition.
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J. Li et al. Table 1 Crystal data, data collection and structure refinement of compounds 1, 5 and 7
Compound 5
Compound 7
Formula
C28H22O6
C17H16N2O2S
C21H24N2O2
Mr
454.14
312.09
336.18
Temperature (K)
293 (2)
293 (2)
293 (2)
Crystal system
Orthorhombic
Monoclinic
Triclinic
Space group ˚) a (A
Pca21
C2/c
Pı¯
20.5625 (15)
23.3329 (17)
9.1207 (6)
˚) b (A ˚ c (A)
10.5042 (5)
9.0247 (4)
10.4078 (9)
20.7650 (9)
16.4155 (9)
12.1974 (10)
a ()
90
90
106.594 (7)
b ()
90
111.021 (7)
99.170 (6)
c () ˚ 3) V (A
90
90
94.836 (6)
4485.1 (4)
3226.6 (3)
1085.09 (15)
Z
4
8
2
Dcalc (g cm-3)
1.346
1.286
1.171
l (Mo Ka) (mm-1) h range ()
0.095 2.39–25.00
0.209 2.44–25.00
0.077 2.85–24.44
Reflections collected
12,502
5630
6940
No. unique data [R(int)]
6715 [0.0407]
2842 [0.0351]
3816 [0.0333]
No. data with I C 2r(I)
3667
1824
1985
R1
0.0644
0.0561
0.0608
xR2 (all data)
0.1711
0.1569
0.1695
CCDC
1,048,632
1,048,633
1,048,634
Results Molecular structure The crystal structures of compounds 1, 5 and 7 are given in Fig. 2. In crystal structure of compound 1, two 4-hydroxycoumarin moieties are linked through a methylene bridge, wherein one hydrogen atom has been replaced with a 4-isopropylphenyl group; and two classical intramolecular hydrogen bonds (O3–H3O4 and O6–H6O1) between a hydroxyl group of one coumarin fragment and a lacton carbonyl group of another coumarin fragment further stabilize the whole structure. In the crystal structures of compounds 5 and 7, the new formed pyran ring and the adjacent ketone ring are both basically planar, and the two planes are also essentially parallel each other. However, the aromatic ring makes a torsion angle to the pyran ring in the two compounds. Estimation of the single and total HB energies in compounds 1–4 The fully optimized molecular structures of biscoumarins 1–4 with atomic numbering calculated at B3LYP level of theory are shown in Fig. 3. Frequency calculations using the same basis sets have been performed to confirm that the
123
Compound 1
stationary points are minima (zero imaginary frequencies) or transition states (one imaginary frequency) on the potential energy surface. For compound 1, under three different basis sets (6-31G*, 6-31 ? G**, and 6-311G*), the calculated results are very close and essentially in agreement with its single crystal data (the values are not shown). The further theoretical study was performed at B3LYP/631G* level for its lower computational cost. We take compound 1 for example to calculate single and total HB energy. The global minimum structure is stabilized by two HBs (1ab); two higher energy structures is stabilized by one HB (1a and 1b) respectively. The O6–H6O1 HB energy is from the energy difference between 1ab and 1a (1a is a global minimum structure with O3–H3O4 HB), was estimated to be -51.814558 kJ/mol coor by the equation E(O6–H6O1) = Ecoor 1ab E1a . Similarly, the O3–H3O4 HB energy is from the energy difference between 1ab and 1b [1b was obtained from the global minimum structure 1ab, but H3 was rotated around the C3—O3 bond until O3–H3O4 HB rupture occurred (Trendafilova et al. 2004; Mihaylov et al. 2006), was calculated to be -66.1104055 kJ/mol by the equation coor E(O6–H6O1) = Ecoor 1ab E1b . The total HB energy in compound 1 was calculated to be -117.9249635 kJ/mol by the equation E(O3–H3O4) ? E(O6–H6O1). For compounds 2–4, their total HB energy is -117.087429,
Synthesis of biscoumarin and dihydropyran derivatives as two novel classes of potential anti-… Fig. 2 Crystal structures of compounds 1, 5 and 7
Fig. 3 Schematic presentation of compounds 1–4
H3 O3
O
O4
C3
R
C12
C1
H
C19
O1
O6 H6
-120.977789 and -120.3450435 kJ mol-1, respectively. The corresponding values are listed in Table 2. Minimal inhibitory concentration (MIC) assay For compounds 1–8, one drug-sensitive S. aureus (S. aureus ATCC 29213) strain and three MRSA strains (MRSA XJ 75302, Mu50, USA 300 LAC) were used in the systematic analysis of their antibacterial activities in vitro (Table 3). Because of the liposolubility of the three compounds, they were dissolved into the solution with 1 % dimethyl sulfoxide (DMSO) at final concentration. Among the eight compounds, compounds 1 and 2 exerted more potent anti-bacterial activity against the tested S. aureus
O
R=
1
R=
2
R=
O
3
R=
O
4
with MIC value ranged from 16 to 32 lg/mL. Compared with compounds 1–8, the MIC values of levofloxacin, ceftazidime, ceftriaxone, gentamicin and piperacillin against S. aureus (ATCC 29213) strains were lower (less than 8 lg/mL) but were higher against other three strains at varying degrees.
Discussion To get ahead of the problem on bacterial resistance to antibiotics, we must look for new strategies and new drugs. There is a close relationship between anti-bacterial activity and the structures of antibiotics, so the discovery of
123
J. Li et al. Table 2 Total electronic energies (in hartree) and HB energies (in kJ/mol) of hydrogen bonded conformers of compounds 1–4 calculated at B3LYP/6-31G* level of theory
System
Total electronic energiesa
1ab
-1570.470356
1a
-1570.45024
1b
-1570.444795
2ab
-1527.817797
2a
-1527.797835
2b
-1527.792401
3ab
-1531.188113
3a
-1531.168027
3b
-1531.162121
4ab
-1567.108786
4a
-1567.088785
4b
-1567.08295
a
E(O6–H6O1)
E(O3–H3O4)
E(total HB) -117.9249635
-51.814558 -66.1104055 -117.087429 -51.410231 -65.677198 -120.977789 -52.735793 -68.241996 -120.3450435 -52.5126255 -67.832418
ZP corrected
Table 3 MIC of compounds 1–8 and antibiotics in Mueller–Hinton broth culture Drugs
MIC (ug/mL) S. aureas (ATCC 29213)
MRSA (XJ 75302)
Mu50 (ATCC 700699)
LAC (USA 300)
Compound 1
32
32
16
32
Compound 2
16
16
16
32
Compound 3
128–256
64–128
64–128
[256
Compound 4
64–128
128–256
64–128
32–64
Compound 5
[256
[256
[256
[256
Compound 6
[256
[256
[256
[256
Compound 7
256
256
256
256
Compound 8 Levofloxacin
256 \0.125 (S)
256 4 (R)
256 4 (R)
256 8 (R)
Ceftazidime
8 (S)
[256 (R)
256 (R)
64 (R)
Ceftriaxone
2 (S)
[256 (R)
256 (R)
32 (R)
Gentamicin
0.12 (S)
64 (R)
32 (R)
0.25 (S)
Piperacillin
2 (S)
[128 (R)
[128 (R)
8 (R)
S means drug susceptibility, R means drug resistance
antibiotics with novel structures is evidently and urgently. Bisoumarin and dihydropyran derivatives is a plant-derived natural product known for its wide pharmacological properties. In this work, we synthesized the two kinds of compounds (1–8) and studied their in vitro antibacterial activities. The results showed that among the eight compounds, novel biscoumarins 1 and 2 were demonstrated to be the most potent bactericidal effects against four S. aureus bacterial strains with the MIC values of 16–32 lg/mL. Additionally, two asymmetrical intramolecular O–HO HBs in biscoumarins 1–4 was considered as an important factor in assisting the molecule to attain the correct configuration for biological activity (Schiøtt et al. 1998). Our theoretical investigation further revealed that the efficient antibacterial activity in compounds 1 and 2 was consistent
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with their weak HB strengths. The reason may be that intramolecular HB strength is related to the stability of chemical structure, which further affects the binding affinity between molecules and target protein. To further define the mechanism underlying the anti-bacterial activity of compounds 1 and 2 and evaluate correlations with their drug efficacy in vivo, additional experiments should be carried out. Acknowledgments This work was supported by grants from Xi’an science and technology project (CXY1443WL07), the National Natural Science Foundation of China (Nos. 81001460 and 81273555) and the Innovation plan of science and technology of Shaanxi Province (2014KTCL03-03). The authors thank the High Performance Computing Center of Tianjin University and Prof. Xuehao He for the services provided.
Synthesis of biscoumarin and dihydropyran derivatives as two novel classes of potential anti-…
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