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Cocrystals of kaempferol, quercetin and myricetin with 4,4′-bipyridine: Crystal structures, analyses of intermolecular interactions and antibacterial properties
Accepted Manuscript Cocrystals of kaempferol, quercetin and myricetin with 4,4′-bipyridine: Crystal structures, analyses of intermolecular interactions and antibacterial properties Yu-Nan Zhang, He-Mei Yin, Yu Zhang, Da-Jun Zhang, Xin Su, Hai-Xue Kuang PII:
S0022-2860(16)31075-4
DOI:
10.1016/j.molstruc.2016.10.034
Reference:
MOLSTR 23035
To appear in:
Journal of Molecular Structure
Received Date: 19 April 2016 Revised Date:
4 October 2016
Accepted Date: 7 October 2016
Please cite this article as: Y.-N. Zhang, H.-M. Yin, Y. Zhang, D.-J. Zhang, X. Su, H.-X. Kuang, Cocrystals of kaempferol, quercetin and myricetin with 4,4′-bipyridine: Crystal structures, analyses of intermolecular interactions and antibacterial properties, Journal of Molecular Structure (2016), doi: 10.1016/j.molstruc.2016.10.034. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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ACCEPTED MANUSCRIPT Cocrystals of kaempferol, quercetin and myricetin with 4,4'-bipyridine: crystal
structures, analyses of intermolecular interactions and antibacterial properties Yu-Nan Zhanga, He-Mei Yina, Yu Zhanga,*, Da-Jun Zhanga, Xin Sua, Hai-Xue Kuangb 1
Institute of Pharmacy in Heilongjiang Province, Jiamusi University, Heilongjiang Province, Jiamusi, 154007,
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China 2
Heilongjiang University of Chinese Medicine, Heilongjiang Province, Harbin 150040, China
*Corresponding Author: (Yu Zhang) E-mail: [email protected]. Tel: +8615765305157
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Abstract: With an aim to explore the interactions of O-H…N between hydroxyl moiety of the flavonoids and the pyridyl ring of N-containing aromatic amines, three flavonols with varying
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B-ring-hydroxyl groups (kaempferol, quercetin, and myricetin) were selected to combine with 4,4'-bipyridine. As a result, three new cocrystals of flavonols were obtained with a solution evaporation approach. These three cocrystals were characterized by single crystal X-ray diffraction, XPRD, IR and NMR methods. The resulting cocrystals were kaempferol: 4,4'-bipyridine (2:1)
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(KAE·BPY·2H2O), quercetin: 4,4'-bipyridine (1:1.5) (QUE·BPY), and myricetin: 4,4'-bipyridine (1:2) (MYR·BPY·H2O). Structural analyses show that an array of hydrogen bonds and π-π stacking interactions interconnect the molecules to form a two-dimensional (2D) supramolecular layer in
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KAE·BPY·2H2O, QUE·BPY, and MYR·BPY·H2O. In the three cocrystals, they present as three different synthons–ⅠR88(58), Ⅰ R44(42) and, Ⅰ R66(29) with 4,4'-bipyridine, respectively–which may
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yield a strategy for constructing the supramolecule. Cocrystals of flavonols combined with N-containing aromatic amines, 7-OH, B-ring-hydroxyl number and/or the location of the flavonols to play a significant part in extending the dimensionality of the cocrystals. The resulting motif formation and crystal packing in these flavonols cocrystals has combined with N-containing aromatic amines. Additionally, the antibacterial properties of the three cocrystals against Staphylococcus aureus (S. aureus) and Escherichia coli (E. coli) have been investigated.
Keywords: cocrystal; kaempferol; quercetin; myricetin; 4,4'-bipyridine; antibacterial
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1. Introduction
Crystal engineering has been defined as the understanding of intermolecular interactions, the packing principles of molecular crystals, and the use of the knowledge generated for rationally designed of novel solids with targeted structures and desired properties [1,2] One of the goals of
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crystal engineering is to recognize the supramolecular synthons to assemble molecular crystals, among which hydrogen bonds (O-H…O, C-H…O, O-H…N, and so on) and aryl packing (π-π and C-H…π) occupy prominent positions due to their pronounced directionality and relatively high
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strength, which is essential for proper design of desired networks [2–4]. There have been rewarding advances in the design of both MOFs and molecular cocrystals [5, 6]. In recent years, cocrystals
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have emerged as a major research area for obtaining new forms of Active Pharmaceutical Ingredients (API) with improved physicochemical properties (e.g., solubility, bioavailability, stability, or melting point) [7–10].
Flavonoids, as one kind of well-known type of APIs, are found throughout the plant kingdom and
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are of scientific interest because of their antioxidant, antitumor, and anti-inflammatory properties [11]. A classical subclass of these compounds is the flavonols, which are characterized by a hydroxyl on C-3 of the flavone scaffold [12]. Most flavonoids possess aromatic rings and/or a
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variety of hydroxyl substitution patterns, which could make them particularly promising for the formation of cocrystals with aryl packing and/or extended hydrogen bond frameworks [13]. In recent
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years, by selecting the appropriate coformers (CCF), a few cocrystals of flavonoids have been successfully synthesized. Examples include cocrystals of quercetin with nicotinic acid, caffeine, isonicotinamide and theobromine [14–16]; cocrystal of hesperetin with nicotinic acid; cocrystal of baicalein with nicotinamide [17]; cocrystal of genistein with isonicotinamide [18]; cocrystals of fisetin, luteolin and genistein with pyridinecarboxamide and/or caffeine [19–21]; and cocrystal of myricetin with piracetam [22]. Noted that previous studies show that the N-containing aromatic amines were selected as coformers, which show that the O-H…N heterosynthon can be the
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ACCEPTED noticeable motif in cocrystallizing flavonoids MANUSCRIPT [23]. However, the structure-directing effect of N-containing aromatic amines is not clear and certainly bears further investigation. Inspired by the aforementioned considerations, a motivation for exploring the interactions of O-H…N between hydroxyl moiety of the flavonols and the pyridyl ring of N-containing aromatic
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amines has been put forward [11]. Hence, in this study we reverse the usual study process of seeking coformers that will cocrystallize with a given active pharmaceutical ingredient; instead, we seek cocrystals of 4,4'-bipyridine, one of the most commonly used and readily available coformers[24, 25], using three different flavonols with varying B-ring-hydroxyl groups to explore the number and
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direction of intermolecular interactions [26–28]. Our interest in flavonols arises because they possess
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a variety of hydroxyl substitution patterns that make them particularly interesting for the formation of extended hydrogen-bonded structures [29]. By contrast, the 4,4'-bipyridine has a rigid linear structure with terminal N atoms, which are coordination potential sites for hydrogen bonds towards surface hydroxyls of flavonoids [30]. Furthermore, 4,4'-bipyridine with a good π-electron conjugated system is also an indispensable factor for the construction of aryl stacking supported supramolecular
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structures [31]. This class of organic molecules may form noncovalent interaction hydrogen bonds with aryl packing coexisting in one crystal structure. Therefore, 4,4'-bipyridine was selected to
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cocrystallize with a series of flavonols (kaempferol, quercetin, and myricetin, as shown in Scheme. 1), and three cocrystals of 4,4'-bipyridine with kaempferol (KAE·BPY·2H2O), quercetin
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(QUE·BPY), and myricetin (MYR·BPY·H2O) were successfully obtained. Their structures and the antibacterial properties were subsequently investigated. The three title compounds show advantages in terms of antibacterial properties against Staphylococcus aureus and Escherichia coli in comparison to their corresponding parent compounds.
2. Experimental 2.1 Materials and Synthetic Methods
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ACCEPTED MANUSCRIPT Kaempferol (>98%), quercetin (>98%), myricetin (>98%), 4,4'-bipyridine dehydrate, and solvents were received from various commercial sources and used without further purification. KAE·BPY·2H2O. Kaempferol (14.3 mg, 0.05 mmol) and 4,4'-bipyridine dehydrate (4.8 mg, 0.025mmol) were combined in 8.0 mL ethanol and 2.0 mL acetone with stirring at 25°C for 3h. The
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filtrate was evaporated slowly at room temperature; block yellow crystals were obtained after 5 days (Fig. S1a). The resulting products were characterized by single crystal X-ray diffraction, XPRD, IR
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and NMR. The other two cocrystals were prepared under similar conditions and post-processing except for the molar ration of flavonols and 4,4'-bipyridine dehydrate. IR data (KBr cm-1): 3693w,
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3211s, 2974s, 2687m, 2642m, 2614m, 1988w, 1898w, 1761w, 1611s, 1525m, 1454m, 1375m, 1320m, 1180s, 1081s, 1017s, 835s, 733w, 634m, 576m, 477s, 436m (Fig. S2) [32]. QUE·BPY. This cocrystal was prepared by a procedure similar to that which yielded KAE·BPY·2H2O, except using quercetin (15.1mg, 0.05mmol) instead of kaempferol, and
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4,4'-bipyridine dehydrate (19.2mg, 0.1mmol). The dark block yellow crystals were obtained after 20 days (Fig. S1b). IR data (KBr cm-1): 3293s, 3097w, 2925m, 2856m, 2518m, 1832m, 1649s, 1597s,
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1504s, 1411s, 1371s, 1313s, 1240s, 1205m, 1170s, 1093m, 995s, 929w, 884m, 806s, 765m, 733m, 622s, 600m, 460m (Fig. S3) [33].
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MYR·BPY·H2O. Myricetin (15.9mg, 0.05mmol) and 4,4'-bipyridine dehydrate (9.6mg, 0.05mmol) were taken in a 1:1M ratio and dissolved in an ethanol-acetone solution (v/v=4:1 10mL); the solution was stirred at 25°C. After 3h, the filtrate was allowed to stand at room temperature for slow evaporation. The yellow bulk crystals were obtained 10 days later (Fig. S1a). IR data (KBr cm-1): 3718w, 3341s, 3290s, 3099m, 3057m, 2704w, 2573w, 1940w, 1655s, 1597s, 1503s, 1321s, 1205s,
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ACCEPTED MANUSCRIPT 1168s, 1110s, 1053s, 1026s, 999s, 933m, 839m, 808s, 767m, 729m, 646s, 619s, 573m, 524m, 484m (Fig. S4) [34, 35]. 2.2 Infrared spectroscopy analyses (IR)
Samples were scanned in the 400–4000cm-1 region with KBr pellet. 2.3 X-ray powder diffraction (XPRD)
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Infrared spectroscopy analyses were collected on an Alpha Centaur IR spectrophotometer.
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XPRD were carried out on a Bruker equipped with a Rigaku D/max 2500 V PC diffractometer using Cu Kα radiation. The equipment was operated at 30kV and 40 mA, and data were collected at
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room temperature in the range of 2θ=5–35°. 2.4 Single crystal X-ray diffraction analyses
Single crystal X-ray diffraction data collection of cocrystals were performed using a Bruker APEX2 diffractometer with graphite-monochromated Mo Kα radiation (λ=0.71073Å) at 293 K.
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Selected crystallographic data are provided in Table. 1. Multi-scan absorption corrections were applied. The structure was solved by the direct methods and refined by full-matrix least squares on
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F2 using the SHELXS–14 crystallographic software package [36, 37], with anisotropic thermal parameters for all non-H atoms. All H atoms were found in different Fourier maps, but in the final
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refinement cycles, they were repositioned in their calculated positions and refined using a riding model. Simulated XPRD patterns were calculated the PowderCell 2.4 for Windows package by XPRD patterns and DIAMOND was applied for creation of figures [38, 39] 2.5 NMR solution studies The NMR spectra were acquired on a Bruker Avance III 600MHz apparatus equipped with a 5-mm PABBO probe (Bruker Corporation, Fällanden, Switzerland) at room temperature. Typically,
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E. coli. The three cocrystals and their corresponding parent compounds were respectively injected into sterile filter papers at final concentration of 10, 20 or 30 mmol/L. Another sterile filter paper
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was injected with DMSO to act as the control.
3. Results and discussion
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3.1 Single crystal X-ray diffraction
The asymmetric unit of KAE·BPY·2H2O comprises two kaempferol molecules, one 4,4'-bipyridine molecule, and two water molecules in their neutral forms. Four kaempferol molecules, two 4,4'-bipyridine molecules, and two water molecules connect by turns to form an octamer (Fig.
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1a) with a large unique synthon I R88(58) via O4'A-H4'A…O2W, O2W-H2W…O5B, O7B-H7B…N4C and O7A-H7A…N4'C hydrogen bonds, as shown in Scheme 2. The adjacent
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octamers are connected via strong O3B-H3B…O2W, O3A-H3A…O1W, O1W-H1W…O5A and O4'B-H4'B…O1W hydrogen bonds to generate a 2D supramolecular layer (Fig. 1b). In this 2D layer,
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there are two kinds of synthons Ⅰ R44(18) [O3A-H3A…O1W, O1W-H1W…O5A and O5A-H5A…O4A] and Ⅰ R44(18) [O3B-H3B…O2W, O2W-H2W…O5B and O5B-H5B…O4B] (Scheme 2). As a consequence, the neighboring layers are further extended into a 3D network through the water molecules (the O1W-H1W…O7A and O2W-H2W…O7B hydrogen bonds), (Fig. 1 and Table. 2).
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ACCEPTED MANUSCRIPT There are one quercetin molecule and one half of a 4,4'-bipyridine molecule in the asymmetric unit of QUE·BPY, which is shown in Fig. 2a. Within QUE·BPY, two quercetin molecules and two 4,4'-bipyridine molecules alternately embrace to form a tetramer through the synthon Ⅳ R44(42), with intermolecular O4'-H4'···N4'D and O7-H7…N4D hydrogen bonds (Scheme 2). There also
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exists a 4,4'-bipyridine molecule in the internal of tetramer, which is supported by π…π stacking interactions. The tetramers are further linked by interdimer O3-H3…O4 hydrogen bond to form a 1D
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chain along the a axis, in which the synthon Ⅴ R22(10) is constructed by carbonyl and hydroxyl groups (Scheme 2). The neighboring chains afford a 2D layer through the O5'-H5'…O7 hydrogen
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bond. Significantly, the adjacent layers are further linked through C2'D-H2'D…O5' interlayer hydrogen bonds and π-π stacking interactions to generate a 3D structure (Fig. 2 and Table. 3). In the molecular structure of MYR·BPY·H2O, the asymmetric unit comprises one myricetin molecule, three 4,4'-bipyridine molecules, and one water molecule (Fig. 3a). Two myricetin
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molecules are linked by two water molecules through O4'-H4'···O1W and O1W-H1W'…O4' intermolecular hydrogen bonds to form a tetramer, and the tetramers are further linked by an
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interdimer O3-H3···O4 hydrogen bond with a synthon Ⅵ R22(10) (Scheme 2) to generate a chain. Meanwhile, as shown in the Fig. 3b, the adjacent chains connect with each other to form a 2D layer
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through synthon Ⅶ R66(29) (Scheme 2) [O5'-H5'…N4C, O3'-H3'…N4'C, O1W-H1W'…O3', O1W-H1W…N4D, and O4'-H4'…O1W]. Finally, the 2D layers are held together by O7-H7···N4E and C2D-H2D...O4' hydrogen bonds and π-π stacking interactions to form the 3D structure of MYR·BPY·H2O, which is displayed in Fig. 3c. The cocrystals of KAE·BPY·2H2O, QUE·BPY and MYR·BPY·H2O present three different synthons ⅠR88(58), Ⅳ R44(42), and Ⅶ R66(29) with 4,4'-bipyridine, respectively, which may show
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ACCEPTED MANUSCRIPT the strategy in constructing the supramolecular structure. Significantly, the 4,4'-bipyridine molecule is involved in the hydrogen bonds system, which plays a crucial role in determining the structure of the self-assembled cocrystal in KAE·BPY·2H2O, QUE·BPY, and MYR·BPY·H2O. 3.2 XPRD
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The XPRD was used to check the crystalline phase purity of KAE·BPY·2H2O, QUE·BPY, and MYR·BPY·H2O. The results show that the patterns of the products are different from either that of
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flavonols or 4,4'-bipyridine dehydrate (Fig. 4). In addition, all the peaks displayed in the measured patterns closely match those in the simulated patterns generated from single crystal diffraction data,
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confirming the formation of the corresponding molecular compounds KAE·BPY·2H2O, QUE·BPY, and MYR·BPY·H2O. 3.3 Antibacterial properties
Results of inhibitory areas at concentrations of 30mmol/L are shown in Fig. 5. Meanwhile, the
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diameter values (mm) of inhibitory areas are also listed in Table 5. On nutrient agar plates inoculated with S. aureus and E. coli, we see clearly that the inhibitory areas created around the filter papers
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injected with the three cocrystals are wider than the inhibitory areas of their corresponding parent flavonols tested at the same concentrations, and of the control. The inhibition effects of three
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cocrystals depend on the concentration of test samples; the test samples with higher concentrations created wider inhibitory areas (Fig. S5-S6). 3.4NMR solution study 1
H NMR and
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C NMR spectra records for crystalline samples of KAE·BPY·2H2O, QUE·BPY
and MYR·BPY·H2O dissolved in DMSO-d6 (Fig. S7-S12) confirmed their identity, purity and 4,4'-bipyridine stoichiometric ratio.
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4. Conclusions
In this paper, three new cocrystals of flavonols with varying B-ring-hydroxyl groups (kaempferol, quercetin and myricetin) combined with 4,4'-bipyridine were obtained using a solution evaporation approach. This was done with the aim of exploring the interactions of O-H…N between hydroxyl
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moiety of the flavonoids and the pyridyl ring of N-containing aromatic amines, namely KAE·BPY·2H2O, QUE·BPY and MYR·BPY·H2O. The single crystal X-ray analyses reveal that an
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array of hydrogen bonds and π-π stacking interactions interconnect the molecules to form 2D supramolecular layer frameworks in all three cocrystals. The three cocrystals present three different
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synthons–ⅠR88(58), Ⅰ R44(42), and Ⅰ R66(29) with 4,4'-bipyridine, respectively–which may show the strategy in constructing the supramolecule. Interestingly, the number of BPY molecules are one, two, and three in the molecular structures of KAE·BPY·2H2O, QUE·BPY and MYR·BPY·H2O, respectively. In other words, kaempferol possesses one hydroxyl group, quercetin possesses two, and
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myricetin possesses three; such differences cause the difference in acidity between the flavonoids. Kaempferol is the weakest acid, followed by quercetin, while myricetin is the most acidic of them all.
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However, BPY is an N-containing aromatic amine with alkali. Therefore, we speculate that kaempferol might form intermolecular hydrogen bonds with one BPY molecule because of it is the
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weakest acid of the abovementioned flavonols. Quercetin has mid-range acidity among these three flavonols; therefore, quercetin might form intermolecular hydrogen bonds with two BPY molecules. Myricetin, the most acidic, might combine with three BPY molecules to form MYR·BPY·H2O. The result demonstrates that the higher the acidity of a flavonol, the more BPY molecules could form intermolecular hydrogen bonds with that flavonol. Most notably, the three cocrystals all share one thing in common—which is that one BPY molecule is connected to flavonol in 7-OH. That being
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ACCEPTED MANUSCRIPT said, another BPY molecule is connected with 4'-OH of quercetin in QUE·BPY, two BPY molecules are connected with 3'-OH and 5'-OH of myricetin in MYR·BPY·H2O. These results imply that 7-OH of flavonol preferentially form intermolecular hydrogen bonds with N-containing aromatic amines, followed by the 3'-OH/5'-OH or 4'-OH.
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In summary, we have provided an insight into three examples of flavonols. The results show that 7-OH, and B-ring-hydroxyl number and/or location of flavonols are key factors for cocrystal
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formation. The motif formation and crystal packing in cocrystals of flavonols combined with N-containing aromatic amines. Furthermore, three cocrystals all exhibit admirable antibacterial
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properties against S. aureus and E. coli, which may be effectively applied in antibacterial materials.
Supplementary Date
Crystallographic data in CIF format. CCDC reference numbers: 1434453 for KAE·BPY·2H2O, 1434450 for QUE·BPY and 1434451 for MYR·BPY·H2O. These data can be obtained free of
Acknowledgements
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charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
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This work was supported by the China Postdoctoral Science Foundation (2014M561382), the
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Postgraduate Science and Technology Innovation Project of Jiamusi University (LM2015_094) and the Innovation Team Project of Jiamusi University (CXTD-2013-05).
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Figure captions
Scheme. 1. Molecular structures of kaempferol, quercetin, myricetin and 4,4'-bipyridine Scheme.
2.
Supramolecular
synthons
of
cocrystals
KAE·BPY·2H2O,
QUE·BPY
and
MYR·BPY·H2O
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Fig. 1. Structures of the (a) octamer, (b) 2D supramolecular layer (the hydrogen bonds are indicated as broken lines in this and the subsequent figures), (c) 3D network in KAE·BPY·2H2O Fig. 2. Structures of the (a) tetramer, (b) 2D supramolecular layer (the hydrogen bonds are indicated
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as broken lines in this and the subsequent figures), (c) 3D network in QUE·BPY
Fig. 3. Structures of the (a) tetramer, (b) 2D supramolecular layer (the hydrogen bonds are indicated
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as broken lines in this and the subsequent figures), (c) 3D network in MYR·BPY·H2O Fig. 4. XPRD patterns for (a) KAE·BPY·2H2O (b) QUE·BPY and (c) MYR·BPY·H2O Fig. 5. Results of inhibitory areas of three cocrystals on microbes at concentrations of 30mmol/L Table 1. Crystallographic data for three cocrystals
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Table 2. Hydrogen bond lengths/Å and angles/° for KAE·BPY·2H2O Table 3. Hydrogen bond lengths/Å and angles/° for QUE·BPY Table 4. Hydrogen bond lengths/Å and angles/° for MYR·BPY·H2O
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Table 5. The diameter values (mm) of inhibitory areas of KAE·BPY·2H2O, QUE·BPY and
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MYR·BPY·H2O on bacteria
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Table Cocrystals of kaempferol, quercetin and myricetin with 4,4'-bipyridine: crystal structures, analysis of intermolecular
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interactions and spectral characterization Yu-Nan Zhanga, He-Mei Yina, Yu Zhanga,*, Da-Jun Zhanga, Xin Sua, Hai-Xue Kuangb a
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Table. 1 Crystallographic data for three cocrystals KAE·BPY·2H2O CCDC No. Formulae Formula weight(g mol-1)
QUE·BPY
1434453 1434450 2C15H10O6 · C10H8N2 · 2H2O C15H10O7 · 1.5C10H8N2 764.68 536.51 _
P1 Triclinic 8.6015(5) 9.8233(6) 22.2693(15) 77.584(5) 86.775(5) 68.900(6) 1714.0(2) 2 0.114 1.482 0.1417 0.0722 0.0350 3.545-24.998 6060 / 529 / 0 12,016 / 6060 1.000 0.195 / -0.243
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Space group Cystal system a(Å) b(Å) c(Å) α(o) β(o) γ(o) V (Å3) Z µ (mm-1) Dcalc (g⋅cm-3) wR2 [reflections] R [I > 2σ(I)] Rint θ(°) Data/parameters/restraints Reflns collected/unique GOFs ∆ρ max/∆ρ min (e Å-3)
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Institute of Pharmacy in Heilongjiang Province, Jiamusi University, Heilongjiang Province, Jiamusi, 154007, China b Heilongjiang University of Chinese Medicine, Heilongjiang Province, Harbin 150040, China *Corresponding author: (Yu Zhang) E-mail: [email protected]. Tel: +8615765305157
_
P1 Triclinic 9.8554(6) 10.8071(10) 13.0414(9) 99.877(7) 94.907(5) 106.385(6) 1299.61(18) 2 0.099 1.371 0.1647 0.0550 0.0181 3.003-25.999 5108/ 366 / 0 9989 / 5108 1.000 0.310 / -0.222
MYR·BPY·H2O 1434451 C15H10O8 ·2C10H8N2· H2O 648.61 _
P1 Triclinic 9.3467(8) 10.2752(8) 17.7595(15) 82.336(7) 84.365(7) 63.362(8) 1509.5(2) 2 0.105 1.427 0.1353 0.0767 0.0945 3.373-24.997 5297 / 438 / 16 9541 / 5297 1.002 0.330 / -0.366
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R1 = ∑||F0|-|FC||/∑|F0|; wR2 = ∑[w(F02-FC2)2]/∑[w(F02)2]1/2
Table 2. Hydrogen bond lengths/Å and angles/° for KAE·BPY·2H2O
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D-H···A d(D-H) d(H···A) d(D···A) ∠DHA O5A-H5A···O4A 0.82 1.85 148.70 2.588(3) i O5A-H5A···O4A 0.82 2.63 112.70 3.041(3) ⅱ 0.82 1.86 168.70 2.665(3) O7A-H7A···N4'C ⅲ O3A-H3A···O1W 0.82 1.93 159.80 2.712(3) O3B-H3B···O4B 0.82 2.32 112.70 2.739(3) ⅳ O3B-H3B···O2W 0.82 1.94 154.50 2.707(3) ⅳ O7B-H7B···N4C 0.82 1.88 163.60 2.675(3) O5B-H5B···O4B 0.82 1.86 148.10 2.596(3) ⅳ 0.82 1.90 160.80 2.692(3) O4'B-H4'B···O1W O4'A-H4'A···O2W 0.82 1.91 166.70 2.712(3) ⅳ C3C-H3C···O4'A 0.93 2.61 138.10 3.357(4) ⅳ 0.91(4) 1.90(5) 164(4) 2.791(3) O1W-H1W···O5A ⅳ O1W-H1W'···O7A 0.75(3) 2.18(3) 157(4) 2.880(4) 0.76(6) 2.01(6) 167(6) 2.754(4) O2W-H2W'···O5Bⅳ O2W-H2W···O7B 0.95(6) 2.02(6) 157(4) 2.920(4) Symmetry codes: (ⅳ) -x+2, -y+2, -z; (ⅳ) x, y+1, z-1; (ⅳ) x+1, y, z; (ⅳ) x-1, y+1, z; (ⅳ) x, y-1, z; (ⅳ) x, y+1, z; (ⅳ) -x, -y+2, -z+1; (ⅳ) -x+1, -y+2, -z; (ⅳ) -x, -y+2, -z; (ⅳ) -x, -y+1, -z+1.
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Table 3. Hydrogen bond lengths/Å and angles/° for QUE·BPY D-H···A d(D-H) d(H···A) d(D···A) ∠DHA ⅰ C2'D-H2'D···O5' 0.93 2.53 145.9 3.341(3) O5'-H5'···O4' 0.82 2.30 111.5 2.7110(19) ⅱ O5'-H5'···O7 0.82 1.99 157.4 2.7650(18) ⅲ O4'-H4'···N4'D 0.82 1.90 177.9 2.723(2) ⅳ O7-H7···N4D 0.82 1.86 169 2.665(2) O3-H3···O4 0.82 2.28 112.9 2.711(2) ⅴ O3-H3···O4 0.82 1.94 148.8 2.6774(18) O5-H5···O4 0.82 1.90 147.6 2.6251(19) C6'-H6'···O3 0.93 2.22 125.8 2.868(2) Symmetry codes: (ⅳ) -x+1, -y+1, -z+2; (ⅳ) x, y, z+1; (ⅳ) x-1, y, z; (ⅳ) -x, -y+1, -z+1; (ⅳ) -x+1, -y, -z+1. Table 4. Hydrogen bond lengths/Å and angles/° for MYR·BPY·H2O D-H···A d(D-H) d(H···A) ∠DHA O3-H3...O4 0.82 2.269 114.33 ⅰ O3-H3...O4 0.82 1.985 153.59
d(D···A) 2.711 2.744
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ⅱ
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Table 5. The diameter values (mm) of inhibitory areas of KAE·BPY·2H2O, QUE·BPY and MYR·BPY·H2O on bacteria S. aureus (mm) E. coli (mm) 10 20 30 (mmol/L) (mmol/L) (mmol/L) 11
9
10
18
14
18
kaempferol
7
8
7
10
12
9
QUE·BPY
9
11
12
15
14
17
quercetin
8
9
9
11
12
10
MYR·BPY·H2O
10
11
10
20
24
26
myricetin
9
8
9
18
22
22
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KAE·BPY·2H2O
10 20 30 (mmol/L) (mmol/L) (mmol/L)
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Figures Cocrystals
of
kaempferol,
quercetin
and
myricetin
with
4,4'-bipyridine: crystal structures, analyses of intermolecular
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interactions and antibacterial properties
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Yu-Nan Zhanga, He-Mei Yina, Yu Zhanga,*, Da-Jun Zhanga, Xin Sua, Hai-Xue Kuangb a Institute of Pharmacy in Heilongjiang Province, Jiamusi University, Heilongjiang Province, Jiamusi, 154007, China b Heilongjiang University of Chinese Medicine, Heilongjiang Province, Harbin 150040, China *Corresponding author: (Yu Zhang) E-mail: [email protected]. Tel: +8615765305157
Fig. 1. Structures of the (a) hexamer, (b) 2D hydrogen bonds layer (the hydrogen bonds are indicated as broken lines in this and the subsequent figures), (c) 3D network in KAE·BPY·2H2O
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Fig. 2. Structures of the (a) tetramer, (b) 2D hydrogen bonds layer (the hydrogen bonds are indicated as broken lines in this and the subsequent figures), (c) 3D network in QUE·BPY
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Fig. 3. Structures of the (a) tetramer, (b) 2D hydrogen bonds layer (the hydrogen
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bonds are indicated as broken lines in this and the subsequent figures), (c) 3D network in MYR·BPY·H2O
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Fig. 4. XPRD patterns for (a) KAE·BPY·2H2O (b) QUE·BPY and (c)
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MYR·BPY·H2O
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Fig. 5. Results of inhibitory areas of three cocrystals on microbes at concentrations of
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30mmol/L
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Schemes Cocrystals
of
kaempferol,
quercetin
and
myricetin
with
4,4'-bipyridine: crystal structures, analyses of intermolecular
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interactions and antibacterial properties
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Yu-Nan Zhanga, He-Mei Yina, Yu Zhanga,*, Da-Jun Zhanga, Xin Sua, Hai-Xue Kuangb a Institute of Pharmacy in Heilongjiang Province, Jiamusi University, Heilongjiang Province, Jiamusi, 154007, China b Heilongjiang University of Chinese Medicine, Heilongjiang Province, Harbin 150040, China *Corresponding author: (Yu Zhang) E-mail: [email protected]. Tel: +8615765305157
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Scheme. 1 Molecular structures of kaempferol, quercetin, myricetin and 4,4'-bipyridine
Scheme. 2. Supramolecular synthons of cocrystals KAE·BPY·2H2O, QUE·BPY and MYR·BPY·H2O
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Highlights 1. Three cocrystals of flavonols with varying B-ring-hydroxyl groups
were obtained in solution evaporation approach.
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(kaempferol, quercetin and myricetin) combined with 4,4'-bipyridine
2. In cocrystals of KAE·BPY·2H2O, QUE·BPY and MYR·BPY·H2O,
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R66(29) with 4,4'-bipyridine, respectively.
R88(58),
R44(42) and
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they present three different synthons
3. The three cocrystals all show admirable antibacterial properties against
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S. aureus and E. coli，as related to parent flavonols, respectively.
S0022-2860(16)31075-4
DOI:
10.1016/j.molstruc.2016.10.034
Reference:
MOLSTR 23035
To appear in:
Journal of Molecular Structure
Received Date: 19 April 2016 Revised Date:
4 October 2016
Accepted Date: 7 October 2016
Please cite this article as: Y.-N. Zhang, H.-M. Yin, Y. Zhang, D.-J. Zhang, X. Su, H.-X. Kuang, Cocrystals of kaempferol, quercetin and myricetin with 4,4′-bipyridine: Crystal structures, analyses of intermolecular interactions and antibacterial properties, Journal of Molecular Structure (2016), doi: 10.1016/j.molstruc.2016.10.034. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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ACCEPTED MANUSCRIPT Cocrystals of kaempferol, quercetin and myricetin with 4,4'-bipyridine: crystal
structures, analyses of intermolecular interactions and antibacterial properties Yu-Nan Zhanga, He-Mei Yina, Yu Zhanga,*, Da-Jun Zhanga, Xin Sua, Hai-Xue Kuangb 1
Institute of Pharmacy in Heilongjiang Province, Jiamusi University, Heilongjiang Province, Jiamusi, 154007,
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China 2
Heilongjiang University of Chinese Medicine, Heilongjiang Province, Harbin 150040, China
*Corresponding Author: (Yu Zhang) E-mail: [email protected]. Tel: +8615765305157
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Abstract: With an aim to explore the interactions of O-H…N between hydroxyl moiety of the flavonoids and the pyridyl ring of N-containing aromatic amines, three flavonols with varying
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B-ring-hydroxyl groups (kaempferol, quercetin, and myricetin) were selected to combine with 4,4'-bipyridine. As a result, three new cocrystals of flavonols were obtained with a solution evaporation approach. These three cocrystals were characterized by single crystal X-ray diffraction, XPRD, IR and NMR methods. The resulting cocrystals were kaempferol: 4,4'-bipyridine (2:1)
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(KAE·BPY·2H2O), quercetin: 4,4'-bipyridine (1:1.5) (QUE·BPY), and myricetin: 4,4'-bipyridine (1:2) (MYR·BPY·H2O). Structural analyses show that an array of hydrogen bonds and π-π stacking interactions interconnect the molecules to form a two-dimensional (2D) supramolecular layer in
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KAE·BPY·2H2O, QUE·BPY, and MYR·BPY·H2O. In the three cocrystals, they present as three different synthons–ⅠR88(58), Ⅰ R44(42) and, Ⅰ R66(29) with 4,4'-bipyridine, respectively–which may
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yield a strategy for constructing the supramolecule. Cocrystals of flavonols combined with N-containing aromatic amines, 7-OH, B-ring-hydroxyl number and/or the location of the flavonols to play a significant part in extending the dimensionality of the cocrystals. The resulting motif formation and crystal packing in these flavonols cocrystals has combined with N-containing aromatic amines. Additionally, the antibacterial properties of the three cocrystals against Staphylococcus aureus (S. aureus) and Escherichia coli (E. coli) have been investigated.
Keywords: cocrystal; kaempferol; quercetin; myricetin; 4,4'-bipyridine; antibacterial
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1. Introduction
Crystal engineering has been defined as the understanding of intermolecular interactions, the packing principles of molecular crystals, and the use of the knowledge generated for rationally designed of novel solids with targeted structures and desired properties [1,2] One of the goals of
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crystal engineering is to recognize the supramolecular synthons to assemble molecular crystals, among which hydrogen bonds (O-H…O, C-H…O, O-H…N, and so on) and aryl packing (π-π and C-H…π) occupy prominent positions due to their pronounced directionality and relatively high
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strength, which is essential for proper design of desired networks [2–4]. There have been rewarding advances in the design of both MOFs and molecular cocrystals [5, 6]. In recent years, cocrystals
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have emerged as a major research area for obtaining new forms of Active Pharmaceutical Ingredients (API) with improved physicochemical properties (e.g., solubility, bioavailability, stability, or melting point) [7–10].
Flavonoids, as one kind of well-known type of APIs, are found throughout the plant kingdom and
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are of scientific interest because of their antioxidant, antitumor, and anti-inflammatory properties [11]. A classical subclass of these compounds is the flavonols, which are characterized by a hydroxyl on C-3 of the flavone scaffold [12]. Most flavonoids possess aromatic rings and/or a
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variety of hydroxyl substitution patterns, which could make them particularly promising for the formation of cocrystals with aryl packing and/or extended hydrogen bond frameworks [13]. In recent
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years, by selecting the appropriate coformers (CCF), a few cocrystals of flavonoids have been successfully synthesized. Examples include cocrystals of quercetin with nicotinic acid, caffeine, isonicotinamide and theobromine [14–16]; cocrystal of hesperetin with nicotinic acid; cocrystal of baicalein with nicotinamide [17]; cocrystal of genistein with isonicotinamide [18]; cocrystals of fisetin, luteolin and genistein with pyridinecarboxamide and/or caffeine [19–21]; and cocrystal of myricetin with piracetam [22]. Noted that previous studies show that the N-containing aromatic amines were selected as coformers, which show that the O-H…N heterosynthon can be the
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ACCEPTED noticeable motif in cocrystallizing flavonoids MANUSCRIPT [23]. However, the structure-directing effect of N-containing aromatic amines is not clear and certainly bears further investigation. Inspired by the aforementioned considerations, a motivation for exploring the interactions of O-H…N between hydroxyl moiety of the flavonols and the pyridyl ring of N-containing aromatic
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amines has been put forward [11]. Hence, in this study we reverse the usual study process of seeking coformers that will cocrystallize with a given active pharmaceutical ingredient; instead, we seek cocrystals of 4,4'-bipyridine, one of the most commonly used and readily available coformers[24, 25], using three different flavonols with varying B-ring-hydroxyl groups to explore the number and
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direction of intermolecular interactions [26–28]. Our interest in flavonols arises because they possess
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a variety of hydroxyl substitution patterns that make them particularly interesting for the formation of extended hydrogen-bonded structures [29]. By contrast, the 4,4'-bipyridine has a rigid linear structure with terminal N atoms, which are coordination potential sites for hydrogen bonds towards surface hydroxyls of flavonoids [30]. Furthermore, 4,4'-bipyridine with a good π-electron conjugated system is also an indispensable factor for the construction of aryl stacking supported supramolecular
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structures [31]. This class of organic molecules may form noncovalent interaction hydrogen bonds with aryl packing coexisting in one crystal structure. Therefore, 4,4'-bipyridine was selected to
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cocrystallize with a series of flavonols (kaempferol, quercetin, and myricetin, as shown in Scheme. 1), and three cocrystals of 4,4'-bipyridine with kaempferol (KAE·BPY·2H2O), quercetin
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(QUE·BPY), and myricetin (MYR·BPY·H2O) were successfully obtained. Their structures and the antibacterial properties were subsequently investigated. The three title compounds show advantages in terms of antibacterial properties against Staphylococcus aureus and Escherichia coli in comparison to their corresponding parent compounds.
2. Experimental 2.1 Materials and Synthetic Methods
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ACCEPTED MANUSCRIPT Kaempferol (>98%), quercetin (>98%), myricetin (>98%), 4,4'-bipyridine dehydrate, and solvents were received from various commercial sources and used without further purification. KAE·BPY·2H2O. Kaempferol (14.3 mg, 0.05 mmol) and 4,4'-bipyridine dehydrate (4.8 mg, 0.025mmol) were combined in 8.0 mL ethanol and 2.0 mL acetone with stirring at 25°C for 3h. The
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filtrate was evaporated slowly at room temperature; block yellow crystals were obtained after 5 days (Fig. S1a). The resulting products were characterized by single crystal X-ray diffraction, XPRD, IR
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and NMR. The other two cocrystals were prepared under similar conditions and post-processing except for the molar ration of flavonols and 4,4'-bipyridine dehydrate. IR data (KBr cm-1): 3693w,
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3211s, 2974s, 2687m, 2642m, 2614m, 1988w, 1898w, 1761w, 1611s, 1525m, 1454m, 1375m, 1320m, 1180s, 1081s, 1017s, 835s, 733w, 634m, 576m, 477s, 436m (Fig. S2) [32]. QUE·BPY. This cocrystal was prepared by a procedure similar to that which yielded KAE·BPY·2H2O, except using quercetin (15.1mg, 0.05mmol) instead of kaempferol, and
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4,4'-bipyridine dehydrate (19.2mg, 0.1mmol). The dark block yellow crystals were obtained after 20 days (Fig. S1b). IR data (KBr cm-1): 3293s, 3097w, 2925m, 2856m, 2518m, 1832m, 1649s, 1597s,
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1504s, 1411s, 1371s, 1313s, 1240s, 1205m, 1170s, 1093m, 995s, 929w, 884m, 806s, 765m, 733m, 622s, 600m, 460m (Fig. S3) [33].
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MYR·BPY·H2O. Myricetin (15.9mg, 0.05mmol) and 4,4'-bipyridine dehydrate (9.6mg, 0.05mmol) were taken in a 1:1M ratio and dissolved in an ethanol-acetone solution (v/v=4:1 10mL); the solution was stirred at 25°C. After 3h, the filtrate was allowed to stand at room temperature for slow evaporation. The yellow bulk crystals were obtained 10 days later (Fig. S1a). IR data (KBr cm-1): 3718w, 3341s, 3290s, 3099m, 3057m, 2704w, 2573w, 1940w, 1655s, 1597s, 1503s, 1321s, 1205s,
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Samples were scanned in the 400–4000cm-1 region with KBr pellet. 2.3 X-ray powder diffraction (XPRD)
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Infrared spectroscopy analyses were collected on an Alpha Centaur IR spectrophotometer.
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XPRD were carried out on a Bruker equipped with a Rigaku D/max 2500 V PC diffractometer using Cu Kα radiation. The equipment was operated at 30kV and 40 mA, and data were collected at
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room temperature in the range of 2θ=5–35°. 2.4 Single crystal X-ray diffraction analyses
Single crystal X-ray diffraction data collection of cocrystals were performed using a Bruker APEX2 diffractometer with graphite-monochromated Mo Kα radiation (λ=0.71073Å) at 293 K.
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Selected crystallographic data are provided in Table. 1. Multi-scan absorption corrections were applied. The structure was solved by the direct methods and refined by full-matrix least squares on
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F2 using the SHELXS–14 crystallographic software package [36, 37], with anisotropic thermal parameters for all non-H atoms. All H atoms were found in different Fourier maps, but in the final
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refinement cycles, they were repositioned in their calculated positions and refined using a riding model. Simulated XPRD patterns were calculated the PowderCell 2.4 for Windows package by XPRD patterns and DIAMOND was applied for creation of figures [38, 39] 2.5 NMR solution studies The NMR spectra were acquired on a Bruker Avance III 600MHz apparatus equipped with a 5-mm PABBO probe (Bruker Corporation, Fällanden, Switzerland) at room temperature. Typically,
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E. coli. The three cocrystals and their corresponding parent compounds were respectively injected into sterile filter papers at final concentration of 10, 20 or 30 mmol/L. Another sterile filter paper
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3. Results and discussion
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3.1 Single crystal X-ray diffraction
The asymmetric unit of KAE·BPY·2H2O comprises two kaempferol molecules, one 4,4'-bipyridine molecule, and two water molecules in their neutral forms. Four kaempferol molecules, two 4,4'-bipyridine molecules, and two water molecules connect by turns to form an octamer (Fig.
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1a) with a large unique synthon I R88(58) via O4'A-H4'A…O2W, O2W-H2W…O5B, O7B-H7B…N4C and O7A-H7A…N4'C hydrogen bonds, as shown in Scheme 2. The adjacent
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octamers are connected via strong O3B-H3B…O2W, O3A-H3A…O1W, O1W-H1W…O5A and O4'B-H4'B…O1W hydrogen bonds to generate a 2D supramolecular layer (Fig. 1b). In this 2D layer,
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there are two kinds of synthons Ⅰ R44(18) [O3A-H3A…O1W, O1W-H1W…O5A and O5A-H5A…O4A] and Ⅰ R44(18) [O3B-H3B…O2W, O2W-H2W…O5B and O5B-H5B…O4B] (Scheme 2). As a consequence, the neighboring layers are further extended into a 3D network through the water molecules (the O1W-H1W…O7A and O2W-H2W…O7B hydrogen bonds), (Fig. 1 and Table. 2).
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exists a 4,4'-bipyridine molecule in the internal of tetramer, which is supported by π…π stacking interactions. The tetramers are further linked by interdimer O3-H3…O4 hydrogen bond to form a 1D
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chain along the a axis, in which the synthon Ⅴ R22(10) is constructed by carbonyl and hydroxyl groups (Scheme 2). The neighboring chains afford a 2D layer through the O5'-H5'…O7 hydrogen
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bond. Significantly, the adjacent layers are further linked through C2'D-H2'D…O5' interlayer hydrogen bonds and π-π stacking interactions to generate a 3D structure (Fig. 2 and Table. 3). In the molecular structure of MYR·BPY·H2O, the asymmetric unit comprises one myricetin molecule, three 4,4'-bipyridine molecules, and one water molecule (Fig. 3a). Two myricetin
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molecules are linked by two water molecules through O4'-H4'···O1W and O1W-H1W'…O4' intermolecular hydrogen bonds to form a tetramer, and the tetramers are further linked by an
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interdimer O3-H3···O4 hydrogen bond with a synthon Ⅵ R22(10) (Scheme 2) to generate a chain. Meanwhile, as shown in the Fig. 3b, the adjacent chains connect with each other to form a 2D layer
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through synthon Ⅶ R66(29) (Scheme 2) [O5'-H5'…N4C, O3'-H3'…N4'C, O1W-H1W'…O3', O1W-H1W…N4D, and O4'-H4'…O1W]. Finally, the 2D layers are held together by O7-H7···N4E and C2D-H2D...O4' hydrogen bonds and π-π stacking interactions to form the 3D structure of MYR·BPY·H2O, which is displayed in Fig. 3c. The cocrystals of KAE·BPY·2H2O, QUE·BPY and MYR·BPY·H2O present three different synthons ⅠR88(58), Ⅳ R44(42), and Ⅶ R66(29) with 4,4'-bipyridine, respectively, which may show
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ACCEPTED MANUSCRIPT the strategy in constructing the supramolecular structure. Significantly, the 4,4'-bipyridine molecule is involved in the hydrogen bonds system, which plays a crucial role in determining the structure of the self-assembled cocrystal in KAE·BPY·2H2O, QUE·BPY, and MYR·BPY·H2O. 3.2 XPRD
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The XPRD was used to check the crystalline phase purity of KAE·BPY·2H2O, QUE·BPY, and MYR·BPY·H2O. The results show that the patterns of the products are different from either that of
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flavonols or 4,4'-bipyridine dehydrate (Fig. 4). In addition, all the peaks displayed in the measured patterns closely match those in the simulated patterns generated from single crystal diffraction data,
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confirming the formation of the corresponding molecular compounds KAE·BPY·2H2O, QUE·BPY, and MYR·BPY·H2O. 3.3 Antibacterial properties
Results of inhibitory areas at concentrations of 30mmol/L are shown in Fig. 5. Meanwhile, the
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diameter values (mm) of inhibitory areas are also listed in Table 5. On nutrient agar plates inoculated with S. aureus and E. coli, we see clearly that the inhibitory areas created around the filter papers
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injected with the three cocrystals are wider than the inhibitory areas of their corresponding parent flavonols tested at the same concentrations, and of the control. The inhibition effects of three
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cocrystals depend on the concentration of test samples; the test samples with higher concentrations created wider inhibitory areas (Fig. S5-S6). 3.4NMR solution study 1
H NMR and
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C NMR spectra records for crystalline samples of KAE·BPY·2H2O, QUE·BPY
and MYR·BPY·H2O dissolved in DMSO-d6 (Fig. S7-S12) confirmed their identity, purity and 4,4'-bipyridine stoichiometric ratio.
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4. Conclusions
In this paper, three new cocrystals of flavonols with varying B-ring-hydroxyl groups (kaempferol, quercetin and myricetin) combined with 4,4'-bipyridine were obtained using a solution evaporation approach. This was done with the aim of exploring the interactions of O-H…N between hydroxyl
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moiety of the flavonoids and the pyridyl ring of N-containing aromatic amines, namely KAE·BPY·2H2O, QUE·BPY and MYR·BPY·H2O. The single crystal X-ray analyses reveal that an
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array of hydrogen bonds and π-π stacking interactions interconnect the molecules to form 2D supramolecular layer frameworks in all three cocrystals. The three cocrystals present three different
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synthons–ⅠR88(58), Ⅰ R44(42), and Ⅰ R66(29) with 4,4'-bipyridine, respectively–which may show the strategy in constructing the supramolecule. Interestingly, the number of BPY molecules are one, two, and three in the molecular structures of KAE·BPY·2H2O, QUE·BPY and MYR·BPY·H2O, respectively. In other words, kaempferol possesses one hydroxyl group, quercetin possesses two, and
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myricetin possesses three; such differences cause the difference in acidity between the flavonoids. Kaempferol is the weakest acid, followed by quercetin, while myricetin is the most acidic of them all.
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However, BPY is an N-containing aromatic amine with alkali. Therefore, we speculate that kaempferol might form intermolecular hydrogen bonds with one BPY molecule because of it is the
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weakest acid of the abovementioned flavonols. Quercetin has mid-range acidity among these three flavonols; therefore, quercetin might form intermolecular hydrogen bonds with two BPY molecules. Myricetin, the most acidic, might combine with three BPY molecules to form MYR·BPY·H2O. The result demonstrates that the higher the acidity of a flavonol, the more BPY molecules could form intermolecular hydrogen bonds with that flavonol. Most notably, the three cocrystals all share one thing in common—which is that one BPY molecule is connected to flavonol in 7-OH. That being
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ACCEPTED MANUSCRIPT said, another BPY molecule is connected with 4'-OH of quercetin in QUE·BPY, two BPY molecules are connected with 3'-OH and 5'-OH of myricetin in MYR·BPY·H2O. These results imply that 7-OH of flavonol preferentially form intermolecular hydrogen bonds with N-containing aromatic amines, followed by the 3'-OH/5'-OH or 4'-OH.
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In summary, we have provided an insight into three examples of flavonols. The results show that 7-OH, and B-ring-hydroxyl number and/or location of flavonols are key factors for cocrystal
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formation. The motif formation and crystal packing in cocrystals of flavonols combined with N-containing aromatic amines. Furthermore, three cocrystals all exhibit admirable antibacterial
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properties against S. aureus and E. coli, which may be effectively applied in antibacterial materials.
Supplementary Date
Crystallographic data in CIF format. CCDC reference numbers: 1434453 for KAE·BPY·2H2O, 1434450 for QUE·BPY and 1434451 for MYR·BPY·H2O. These data can be obtained free of
Acknowledgements
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charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
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This work was supported by the China Postdoctoral Science Foundation (2014M561382), the
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Postgraduate Science and Technology Innovation Project of Jiamusi University (LM2015_094) and the Innovation Team Project of Jiamusi University (CXTD-2013-05).
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[39] K. Brandenburg, DIAMOND. Crystal Impact GbR, Bonn, Germany, 2005.
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Figure captions
Scheme. 1. Molecular structures of kaempferol, quercetin, myricetin and 4,4'-bipyridine Scheme.
2.
Supramolecular
synthons
of
cocrystals
KAE·BPY·2H2O,
QUE·BPY
and
MYR·BPY·H2O
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Fig. 1. Structures of the (a) octamer, (b) 2D supramolecular layer (the hydrogen bonds are indicated as broken lines in this and the subsequent figures), (c) 3D network in KAE·BPY·2H2O Fig. 2. Structures of the (a) tetramer, (b) 2D supramolecular layer (the hydrogen bonds are indicated
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as broken lines in this and the subsequent figures), (c) 3D network in QUE·BPY
Fig. 3. Structures of the (a) tetramer, (b) 2D supramolecular layer (the hydrogen bonds are indicated
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as broken lines in this and the subsequent figures), (c) 3D network in MYR·BPY·H2O Fig. 4. XPRD patterns for (a) KAE·BPY·2H2O (b) QUE·BPY and (c) MYR·BPY·H2O Fig. 5. Results of inhibitory areas of three cocrystals on microbes at concentrations of 30mmol/L Table 1. Crystallographic data for three cocrystals
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Table 2. Hydrogen bond lengths/Å and angles/° for KAE·BPY·2H2O Table 3. Hydrogen bond lengths/Å and angles/° for QUE·BPY Table 4. Hydrogen bond lengths/Å and angles/° for MYR·BPY·H2O
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Table 5. The diameter values (mm) of inhibitory areas of KAE·BPY·2H2O, QUE·BPY and
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MYR·BPY·H2O on bacteria
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Table Cocrystals of kaempferol, quercetin and myricetin with 4,4'-bipyridine: crystal structures, analysis of intermolecular
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interactions and spectral characterization Yu-Nan Zhanga, He-Mei Yina, Yu Zhanga,*, Da-Jun Zhanga, Xin Sua, Hai-Xue Kuangb a
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Table. 1 Crystallographic data for three cocrystals KAE·BPY·2H2O CCDC No. Formulae Formula weight(g mol-1)
QUE·BPY
1434453 1434450 2C15H10O6 · C10H8N2 · 2H2O C15H10O7 · 1.5C10H8N2 764.68 536.51 _
P1 Triclinic 8.6015(5) 9.8233(6) 22.2693(15) 77.584(5) 86.775(5) 68.900(6) 1714.0(2) 2 0.114 1.482 0.1417 0.0722 0.0350 3.545-24.998 6060 / 529 / 0 12,016 / 6060 1.000 0.195 / -0.243
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Space group Cystal system a(Å) b(Å) c(Å) α(o) β(o) γ(o) V (Å3) Z µ (mm-1) Dcalc (g⋅cm-3) wR2 [reflections] R [I > 2σ(I)] Rint θ(°) Data/parameters/restraints Reflns collected/unique GOFs ∆ρ max/∆ρ min (e Å-3)
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Institute of Pharmacy in Heilongjiang Province, Jiamusi University, Heilongjiang Province, Jiamusi, 154007, China b Heilongjiang University of Chinese Medicine, Heilongjiang Province, Harbin 150040, China *Corresponding author: (Yu Zhang) E-mail: [email protected]. Tel: +8615765305157
_
P1 Triclinic 9.8554(6) 10.8071(10) 13.0414(9) 99.877(7) 94.907(5) 106.385(6) 1299.61(18) 2 0.099 1.371 0.1647 0.0550 0.0181 3.003-25.999 5108/ 366 / 0 9989 / 5108 1.000 0.310 / -0.222
MYR·BPY·H2O 1434451 C15H10O8 ·2C10H8N2· H2O 648.61 _
P1 Triclinic 9.3467(8) 10.2752(8) 17.7595(15) 82.336(7) 84.365(7) 63.362(8) 1509.5(2) 2 0.105 1.427 0.1353 0.0767 0.0945 3.373-24.997 5297 / 438 / 16 9541 / 5297 1.002 0.330 / -0.366
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R1 = ∑||F0|-|FC||/∑|F0|; wR2 = ∑[w(F02-FC2)2]/∑[w(F02)2]1/2
Table 2. Hydrogen bond lengths/Å and angles/° for KAE·BPY·2H2O
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D-H···A d(D-H) d(H···A) d(D···A) ∠DHA O5A-H5A···O4A 0.82 1.85 148.70 2.588(3) i O5A-H5A···O4A 0.82 2.63 112.70 3.041(3) ⅱ 0.82 1.86 168.70 2.665(3) O7A-H7A···N4'C ⅲ O3A-H3A···O1W 0.82 1.93 159.80 2.712(3) O3B-H3B···O4B 0.82 2.32 112.70 2.739(3) ⅳ O3B-H3B···O2W 0.82 1.94 154.50 2.707(3) ⅳ O7B-H7B···N4C 0.82 1.88 163.60 2.675(3) O5B-H5B···O4B 0.82 1.86 148.10 2.596(3) ⅳ 0.82 1.90 160.80 2.692(3) O4'B-H4'B···O1W O4'A-H4'A···O2W 0.82 1.91 166.70 2.712(3) ⅳ C3C-H3C···O4'A 0.93 2.61 138.10 3.357(4) ⅳ 0.91(4) 1.90(5) 164(4) 2.791(3) O1W-H1W···O5A ⅳ O1W-H1W'···O7A 0.75(3) 2.18(3) 157(4) 2.880(4) 0.76(6) 2.01(6) 167(6) 2.754(4) O2W-H2W'···O5Bⅳ O2W-H2W···O7B 0.95(6) 2.02(6) 157(4) 2.920(4) Symmetry codes: (ⅳ) -x+2, -y+2, -z; (ⅳ) x, y+1, z-1; (ⅳ) x+1, y, z; (ⅳ) x-1, y+1, z; (ⅳ) x, y-1, z; (ⅳ) x, y+1, z; (ⅳ) -x, -y+2, -z+1; (ⅳ) -x+1, -y+2, -z; (ⅳ) -x, -y+2, -z; (ⅳ) -x, -y+1, -z+1.
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Table 3. Hydrogen bond lengths/Å and angles/° for QUE·BPY D-H···A d(D-H) d(H···A) d(D···A) ∠DHA ⅰ C2'D-H2'D···O5' 0.93 2.53 145.9 3.341(3) O5'-H5'···O4' 0.82 2.30 111.5 2.7110(19) ⅱ O5'-H5'···O7 0.82 1.99 157.4 2.7650(18) ⅲ O4'-H4'···N4'D 0.82 1.90 177.9 2.723(2) ⅳ O7-H7···N4D 0.82 1.86 169 2.665(2) O3-H3···O4 0.82 2.28 112.9 2.711(2) ⅴ O3-H3···O4 0.82 1.94 148.8 2.6774(18) O5-H5···O4 0.82 1.90 147.6 2.6251(19) C6'-H6'···O3 0.93 2.22 125.8 2.868(2) Symmetry codes: (ⅳ) -x+1, -y+1, -z+2; (ⅳ) x, y, z+1; (ⅳ) x-1, y, z; (ⅳ) -x, -y+1, -z+1; (ⅳ) -x+1, -y, -z+1. Table 4. Hydrogen bond lengths/Å and angles/° for MYR·BPY·H2O D-H···A d(D-H) d(H···A) ∠DHA O3-H3...O4 0.82 2.269 114.33 ⅰ O3-H3...O4 0.82 1.985 153.59
d(D···A) 2.711 2.744
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Table 5. The diameter values (mm) of inhibitory areas of KAE·BPY·2H2O, QUE·BPY and MYR·BPY·H2O on bacteria S. aureus (mm) E. coli (mm) 10 20 30 (mmol/L) (mmol/L) (mmol/L) 11
9
10
18
14
18
kaempferol
7
8
7
10
12
9
QUE·BPY
9
11
12
15
14
17
quercetin
8
9
9
11
12
10
MYR·BPY·H2O
10
11
10
20
24
26
myricetin
9
8
9
18
22
22
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KAE·BPY·2H2O
10 20 30 (mmol/L) (mmol/L) (mmol/L)
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Figures Cocrystals
of
kaempferol,
quercetin
and
myricetin
with
4,4'-bipyridine: crystal structures, analyses of intermolecular
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interactions and antibacterial properties
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Yu-Nan Zhanga, He-Mei Yina, Yu Zhanga,*, Da-Jun Zhanga, Xin Sua, Hai-Xue Kuangb a Institute of Pharmacy in Heilongjiang Province, Jiamusi University, Heilongjiang Province, Jiamusi, 154007, China b Heilongjiang University of Chinese Medicine, Heilongjiang Province, Harbin 150040, China *Corresponding author: (Yu Zhang) E-mail: [email protected]. Tel: +8615765305157
Fig. 1. Structures of the (a) hexamer, (b) 2D hydrogen bonds layer (the hydrogen bonds are indicated as broken lines in this and the subsequent figures), (c) 3D network in KAE·BPY·2H2O
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Fig. 2. Structures of the (a) tetramer, (b) 2D hydrogen bonds layer (the hydrogen bonds are indicated as broken lines in this and the subsequent figures), (c) 3D network in QUE·BPY
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Fig. 3. Structures of the (a) tetramer, (b) 2D hydrogen bonds layer (the hydrogen
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Fig. 4. XPRD patterns for (a) KAE·BPY·2H2O (b) QUE·BPY and (c)
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Fig. 5. Results of inhibitory areas of three cocrystals on microbes at concentrations of
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Schemes Cocrystals
of
kaempferol,
quercetin
and
myricetin
with
4,4'-bipyridine: crystal structures, analyses of intermolecular
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interactions and antibacterial properties
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Yu-Nan Zhanga, He-Mei Yina, Yu Zhanga,*, Da-Jun Zhanga, Xin Sua, Hai-Xue Kuangb a Institute of Pharmacy in Heilongjiang Province, Jiamusi University, Heilongjiang Province, Jiamusi, 154007, China b Heilongjiang University of Chinese Medicine, Heilongjiang Province, Harbin 150040, China *Corresponding author: (Yu Zhang) E-mail: [email protected]. Tel: +8615765305157
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Scheme. 1 Molecular structures of kaempferol, quercetin, myricetin and 4,4'-bipyridine
Scheme. 2. Supramolecular synthons of cocrystals KAE·BPY·2H2O, QUE·BPY and MYR·BPY·H2O
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Highlights 1. Three cocrystals of flavonols with varying B-ring-hydroxyl groups
were obtained in solution evaporation approach.
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(kaempferol, quercetin and myricetin) combined with 4,4'-bipyridine
2. In cocrystals of KAE·BPY·2H2O, QUE·BPY and MYR·BPY·H2O,
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R66(29) with 4,4'-bipyridine, respectively.
R88(58),
R44(42) and
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they present three different synthons
3. The three cocrystals all show admirable antibacterial properties against
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S. aureus and E. coli，as related to parent flavonols, respectively.