Mechanochemical Assembly of Nalidixic Acid Bioinspired Metal

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Mechanochemical assembly of nalidixic acid bio-inspired metalorganic compounds and complexes towards improved solubility Vania Andre, Filipa Galego, and Marta Martins Cryst. Growth Des., Just Accepted Manuscript • DOI: 10.1021/acs.cgd.7b01523 • Publication Date (Web): 01 Mar 2018 Downloaded from http://pubs.acs.org on March 2, 2018

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Crystal Growth & Design

Mechanochemical assembly of nalidixic acid bio-inspired metal-organic compounds and complexes towards improved solubility

Vânia Andréa*, Filipa Galegoa, Marta Martinsa a

Centro de Química Estrutural, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais 1,

1049-001 Lisbon, Portugal;

* [email protected]

ABSTRACT Nalidixic acid is an antibiotic from the quinolones family whose bioavailability is limited due to its low solubility. The development of complexes and bio-inspired metal organic frameworks has been explored as a way to achieve controlled drug delivery and release and we demonstrate that they can also be used to tune drugs’ physicochemical properties, such as solubility. Herein we disclose a series of complexes and frameworks of nalidixic acid and Zn. One of these frameworks duplicates the solubility of nalidixic acid and it is stable on shelf and to 77% of room humidity. The incorporation of a second ligand into the frameworks is also presented showing the possibility to develop extended networks with further potential applications.

INTRODUCTION Solubility is amongst the fundamental parameters that dictate the rate and extent of drug absorption and bioavailability.1, 2 However, in drug discovery, almost 70% of new drug candidates show poor water solubility.3 To overcome the solubility limitations, several techniques have been explored, such as: (a) physical modifications, which include particle size reduction, modification of crystal habit; (b) chemical modifications, as pH change, use of buffers, derivatization complexation and salt formation; and (c) miscellaneous methods, like supercritical fluid processes, use of adjuvants as 1

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surfactants, solubilizers, and novel excipients.4 Still, solubility remains a major challenge for formulation scientists. Nalidixic acid is an example of a pharmaceutical compound with low bioavailability resultant from a low solubility.5 This quinolone antibiotic is used to treat urinary tract infections caused by some bacteria, and it is effective primarily against gram-negative bacteria, with minor anti-gram-positive activity. Nalidixic acid is known two exist in two polymorphic forms6-8 and also a few cocrystals with different parabens were reported.6, 9 Regarding metal complexes, some work has already been disclosed involving the coordination of nalidixic acid to Cu, Ru, Cd, Zn and Pt.10-17 None of these coordination compounds forms frameworks and, with exception of a Zn complex, they all involve a second organic ligand (Table I). The coordination of nalidixic acid to the metal sites is always achieved via the carbonyl and carboxylic moieties. The Ru compounds have been explored as potential anti-cancer agents, and the DNA and protein binding profile of the Cu complexes have been studied.10, 17 Quite recently, also a novel ionic Ag(I)−piperazinium nalidixic acid conjugate was reported as a potential antitumor agent.18

Table I – Summary of the previously reported nalidixic acid coordination complexes CSD19 code

Metal site

Co-ligand

FODJOX

Cu

HAHYUM

Ru

HUPCOM

Cd

MIKXOV

Ru

TOLDOP

Cu

VUQXIP

Cu

1,10phenanthroline 1-isopropyl-4methylbenzene 1,10phenanthroline 1,4,7trithiacyclononaneS,S’,S’’ Cyclohexane-1,2diamine Histamine-N,N’

Extra coordination H2 O

Counter ion

Solvate/hydrate

NO3-

H2O

Cl

_

Toluene solvate

Cl

_

_

DMSO

PF6-

H2O

_

_

_

H2 O

Cl-

H2O

2


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_

Cl-

H2O

Zn

Cyclohexane-1,2diamine _

H2 O

ClO4-

H2O

ZOVFAR

Pt

_

NH3

NALD-

H2O

QATVIT

Cu

2,2’-bipyridine

H2 O

ClO4-

H2O

YOPJOE

Zn

ZEFFIZ

The possibility of forming metal-organic frameworks (MOFs) with nalidixic acid has not yet been reported. MOFs are very interesting structures with a very wide range of applications in chemical and materials sciences.20-33 More recently some bio-inspired MOFs (BioMOFs) have been developed for biomedical and pharmaceutical purposes, working as drug carriers in systems for controlled drug delivery and release,28, 34-43 contrast agents for magnetic resonance imaging (MRI),44 or for other potential biomedical/pharmaceutical applications,34 such as in cancer therapy.45, 46 In BioMOFs, the organic ligands must be endogenous molecules - either active pharmaceutical ingredients (API) - or other bioactive organic molecules and the choice of the metals used must be judicious47 BioMOFs can be designed by mainly two different approaches: i) include the active molecule directly as the ligand of the framework; ii) incorporate/encapsulate the active molecule as a guest within the pores of the MOF built with an organic molecule generally regarded as safe (GRAS), an endogenous compound or another bioactive molecule. BioMOFs resulting from the direct incorporation of the active molecule are clearly advantageous as controlled delivery systems: they eliminate the need for porosity; the release of the active pharmaceutical ingredient (API) or bioactive molecules results from the degradation of the framework; reduced side effects; the metal may have a synergetic effect; co-delivery of drugs is possible if two APIs are involved in the framework both as ligands and guests.47 BioMOFs are promising candidates for the development of more effective therapies. 3



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Bearing all this in mind, the aim of the study presented herein is to develop new MOFs, coordination polymers and also metal complexes to minimize the solubility problems of nalidixic acid. We unveil a stable novel nalidixic acid:Zn coordination polymer with twice the solubility of nalidixic acid. Three nalidixic acid:Zn complexes and a ternary complex with oxalic acid are structurally characterized, as well as a ternary coordination polymerwith biphenyl-4,4’-dicarboxylic acid. The goal of using co-ligands in this study was to form extended networks using carboxylic acids as coligands instead of the N-based ligands that had been previously reported. Oxalic and biphenyl-4,4’-dicarboxylic acids were chosen to test different types of molecules enclosing carboxylic acids in two opposite sites: while oxalic acid is smaller and more flexible, biphenyl-4,4’-dicarboxylic acid is larger and less flexible, and this study indicates what type of structures would yield from the use of similar co-ligands. Even though none of these compounds are listed as “generally regarded as safe” by FDA, oxalic acid naturally occurs in many plants and vegetables and it is produced in the body by metabolism of glycolic acid and ascorbic acid; it is not metabolized but it is excreted in the urine. Mechanochemistry has been widely explored as an efficient, fast, and clean synthetic method for the successful preparation of MOFs, coordination polymers48-59 and metal complexes,60-62 and it was the main synthetic technique chosen for this work, with particular emphasis on liquid-assisted grinding (LAG).

RESULTS AND DISCUSSION While exploring the mechanochemical synthesis of metal-organic frameworks with nalidixic acid, we have unveiled a coordination polymer (CP) with Zn (CP-1), whose full characterization is presented herein, including its shelf stability and stability at 77% 4


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RH, as well as its solubility. We further present the structural aspects of three complexes with Zn (Complexes 1-3) that were obtained in some of the recrystallization attempts of CP-1. We considered that it was interesting to further study the possibility to build networks with a co-ligand. To best of our knowledge, in the structures previously reported enclosing nalidixic acid and a co-ligand the coordination to the second ligand is mainly achieved via N groups. In this work we have accomplished the formation of ternary compounds with carboxylic acids: oxalic acid (Complex-4) and biphenyl-4,4’-dicarboxylic acid (CP-2), whose structural characterization is discussed. Unfortunately, only CP-1 was obtained as a pure compound and therefore the full characterization was only possible in this case.

Scheme I – Schematic representation of the compounds discussed herein

Structural characterization, supramolecular features and Hirshfeld surface analysis of Nalidixic acid:Zn coordination polymer (CP-1) CP-1 crystallizes in the monoclinic P21/c space group and its asymmetric unit consists of one zinc atom coordinated to one nalidixic acid moiety via the carboxylate and carbonyl groups (Figure 1.a), and three water molecules that fulfil the Zn octahedral geometry (coordination number 6, Figure 1.b). Nalidixic acid is deprotonated, as confirmed by the C-O distances in the carboxylate moiety (1.252(2) and 1.255(2) Å), 5



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and the charge balance is further achieved by a nitrate counterion that is also present in the asymmetric unit. The bond lengths involved in the coordination of nalidixic acid to Zn are slightly shorter than the bond lengths involved in the water coordination (ZnOC=O 2.0704(15) Å, Zn-OCOO- 2.0494(15) and 2.0735(14) Å, Zn-OW 2.1340(16), 2.0712(18) and 2.097(3) Å). The OC=O-Zn-OCOO-/COOH angles are of 88.53(6), 86.56(6) and 174.77(6)°, being this last one responsible for the formation of a coordination polymer.

(a)

(b)

Figure 1 – CP-1 coordination modes (a) schematic representation of the binding sites; (b) octahedral geometry around the Zn metal center

All the oxygen atoms of nalidixic acid coordinate to the metal site giving rise to a 1D framework, with zigzag chains growing along the b axis (Figure 2a). Adjacent chains align in parallel along b with the axial water molecules pointing towards each other, and the nitrate counterions lie in the space left between these chains (Figure 2b). The water molecules are involved in several hydrogen bonds (Table IV) with the carboxylate (O1w˗H⋅⋅⋅O2) and pyridinic (O2w˗H⋅⋅⋅N2) moieties of nalidixic acid, as well as with the nitrate anions (O1w˗H⋅⋅⋅O4, O1w˗H⋅⋅⋅O6, O2w˗H⋅⋅⋅O5, O3w˗H⋅⋅⋅O5, O3w˗H⋅⋅⋅O6). These hydrogen bonds reinforce the supramolecular arrangement of the structure.

6


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(a)

(b)

Figure 2 – Supramolecular arrangement of CP-1 depicting (a) the 1D zigzag chain formed along the b axis; (b) the nitrate counterions lying in the space left between the zigzag chains.

Hirshfeld surface analysis and the respective 2D fingerprint plots allow the analysis of the several intermolecular interactions existent in the reported crystal structures. Hirshfeld surfaces are characteristic of a given crystal structures with its unique set of atomic electron densities.63 The Hirshfeld surface of a molecule is represented as function of the descriptor dnorm that comprises two factors: de - distance from the point to the nearest nucleus external to the surface; and di - distance to the nearest nucleus internal to the surface.64, 65 The combination of de and di in the form of a 2D fingerprint plot displays a summary of the intermolecular contacts in the crystal.66 The Hirshfeld surfaces mapped over dnorm and the 2D fingerprint plots for CP-1 are displayed in Figure 3. The previously discussed hydrogen bond interactions between oxygen (O) and hydrogen (H) atoms and between the nitrogen (N) and hydrogen (H) atoms can be observed in the Hirshfeld surface as the red spots. Both these O-H and NH intermolecular interactions appear as discrete spikes in the 2D fingerprint plot, with the O-H having a bigger relevance (42% vs 3.7%). The H-H interactions appear in the middle scattered points in the 2D fingerprint map and comprise 32.8% of the total Hirshfeld surface. Apart from those above interactions, the π⋅⋅⋅π (C–C), lone-pair⋯π (O–C), and lone-pair⋯lone-pair (O–O) interactions are also observed, corresponding respectively to 4.7%, 0.6% and 2.4% of the total Hirshfeld surface. 7



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Figure 3 – Hirshfeld surface mapped with dnorm, with surfaces shown as transparent to allow the visualization of the compound (top) and two dimensional fingerprint plots (bottom) for CP-1

Infrared spectroscopy (Figure 4) was used to confirm the structural characterization of CP-1. The IR spectrum confirms the presence of the carboxylate moiety, as the asymmetric stretch is strongly detected at 1607 cm-1 and the symmetric stretch shows a strong band at 1384 cm-1. The peak at 1629 cm-1 is due to the C=O stretch of the carbonyl, and the shift of approximately 10 cm-1 compared to the free ligand (υ(C=O) in the ligand is detected at 1620 cm-1) suggests the coordination via this group. The stretch of the Zn-O bond is detected at 1135 cm-1. The broad band found in the 3000-3600 cm-1 region is representative of the hydrogen bonds found in this structure as well as the stretching vibration of the coordinated water molecules.

8


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100

80

Transmitance / %

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


60

40

20

0 4000

3500

3000

2500

2000

Wave number / cm

1500

1000

500

-1

Figure 4 – Infra-red spectroscopy for CP-1

Stability and solubility of CP-1 The thermal stability of CP-1 was assessed by DSC and TGA (Figure 5). CP-1 is stable until approximately 70ºC, temperature at which a phase transition corresponding to a 8.7% mass loss is initiated. This loss corresponds to two water molecules leaving the structure. Until 198.3ºC the third water molecule is lost, corresponding to a 4.4% mass loss in the TGA. A series of phenomena are detected at higher temperatures leading to the melt and decomposition of the compound.

Figure 5 – DSC and TGA for CP-1 9



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Bearing in mind a possible pharmaceutical application, it is very important to assess the shelf stability and stability at higher % room humidity (RH) of CP-1. Samples left under ambient conditions were regularly analysed for 5 months, maintaining the same form. Samples left in a 77% RH chamber were also regularly analysed for 5 months also maintaining the same form (Figure 6). This is a positive indication of the stability of CP-1 under these conditions.

5

10

15

20

25

30

35

40

45

50

55

60

2-θ / º

Figure 6 – Powder diffractograms showing (from top to bottom) the starting powder, the powder after 5 months at ambient conditions, the powder after 5 months at 77% RH and a calculated powder pattern simulated from the SCXRD structure

Also the solubility of CP-1 was determined using HPLC. CP-1 has twice the solubility of nalidixic acid (3.3(2)x10-4 vs 1.6(2) x10-4 molal, respectively).

Structural characterization, supramolecular features and Hirshfeld surface analysis of Nalidixic acid:Zn Complex 1 (Complex-1) Complex-1 crystallizes in the P21/c monoclinic space group, and its asymmetric unit of Complex-1 is formed by a zinc atom residing in an inversion centre coordinated to a deprotonated nalidixic acid (C-O distances in the carboxylate moiety: 1.267(5) and

10


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1.234(5) Å), and a water molecule. Nalidixic acid coordinates to the metal centre via the carbonyl and one oxygen of the carboxylate moieties (OC=O-Zn-OCOO-/COOH angles: 92.08(13) and 87.92(13)°), with the remaining O atom of nalidixic acid not being involved in any coordination and thus not giving rise to a network (Figure 7.a). The Zn centre assumes an octahedral geometry (coordination number 6, Figure 7.b), exhibiting shorter bond distances to nalidixic acid than water molecules (Zn-OC=O 2.1084(3) Å, Zn-OCOO- 1.995(3) Å, and Zn-OW 2.207(3) Å)). This complex contains no hydration water.

(a)

(b)

Figure 7 – Complex-1 coordination modes (a) schematic representation of the binding sites; (b) octahedral geometry around the Zn metal center The inversion centre around the Zn atom generates metal complexes with two nalidixic acid moieties. These complexes align perpendicularly along the bc plane (Figure 8.a), giving rise to ordered zig zag lines along the ab plane (Figure 8.b). The complex moieties in consecutive lines are shifted and axial water molecules are not pointing each other, allowing the chains to become closer, resulting in higher packing efficiency than in CP-1 (70.5 vs 73.9%).

11



(a)

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(b)

Figure 8 – Supramolecular arrangement of Complex-1 depicting (a) the perpendicular orientation of the complexes along the bc plane and (b) the zig zag chains formed in the ab plane

Even though no classical hydrogen bonds are listed for this structure, the Hirshfeld surface map of Complex-1 (Figure 9) denotes strong interactions between the water molecules coordinated to Zn and the carbonyl and carboxylate oxygen atoms of the neighbouring complexes, shown by the red spots in the dnorm map and the spikes in the 2D fingerprint plot corresponding to the O-H interactions, that correspond to 22.8% of the total Hirshfeld surface. The H-H interactions comprise 35.7% of the total Hirshfeld surface. Apart from those above interactions, the π⋅⋅⋅π (C–C), lone-pair⋯π (O–C), and lone-pair⋯lone-pair (O–O) interactions are also observed, corresponding respectively to 7.3%, 3.9% and 10.3% of the total Hirshfeld surface.

12


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Figure 9 - Hirshfeld surface mapped with dnorm, with surfaces shown as transparent to allow the visualization of the compound (top) and two dimensional fingerprint plots (bottom) for Complex-1

Structural characterization, supramolecular features and Hirshfeld surface analysis of Nalidixic acid:Zn Complex 2 (Complex-2) Complex-2 crystallizes in the P-1 triclinic space group, and its asymmetric unit is comprised of a zinc atom coordinated to two nalidixic acids moieties via the carbonyl and carboxylate moieties (Figure 10.a), leaving however one of the oxygen atoms noncoordinated and thus no network is formed. A water molecule is further coordinated to Zn, fulfilling a square pyramidal geometry (Figure 10.b), being all the Zn-O bond distances similar (Zn-OC=O 2.026(6) and 2.031(6) Å, Zn-OCOO- 2.001(6) and 1.986(5) Å, and Zn-OW 2.014(5) Å)). Nalidixic acid is again deprotonated and the carboxylate groups keep the charge balance. A hydration water molecule is also present in this structure. The OC=O-Zn-OCOO-/COOH angles are all very similar (88.8(3), 88.6(2), 88.4(3) and 83.3(3)°) and one of the O in the carboxylate moieties is never involved in any coordination, not giving rise to the formation of networks.

13



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(a)

(b)

Figure 10 – Complex-2 coordination modes (a) schematic representation of the binding sites; (b) Square pyramidal geometry around the Zn metal center

In Complex-2, the complexes enclosing two nalidixic acid moieties pack in a parallel fashion, organizing themselves in chains that grow along the diagonal of the bc plane (Figure 11.a). The complex moieties are anti-parallel oriented and with a slight shift. In a view along the c axis, it is possible to infer that the water molecules lie in channels left by the complex unit (Figure 11.b). Hydrogen bond interactions are established between the water molecules and the carboxylate moieties of nalidixic acid. The coordinated water is involved in interactions with both the coordinated (O1w˗H⋅⋅⋅O4) and the free (O1w˗H⋅⋅⋅O2) oxygen atoms of the carboxylate moiety of one of the nalidixic acid moieties, while the hydration water molecule establishes two hydrogen bonds with the coordinated oxygen (O2w˗H⋅⋅⋅O1) of the carboxylate moiety of the other crystallographically independent nalidixic acid. From the six crystal structures described herein, Complex-2 has the lowest packing efficiency (69.8%).

(a)

(b) 14


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Figure 11 – Supramolecular arrangement of Complex-2 depicting the (a) parallel alignment of the complex repeating unit giving rise to lines along the diagonal of the bc plane and (b) positioning of the hydration water molecules in channels in a view along the c axis. Hydration water molecules are represented in blue in the space fill style for a better visualization of their positioning.

The Hirshfeld surface of Complex-2 (Figure 12) clearly shows the strong hydrogen bonds as red spots established between both water molecules and the carboxylate moieties of nalidixic acid. These O-H interactions are represented as spikes in the 2D fingerprint plot, corresponding to 25.7% of the total Hirshfeld surface. H-H contacts contribute with a total of 47.8% for the overall interactions. The π⋅⋅⋅π (C–C), and lonepair⋯π (O–C) correspond respectively to 6.9%, and 3.2% of the total Hirshfeld surface, with the O-O interactions being minimal in this case (0.8%).

Figure 12 - Hirshfeld surface mapped with dnorm, with surfaces shown as transparent to allow the visualization of the compound (top) and two dimensional fingerprint plots (bottom) for Complex-2

15



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Structural characterization, supramolecular features and Hirshfeld surface analysis of Nalidixic acid:Zn Complex 3 (Complex-3) Complex-3 crystallizes in the P-1 triclinic space group and its asymmetric unit contains a Zn metal centre coordinated to a nalidixic acid moiety and four water molecules. A hydration water and the zinc tetrachloride anion are also present in the asymmetric unit. In this case and contrary to the previously described structures, the nalidixic acid is not deprotonated (C-O bond distances in the carboxylic moiety: 1.232(3) and 1.318(4) Å) and the ZnCl42- acts as counterion. The coordination of nalidixic acid to Zn is achieved through the carbonyl and carboxylic acid functional groups (Figure 13.a), with a OC=O-Zn-OCOO-/COOH angle of 85.68(7)° and one of the O in the carboxylate moieties is never involved in any coordination, not giving rise to the formation of networks. The Zn metal centre assumes an octahedral geometry in the complex with nalidixic acid (Zn-OC=O 2.045(2) Å, Zn-OCOO- 2.091(2) Å, and Zn-OW 2.120(2), 2.096(2), 2.074(2) and 2.102(2) Å)) and a tetrahedral geometry in the ZnCl42- counterion (Figure 13.b).

N

N OH O

O M

(a)

(b)

Figure 13 – Complex-3 coordination modes: (a) schematic representation of the coordination sites of nalidixic acid to Zn; (b) octahedral geometry of Zn coordinated to one nalidixic acid and 4 water molecules and tetrahedral geometry in the ZnCl42counterion

16


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In the supramolecular arrangement of Complex-3, it is possible to envisage that the hydration water molecule and ZnCl42- ions are intercalated with the complex and do not form channels in any of the directions (Figure 14). From all the compounds reported herein, Complex-3 is the one with higher number of hydrogen bond interactions, largely due to the higher number of water molecules that it includes. Nalidixic acid establishes a hydrogen bond interaction with the hydration water molecule (O3˗H⋅⋅⋅O5w), which further interacts with chlorides (O5w˗H⋅⋅⋅Cl1 and O5w˗H⋅⋅⋅Cl4) and one of the coordinated water molecules (O2w˗H⋅⋅⋅O5w). The pyridinic moiety of nalidixic acid is involved in a hydrogen bond interaction with one of the coordinated water molecules (O4w˗H⋅⋅⋅N2). All the remaining contacts are established between the coordinated water molecules and the chlorides or among themselves. The packing efficiency of Complex-4 is 72.1%.

Figure 14 – Supramolecular arrangement of Complex-3. Hydration water molecules are represented in blue and the ZnCl42- in pink, both in the space fill style for a better visualization of their positioning

In the Hirshfeld surface of Complex-3, the above described hydrogen bonds are quite visible as the red spots in Figure 15. All the O-H, Cl-H and N-H contacts form spikes in the 2D fingerprint plot, indicating supramolecular architectures involving combinations of N–H (2.4%), O–H (11.6%) and Cl–H (38%) linkages. The predominance of the Cl–H

17



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interactions is due to the ZnCl4 counterion. The H-H contacts are also visible as lighter spots and represent 35.6% of the total contacts.

Figure 15 – Hirshfeld surface mapped with dnorm, with surfaces shown as transparent to allow the visualization of the compound (top) and two dimensional fingerprint plots (bottom) for Complex-3

Structural characterization, supramolecular features and Hirshfeld surface analysis of Nalidixic acid:4,4’-biphenyldicarboxylic acid:Zn coordination polymer (CP-2) CP-2 crystallizes in the P-1 triclinic space group, and its asymmetric consists of a zinc metal centre coordinated to a nalidixic acid, a water molecule and a 4,4’biphenyldicarboxylic acid residing in an inversion centre. Both nalidixic and 4,4’biphenyldicarboxylic acids are deprotonated. Nalidixic acid coordinates to Zn via the carbonyl and carboxylate groups (OC=O-Zn-OCOO-/COOH angles of 87.62(12) and 156.96(12)°), while the 4,4’-biphenyldicarboxylic acid coordinates via the carboxylate (Figure 16.a). It is the interaction with the second O of the carboxylate moiety of nalidixic acid (OC=O-Zn-OCOO-/COOH 156.96(12)°) and the coordination to 4,4’18


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biphenyldicarboxylic acid that lead to the formation of a coordination compound. Zn displays a square pyramidal geometry (coordination number 5, Figure 16.b), with 4,4’biphenyldicarboxylic acid (BPDC) assuming the axial position (Zn-OC=O 1.986(3) Å, Zn-OCOO- 2.053(3) and 2.106(3) Å, Zn-OCOO-,BPDC 1.932(3) Å and Zn-OW 2.011(4) Å)).

(a)

(b)

Figure 16 – CP-2 coordination modes (a) schematic representation of the binding sites; (b) square pyramidal geometry around the Zn metal center

The Zn atoms connect pairs of nalidixic acid moieties while the one-dimensional framework is achieved through the 4,4’-biphenyldicarboxylic acid (Figure 17.a). The 1D frameworks grow along the bc diagonal (Figure 17.b) and, in a view along the c axis, they are aligned without creating VOIDS (Figure 17.c). The water molecule is in an equatorial position and it is involved in two hydrogen bond interactions, one with the 4,4’-biphenyldicarboxylic acid (O1w˗H⋅⋅⋅O5) and the other with nalidixic acid (O1w˗H⋅⋅⋅O2), both bridging together consecutive frameworks. This is the structure described herein with the highest packing efficiency (75.5%). 19



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(a)

(b) (c) Figure 17 – Crystal packing of CP-2 depicting (a) the formation of the framework via the 4,4’-biphenyldicarboxylic acid; (b) the growth of the 1D framework along the bc diagonal, in a view along the a axis; (c) the orientation of the frameworks in a view along the c axis

Both hydrogen bonds previously described are well visible as red spots in the Hirshfeld surface of CP-2 and the spikes on the 2D fingerprint plot confirm it (Figure 18), with the O-H interactions corresponding to 27.8% of the total surface. There H-H represent 43.1% of the total contacts. The π⋅⋅⋅π (C–C), and lone-pair⋯π (O–C) correspond respectively to 13.7%, and 2.2% of the total Hirshfeld surface, with the O-O interactions being minimal (0.6%), similarly to what was observed in complex 2.

20


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Figure 18 - Hirshfeld surface mapped with dnorm, with surfaces shown as transparent to allow the visualization of the compound (top) and two dimensional fingerprint plots (bottom) for CP-2

Structural characterization, supramolecular features and Hirshfeld surface analysis of Nalidixic acid:oxalic acid:Zn Complex (Complex-4) Complex-4 crystallizes in the P21/c monoclinic space group and its asymmetric unit consists of a Zn anion coordinated to a nalidixic acid moiety, half an oxalic acid molecule residing in an inversion centre and two water molecules (Zn-OC=O 2.053(4) Å, Zn-OCOO- 2.080(5) Å, and Zn-OW 2.097(5) and 2.044(5) Å)); there are two further hydration water molecules in the asymmetric unit. The carboxylic moieties of nalidixic and oxalic acids are deprotonated (C-O bond distances: 1.247(9) and 1.267(9) Å for nalidixic acid and 1.252(8) and 1.268(9) Å for oxalic acid) and therefore no counterions are present in the structure. The OC=O-Zn-OCOO-/COOH angle is 87.35(18)°. The metal centre assumes an octahedral geometry (coordination number 6, Figure 19) and no framework is formed in this case, as one of O atoms of the carboxylate groups of nalidixic acid does not coordinate to Zn, (Figure 19) precluding the formation of the framework. Oxalic acid assumes both equatorial and axial positioning, as well as the coordinated waters, while nalidixic acid maintains the equatorial bonds.

21



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Figure 19 – Complex-4 coordination modes (a) schematic representation of the binding sites; (b) octahedral geometry around the Zn metal center

In a view along the b axis, it is possible to see that nalidixic acid molecules are oriented in a parallel fashion, giving rise to lines of nalidixic acid intercalated with oxalic acid lines (Figure 20.b). In a view along the c axis, it is possible to see that small VOIDS of 237.62 Å3 are formed between the zig-zag chains (Figure 20.c). These VOIDS are filled with both hydration water molecules. The packing efficiency is 70.7%,

(a)

(b)

(c) 22


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Figure 20 – Supramolecular packing of Complex-4 depicting (a) the complex formed; (b) the alternated chains of nalidixic acid and oxalic acid in a view along the b axis; (c) the 14.5% of the unit cell volume (237.62Å3)

The absence of strong hydrogens bonds in Complex-4 results in an almost absence of red spots in the Hirshfeld surface of this compound (Figure 21). Discrete spikes are visible in the 2D surface plots corresponding to O-H interaction and that correspond to 30.1% of the total interactions. The most relevant contacts in this case are O-O and H-H contacts with, 25.1 and 23.8%, respectively. The π⋅⋅⋅π (C–C), and lone-pair⋯π (O–C) correspond respectively to 7.3%, and 6.2% of the total Hirshfeld surface, with the O-O interactions having a very significant presence in the supramolecular arrangement of this complex (25.1%).

Figure 21 - Hirshfeld surface mapped with dnorm, with surfaces shown as transparent to allow the visualization of the compound (top) and two dimensional fingerprint plots (bottom) for Complex 4

CONCLUSIONS

23



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Metal organic frameworks and complexes have been used as a way to improve the properties of organic active pharmaceutical ingredients, either as new ways for controlled drug delivery and release or as a way to enhance their properties. In this manuscript, we report six novel crystal structures of CPs and Zn complexes of nalidixic acid. From a structural point of view, it is evident that nalidixic acid always assumes a equatorial positioning and the coordinated water molecules tend to assume the axial positions, even though they might also occupy equatorial positions to fulfil the metal coordination sphere. In the presence of the 4,4’-biphenyldicarboxylic acid, Zn displays a square pyramidal geometry and the axial position is occupied by this ligand. With oxalic acid, an octahedral geometry is attained and this ligand assumes one of the axial and one of the equatorial positions. All the bond lengths and angles are very similar and it is clear that the formation of higher OC=O-Zn-OCOO-/COOH angles (174.77(6) and 156.96(12)° for CP-1 and CP-2, respectively) involving the second oxygen atom of nalidixic acid carboxylate moiety is responsible for the formation of the coordination polymers, as in all the complexes all these angles are in the range 85.68(7) – 92.08(13)°. Water molecules are fulfilling the Zn coordination spheres of these compounds, being responsible in most cases for the formation of hydrogen bonds that reinforce the supramolecular arrangements. However, the introduction of extra ligands often implies the replacement of at least some of these water molecules, as observed in CP-2. The analysis of the Hirshfeld surfaces and fingerprint plots provide further information on the supramolecular architectures of the compounds disclosed herein. The main interactions involved in these architectures are the O-H and H-H linkages. Only complex-3 encloses chlorides and it assumes a major relevance as the Cl-H represent 24


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38% of the total contacts. It is also worth mentioning that the N-H interactions become barely inexistent by the introduction of a second linker, decreasing from 2.4-3.7% in the compounds without a second ligand to 0.2-0.6% when a second ligand with carboxylic acids is introduced. CP-1 is fully characterized and has proven to be stable on shelf and at 77% room humidity. More importantly, it has twice the solubility of nalidixic acid. Nalidixic acid bioavailability is low due to its low solubility and therefore the discovery of a new form with improved solubility is a major achievement. This issue is especially relevant because nalidixic acid is an antibiotic active against gram-negative bacteria, which nowadays represent a great concern because of the resistance mechanism that these bacteria have been developing decreasing in large scale the efficacy of the currently available antibiotic forms. All the other structures described in the manuscript show that there is further potential to explore with these systems.

Experimental All reagents were purchased from Sigma and used without further purification. SYNTHESIS OF MULTICOMPONENT CRYSTAL FORMS

Synthesis of CP-1 and Complex-1: An equimolar mixture of the reagents (59.3 mg of nalidixic acid and 77.1 mg of Zn(NO3)2.6H2O) was ground with 50 µL of water and 200 µL of ammonia by manual LAG for 5 minutes. The powder was washed with ethanol to remove the ammonium nitrate that was formed during the reaction. Single crystals of CP-1 were obtained after 1 week by slow evaporation of the solvent at the room temperature, from the recrystallization of the powder obtained by manual LAG in a 1:1 water:ethanol solution. CP-1 is obtained as a single phase and it corresponds to the form obtained directly from LAG (after washing with ethanol), as proved by PXRD (Figure 22). 25



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Figure 22 – PXRD patterns for the synthesis by LAG (black), the recrystallization in an ethanol:water solution (blue) and the calculated powder pattern simulated from the SCXRD structure (pink)

Recrystallization in acetone yielded a few single crystals mixed with very thin needles. These single crystals were identified as Complex 1.

Synthesis of CP-2 and Complex-2: CP-2

was

synthesized

by

grinding

together

nalidixic

acid,

4,4’-

biphenyldicarboxylic acid and Zn(NO3)2.6H2O in a molar ratio 2:1:2 (58.2 mg of nalidixic acid, 25.5 mg of 4,4’-biphenyldicarboxylic acid and 60.7 mg Zn(NO3)2.6H2O) with 50 µL of water and 50 µL of ammonia using a Retsch MM400 ball mill at 28 rpm for 20 minutes. Two stainless steel balls of 7 mm of diameter were used in the grinding jar during the reaction. Single crystals of CP-2 were obtained from the recrystallization of the powder obtained by LAG in an ethanol solution with a few drops of ammonia for complete dissolution; crystal were obtained after 6 days at room temperature by slow evaporation of the solvent. However, these crystals were not the only phase present in the recrystallization vessel and it was not possible to purify it. Manual LAG synthesis using also a 2:1:2 mixture of nalidixic acid, 4,4’biphenyldicarboxylic acid and Zn(NO3)2.6H2O (56.4 mg of nalidixic acid, 25.9 mg of 4,4’-biphenyldicarboxylic acid and 67.8 mg Zn(NO3)2.6H2O), with 50 µL of water and 26


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200 µL of ammonia, was also attempted, resulting in a new form(s). Recrystallization in aqueous solution with a few drops of ammonia led to the formation of a few single crystals of Complex-2, mixed with another phase(s) that, despite the many attempts, was not possible to identify and separate. Crystals were formed at room temperature, by slow evaporation of the solvent after 12 days.

Synthesis of Complex-3: 100 mg of nalidixic acid were dissolved in 2 mL of a saturated ZnCl2 aqueous solution. The solution was left stirring for 24 hours under ambient conditions and then left to crystallize by slow evaporation of the solvent at room temperature. A few single crystals of Complex-3 were formed. These crystals were not possible to obtain as a single phase and the other phases were not possible to separate or identify.

Synthesis of the Complex-4: Complex-4 was synthesized by manually grinding together nalidixic acid, oxalic acid and ZnCl2 in a molar ratio 1:1:1 (38.4 mg of nalidixic acid, 15.8 mg of oxalic acid and 21.8 mg ZnCl2), with 100 µL of water and 150 µL of ammonia. The reaction was detected after 10 minutes. Single crystals of Complex-4 were obtained after 8 days by slow evaporation at the room temperature, from the recrystallization of the powder obtained by LAG in a methanol solution with a few drops of ammonia for complete dissolution. These single crystals were very thin. Complex-4 was not obtained as a pure phase and could not be isolated.

CHARACTERIZATION

Single crystal X-ray diffraction (SCXRD) Crystals suitable for X-ray diffraction study were mounted on a loop with Fomblin© protective oil. Data was collected on a Bruker AXS-KAPPA APEX II diffractometer at 150 K and on a Bruker AXS-KAPPA D8 - QUEST at 293 K, with graphite-monochromated radiation (Mo Kα, λ=0.71073 Å). The X-ray generator was operated at 50 kV and 30 mA and the X-ray data collection was monitored by the APEX2 and APEX3 programs. All data were corrected for Lorentzian polarization and 27



Page 28 of 37

absorption effects using SAINT67 and SADABS68 programs. SIR9769 and SHELXS9770 were used for structure solution and SHELXL-9770 was used for full matrix leastsquares refinement on F2. These three programs are included in the package of programs WINGX-Version 2014.171. A full-matrix least-squares refinement was used for the non-hydrogen atoms with anisotropic thermal parameters. MERCURY 3.972 was used for packing diagrams. PLATON73 was used for hydrogen bond interactions. Refinement details are listed in the Table II and Table III. All non-hydrogen atoms were refined anisotropically. HOH atoms were added in calculated positions. HNH atoms were located from difference Fourier maps and refined. HCH and HOH atoms were added in calculated positions and refined riding on their respective C and O atoms. Hydrogen bonding details are given in Table IV. Crystal data can be obtained free of charge via www.ccdc.cam.ac.uk/conts/retrieving.html (or from the Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB21EZ, UK; fax: (+44)1223-336-033; or email: [email protected]). CCDC numbers 1583153-1583158.

Table II - Crystallographic details for coordination polymers 1-2 and Complex-4 CP-1

CP-2

Chemical formula

C12H17N3O9Zn

C19H17N2O6Zn

Complex-4 C14H11N3O9Zn

Mr

412.65

434.74

404.61 293

T/K

298

293

Morphology, colour

Needle, colourless

Needle, colourless

Needle, colourless

Crystal size / mm

0.20x0.03x0.02

0.18x0.06x0.04

0.02x0.02x0.02

Crystal system

Monoclinic

Triclinic

Monoclinic

Space group

P21/c

P-1

P21/c

a/Å

8.5145(5)

8.4933(12)

13.5792(8)

b/Å

9.4010(6)

10.4859(16)

16.3815(9)

c/Å

20.5945(14)

11.0589(15)

7.4559(7)

α/°

90

64.890(6)

90

β/°

93.383(2)

71.801(6)

98.054(1)

γ/°

90

81.088(7)

90

V / Å3

1645.61(18)

846.9(2)

1642.2(2)

Z

4

2

4

d / mg.m-3

1.666

1.705

1.637

µ / mm-1

1.546

1.493

1.546

θ min / °

2.382

2.146

5.695

θ max / °

27.940

25.978

29.427

Reflections collected/unique Rint

40483/3923

15576/3291

4225/2985

0.0537

0.0657

0.0598

GoF

1.063

1.072

0.955

Threshold expression

> 2σ(I)

> 2σ(I)

> 2σ(I)

R1 (obsd) wR2 (all)

0.0335

0.0508

0.0761

0.828

0.1141

0.1316

28


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Table III – Crystallographic details for the complexes 1-3 Complex-1

Complex-2

Complex-3 C12H22N2O8Zn2Cl4

Chemical formula

C24H22N4O8Zn

C48H52N8O16Zn2

Mr

559.85

1127.71

594.90

T/K

293

296

293

Morphology, colour

Needle, clolourless

Needle, colourless

Block, colourless

Crystal size / mm

0.20x0.04x0.03

0.08x0.02x0.02

0.17x0.05x0.04

Crystal system

Monoclinic

Triclinic

Triclinic

Space group

P21/c

P-1

P-1

a/Å

4.9616(6)

10.0057(19)

9.127(5)

b/Å

20.975(3)

10.5541(19)

10.142(5)

c/Å

11.1763(15)

12.578(2)

12.625(5)

α/°

90

102.431(12)

108.935(5)

β/°

99.754(8)

96.857(12)

97.161(5)

γ/°

90

104.714(11)

95.754(5)

V / Å3

1146.3(3)

1233.1(4)

1084.4(9)

Z

2

1

2

d / mg.m-3

1.622

1.519

1.822

µ / mm-1

1.132

1.053

2.745

θ min / °

3.451

2.948

2.147

θ max / °

26.432

25.896

27.949

Reflections collected/unique Rint

17114/2333

14564/4624

11931/5158

0.1027

0.1776

0.0330

GoF

1.021

0.908

1.009

Threshold expression

> 2σ(I)

> 2σ(I)

> 2σ(I)

R1 (obsd) wR2 (all)

0.0569

0.0768

0.0319

0.1460

0.2025

0.0675

Table IV - Hydrogen bond details for the main interactions

CP-1

CP-2

Complex-2

Sym. Op.

D-H∙∙∙A

d(H∙∙∙A) (Å) d(D∙∙∙A) (Å) (DĤA) (°)

x, y, z

O1W-H···O2

1.88(3)

2.713(2)

160(3)

-x, -1/2+y, 3/2-z

O1W-H···O4

2.05(2)

2.900(3)

166(3)

-x, -1/2+y, 3/2-z

O1W-H···O6

2.58(2)

3.295(3)

140(2)

x, 3/2-y, 1/2+z

O2W-H···N2

2.05(4)

2.928(3)

175(4)

1-x, -1/2+y, 3/2-z O2W-H···O5

2.06(4)

2.761(3)

164(4)

-x, -1/2+y, 3/2-z

O3W-H···O6

2.00(4)

2.803(4)

150(4)

x, y, z

O3W-H···O5

2.03(4)

2.760(4)

166(4)

2-x, 1-y, 1-z

O1W-H···O5

1.75(5)

2.631(5)

170(6)

1-x, 1-y, 1-z

O1W-H···O2

2.09(4)

2.806(4)

137(6)

1-x, 1-y, 1-z

O1W-H···O4

1.96

2.751(7)

152 29



Complex-3

Page 30 of 37

2-x, 1-y, 1-z

O1W-H···O2

2.08

2.739(8)

134

-1+x, y, z

O2W-H···O1

1.97

2.825(10)

169

x, y, z

O2W-H···O1

1.96

2.710(10)

146

x, y, z

O1W-H···Cl4

2.46(4)

3.202(3)

171(4)

2-x, 1-y, 2-z

O1W-H···Cl2

2.43(4)

3.112(3)

159(4)

x, y, z

O3-H···O5W

1.80

2.616(3)

172

1-x, 1-y, 2-z

O2W-H···O5W

1.91(4)

2.769(3)

170(3)

1-x, 1-y, 2-z

O2W-H···Cl1

2.42(4)

3.166(3)

165(3)

x, -1+y, z

O3W-H···Cl3

2.55(4)

3.276(3)

167(5)

2-x, 1-y, 2-z

O3W-H···Cl2

2.65(5)

3.354(3)

145(4)

1-x, -y, 2-z

O4W-H···O2W

1.95(4)

2.839(3)

175(4)

1-x, -y, 1-z

O4W-H···N2

2.06(3)

2.831(3)

168(3)

1-x, 1-y, 2-z

O5W-H···Cl1

2.38(5)

3.136(3)

178(5)

-1+x, y, z

O5W-H···Cl4

2.36(4)

3.169(3)

162(4)

Table V – Selected bond length (Å) and angles (°) Selected bond lengths / Å

Zn-OC=O

Zn-OCOO-/COOH

Zn-OW

Zn-OLigand2

C-OCOO-/COOH

C-OC=O

CP-1 Complex-1 Complex-2 Complex-3 CP-2 Complex-4 CP-1 Complex-1 Complex-2 Complex-3 CP-2 Complex-4 CP-1 Complex-1 Complex-2 Complex-3 CP-2 Complex-4 CP-1 Complex-1 Complex-2 Complex-3 CP-2 Complex-4 CP-1 Complex-1 Complex-2 Complex-3 CP-2 Complex-4 CP-1 Complex-1 Complex-2 Complex-3 CP-2 Complex-4

Selected bond angles / °

2.0704(15) 2.108(3) 2.026(6) / 2.031(6) 2.045(2) 1.986(3) 2.053(4) 2.0494(15) / 2.0735(14) 1.995(3) 2.001(6) / 1.986(5) 2.091(2) 2.053(3) / 2.106(3) 2.080(5) 2.1340(16) / 2.0712(18) / 2.097(3) 2.207(3) 2.014(5) 2.120(2) / 2.096(2) / 2.074(2) / 2.102(2) 2.011(4) 2.097(5) / 2.044(5) 1.932(3) 2.095(5) / 2.150(4) 1.252(2) / 1.255(2) 1.267(5) / 1.234(5) 1.324(11) / 1.220(11) - 1.288(11) / 1.204(13) 1.232(3) / 1.318(4) 1.303(5) / 1.225(6) 1.247(9) / 1.267(9) 1.253(2) 1.268(6) 1.259(11) / 1.252(10) 1.261(4) 1.265(5) 1.225(9)

OC=O-Zn-OCOO-/COOH

O-C-OCOO-/COOH

CP-1 Complex-1 Complex-2 Complex-3 CP-2 Complex-4 CP-1 Complex-1 Complex-2 Complex-3 CP-2 Complex-4

88.53(6) / 86.56(6) / 174.77(6) 92.08(13) /87.92(13) 88.8(3) / 88.6(2) / 88.4(3) / 83.3(3) 85.68(7) 87.62(12) / 156.96(12) 87.35(18) 123.63(13) 122.3(4) 122.7(6) / 122.8(8) 122.2(2) 122.3(4) 122.4(6)

30


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X-Ray Powder diffraction (XRPD) X-ray powder diffraction data were collected with D8 Advance Bruker AXS θ-2θ diffractometer, with a copper radiation source (Cu Kα, λ=1.5406 Å) and a secondary monochromator, operated at 40 kV and 40 mA. Note that a Ni filter was not used in the data collections and therefore the k-β peak at around ~9º in 2-θ is present in the experimental diffractograms.

Differential Scanning Calorimetry (DSC) and Thermogravimetric Analysis (TGA): Combined TG-DSC measurements were carried out on a SETARAM TG-DTA 92 thermobalance under nitrogen flow with a heating rate of 10°C.min-1. The samples weights were in the range of 5-10 mg.

Fourier Transform Infrared Spectroscopy (FTIR). FTIR spectra were recorded on a Nexus-Thermo Nicolet spectrometer (64 scans and resolution of 4 cm-1) in the 4000-400 cm-1 range. Samples were diluted in KBr (1:100 in weight).

Solubility Studies by High Performance Liquid Chromatography (HPLC). Were carried out in a Dionex system equipped with an Ultimate 3000 pump and a photodiode detector (DAD, Ultimate 3000). A reverse phase column RP-18e (Luna C18(2), 250 × 4.6 mm, 5 µm) from Phenomenex was used with a flow of 1 mL·min−1 . The selected program consisted on a 30 min isocratic elution of 30% of acetonitrile in 70% of 1% of aqueous formic acid, with a flow of 1 mL·min−1. Nalidixic acid was detected at 256.7 nm, with a retention time of 17.6 min.

Acknowledgements: Authors acknowledge Fundação para a Ciência e a Tecnologia for funding (PEst-OE/QUI/UI0100/2013, RECI/QEQ-QIN/0189/2012 and SFRH/BPD/78854/2011). Authors acknowledge MsC. Iolanda Santos and Dr. Alexandra Antunes for the use of the HPLC. Authors acknowledge Dr. Auguste Fernandes for the use of the IR, DSC and TGA. REFERENCES:

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For Table of Contents Use Only

Mechanochemical assembly of nalidixic acid bio-inspired metal-organic compounds and complexes towards improved solubility

Vânia Andréa*, Filipa Galegoa, Marta Martinsa a

Centro de Química Estrutural, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais 1,

1049-001 Lisbon, Portugal;

* [email protected]

Novel nalidixic acid coordination polymers with Zn is stable and shows improved solubility. Further complexes and coordination polymers show the diversity that can be explored in is this type of systems.

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Mechanochemical Assembly of Nalidixic Acid Bioinspired Metal

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