Structure elucidation, biological evaluation and molecular docking studies of 3-aminoquinolinium 2-carboxy benzoate- A proton transferred molecular complex

Accepted Manuscript Structure elucidation, biological evaluation and molecular docking studies of 3aminoquinolinium 2-carboxy benzoate- A proton transferred molecular complex K. Saiadali Fathima, M. Sathiyendran, K. Anitha PII:

S0022-2860(18)30963-3

DOI:

10.1016/j.molstruc.2018.08.020

Reference:

MOLSTR 25541

To appear in:

Journal of Molecular Structure

Received Date: 20 February 2018 Revised Date:

16 July 2018

Accepted Date: 7 August 2018

Please cite this article as: K.S. Fathima, M. Sathiyendran, K. Anitha, Structure elucidation, biological evaluation and molecular docking studies of 3-aminoquinolinium 2-carboxy benzoateA proton transferred molecular complex, Journal of Molecular Structure (2018), doi: 10.1016/ j.molstruc.2018.08.020. 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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Structure Elucidation, Biological Evaluation and Molecular Docking Studies of 3aminoquinolinium 2-carboxy benzoate- A Proton Transferred Molecular Complex K. Saiadali Fathimaa, M. Sathiyendranb, K. Anithaa,* CAD4 Laboratory, Department of Physics, School of Physics, Madurai Kamaraj University, Madurai-625021, Tamilnadu, India b

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a

Chemistry Research Centre, National Engineering College, Kovilpatti-628503, Tamilnadu,

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India

*E-mail address: [email protected]

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Abstract

A new organic molecular complex of 3-aminoquinolinium-2-carboxybenzoate (3AQ2CB) was synthesized and grown as single crystal by employing slow evaporation solution growth technique where 3-aminoquinoline (3AQ) act as a donor and 2-carboxybenzoate (2CB) acts as an acceptor. The density of grown crystal 3AQ2CB was measured by floatation method using

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carbon tetrachloride and xylene as solvents. The molecular structure of the grown crystal was predicted by single crystal X-ray diffraction analysis. The presence of proton and carbon was predicted by 1H and

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C NMR spectral analyses. The vibrational modes of functional group

present in the grown crystal were recorded by FTIR and Raman spectrometer. The UV-Vis

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spectrum 3AQ2CB showed a visible band at 390nm due to the promotion of electron from donor molecule to acceptor molecule. The thermal properties and stability of the 3AQ2CB was

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evaluated by thermogravimetric and differential thermal analysis respectively and 3AQ2CB was found to be stable upto 138ºC. The anti-bacterial and anti-fungal activities of 3AQ2CB complex against selected bacteria were investigated. A molecular docking interaction of 3AQ2CB compound was also studied. Introduction In organic chemistry, heterocyclic synthesis is one of the largest areas in research since it plays a vital role in developing a new class of structural entities and growing rapidly due to several pharmacological properties [1,2]. Among the heterocycles, quinoline and its derivatives display wide range of applications in medicinal chemistry due to their chemical and biological

ACCEPTED MANUSCRIPT properties [3–6]. Moreover they occur both in natural and commercial products such as dyes; especially quinoline alkaloids are found in various plants, animals and microorganism and they are used as efficient drug for the treatment of malaria [1,7–9]. They exhibit significant activity such as anti-fungal, anti-viral, anti-bacterial, anti-cancer, anti-tumour, anti-allergic, hypotensive, anti-HIV, anti-inflammatory and analgesic properties [1,3,9–12] . In addition

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quinoline derivatives attract remarkable interest in coordination chemistry due to their coordination capability and also possess structural, chemical, electrochemical, photophysical, photochemical and catalytic properties [13,14]. The 3-aminoquinoline consists of double-ring structure where a benzene ring is fused to a pyridine ring at two adjacent carbon atoms and an

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amino group is attached in the 3rd position of the pyridine ring. The synthesis and crystal structure of 3-aminoquinoline [15], 3-aminoquinoline Zn (II) complex [13], cadmium (II) and mercury (II) complexes of 3-aminoquinoline [14] have been reported already. This complex

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can be formed by electron rich donor and acceptor molecules. The donor molecule has low ionization potential and acceptor molecule has high ionization potential tend to form a stable intermolecular charge transfer complex[16]. In this work, we report the synthesis, structural elucidation, characterization and biological significance of 3-aminoquinolinium 2-carboxy

Materials and Method Experimental

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benzoate complex.

Equimolar amount of 3-aminoquinoline was dissolved in 5ml methanol which was mixed with

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2-carboxy benzoicacid in 5ml methanol. This mixture was continuously stirred for about 2 hrs at room temperature. After reaching homogeneity, it was filtered and kept undisturbed at room

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temperature. The single crystals were collected after a period of ten days. After a recrystallization process, the good quality single crystals grown with perfect external morphology were harvested after a period of six days. A suitable good quality single crystal of 3AQ2CB was selected for single crystal x-ray

diffraction analysis and the crystal was mounted perfectly on the goniometer. The three dimensional intensity data collection was carried out by an ENRAF Nonius CAD4 diffractometer equipped with graphite mono-chromated MoKα radiation with wavelength 0.71073Å at 293K [17]. The least square fit method was used to evaluate accurate cell parameters using 25 well centered reflections for the observed Bragg angle [18]. The molecular structure was solved by direct method and consecutive fourier difference synthesis as

ACCEPTED MANUSCRIPT implemented in SHELXS-97 program [19–21]. All the hydrogen atoms were fixed geometrically ideal positions and allowed to ride on their parent atoms [11,16,22]. All nonhydrogen atoms were refined using anisotropic displacement parameter and located in best Emap [23,24]. The molecular structure was generated by graphical tools such as MERCURY package, ORTEP and PLATON for windows program [11,25]. 1H NMR and 13C NMR spectra

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were recorded in CDCl3 on Bruker Avance 300 MHz spectrometer and the chemical shifts are reported as δ values in parts per million (ppm) relative to tetramethylsilane (TMS) as standard, with coupling constant (J) values in Hertz (Hz). In 1H NMR, the splitting patterns of the peak such as singlet and multiplet are represented as s and m respectively.

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C NMR data are

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reported with a solvent peak (CDCl3=77.0 MHz) as the internal standard. The distinctive vibrational frequencies of various functional groups of 3AQ2CB crystal structure were observed from the FTIR which was recorded in the range of 4000-400cm-1 using Brucker Optic

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Spectrometer. The micro-Raman spectrum of 3AQ2CB molecular complex was recorded using Lab Raman HR 800. The UV-Vis spectrum was recorded by Shimadzu 2450 UV-Vis spectrometer in the range 200-800nm. The TGA and DTA analysis of the grown crystal was carried out using Perkin Elmer diamond TG/DTA thermal analyser simultaneously. The sample was kept in nitrogen atmosphere in the temperature range of 25ºC-250ºC with a heating

Density Measurement

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rate 100ºC/ min and alumina (Al2 O3) was used as a reference sample.

The density of the grown crystal was estimated by the sink and swim or floatation method by using carbon tetrachloride (1.59gm/cm3) and xylene (0.89gm/cm3) as solvents [26].

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The good quality crystal was taken inside a tube containing carbontetrachloride. As the density of the crystal was lesser than the solvent, the crystal started to float in the liquid.

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Henceforward, the equilibrium position was achieved by adding xylene drop wise to the solution until the crystal started to levitate on the centre of the liquid mixture. At the equilibrium position, the density of the liquid mixture is equal to that of the crystal. The liquid mixture was poured in to a relative density bottle and weight was measured using a chemical balance. The density of the crystal was determined by a standard formula, (Dw) g/cc w1- Weight of the empty relative density bottle (g) w2- Weight of the density bottle with water(g)

ACCEPTED MANUSCRIPT w3- Weight of the density bottle with solution(g) Dw- Density of water 1000 g/cc The density of 3AQ2CB crystal is determined as 1.406g/cc. The crystallographic density was calculated by using the formula and the value is shown in table 1

Single crystal X-ray diffraction Analysis

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g/cc

Table 1 summarizes the data collection, structure solution and refinement details

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for the 3AQ2CB single crystals. It reveals that the molecular structure of present 3AQ2CB compound is crystallized in monoclinic crystal system with centrosymmetric spacegroup P21/n. Table 2 shows bond lengths and bond angles for 3AQ2CB crystal structure. Figure 1a shows

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ORTEP of the 3AQ2CB drawn at 50% probability thermal ellipsoidal with atom numbering scheme.

The asymmetric unit of title crystal has a protonated positively charged 3aminoquinoline cation and negatively charged 2-carboxybenzoate anion. In 3AQ2CB crystal structure, the protonation is observed at the endocylic N site of the cation which is confirmed

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from the increase of C-N bond distances d (N1-C6) = 1.364(4) Å and enhancement of internal angle at N1 in the 3-aminoquinolinium cation (C7-N1-C6= 124.0º(3)) when compared to parent 3-aminoquinoline (C-N-C=117.72 º(11)) molecule [15]. The divergence is due to the conjugation of electrons of carbonyl and nitrogen atom along C-N bond [27] . Moreover, the

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deprotonation in carboxylate group of 2-carboxybenzoate anion is verified through the variation of carboxyl C-O and C=O bond distances d (C17-O2) =1.223(5) Å and d (C17-O1)

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=1.262(4) Å [17]. It is found that the carboxyl group of anion donate a proton to the N atom in aromatic ring of cation, but not to the amino group in cation of 3AQ2CB compound [28]. The dihedral angle between the planes of 3-aminoquinolinium cation and 2-carboxybanzoate anion is 13.74º which indicates that they are aligned parallel to each other. Among intermolecular interactions, hydrogen bonding interaction plays a vital

role in the construction of supramolecular systems in both practical and theoretical perspectives and in determining the structural stability of many chemical complexes [12]. This intermolecular hydrogen bonding interaction between the molecules is absolutely essential for various bioactivities which depend on the structural features of the molecules [29–31]. The hydrogen bonding scheme and intermolecular interaction are used to stabilize the crystal

ACCEPTED MANUSCRIPT packing of the molecule. The 2-carboxybenzoate anions play an important role to form extensive three dimensional hydrogen bonding network by connecting the cations [29,32]. The geometry of the anions is influenced by these hydrogen bonding interactions. Carboxylic acid is one of the most commonly used functional groups in crystal engineering since they generally form robust architectures through O-H…O and N-H…O hydrogen bonded dimers.

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In the present molecule, the crystal packing is stabilized through intramolecular OH…O, intermolecular N-H…O and weak C-H…O hydrogen bonding interactions by connecting the protonated nitrogen (N1) in the ring and amino (N2) atom of cation to the carboxylate oxygen atoms (O1, O2, O3 and O4) of anion [33]. It is found that, all the oxygen

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of the molecule are participating in the hydrogen bonding interactions as donors or acceptors (Table 3). Henceforward, in 3AQ2CB molecule, cation moieties are dimerized to form head-totail dimeric structure via N-H…O hydrogen bond [34]. Table 3 revealed that the donor of

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cation molecule is capable of forming five two centered intramolecular hydrogen bonds, while anion can also form one two centered intramolecular hydrogen bond. But, the nitrogen atom (N2) of cation ring makes bifurcated hydrogen (H2B) bonds with the oxygen atoms (O3 & O4) of their respective anion counterparts leading to a graph-set motif

(4) [34]. These head-to-

tail N-H…O hydrogen bonding interactions lead to two parallel chain motif

(11) which are

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extended along the b axis of the unitcell (figure 2). The intramolecular O3-H3A…O1 hydrogen bond in anion site forms a distinctive graph set S (7) motif [35]. Hence, the packing diagram denotes a intricate three dimensional hydrogen bonding network and these chain type of

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hydrogen bonding motifs are observed in all hydrophilic layers (figure 1b). Hirshfeld Surface Analysis

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Crystal Explorer (Version 3.0) software is used to demonstrate the Hirshfeld surfaces of the 3AQ2CB compound and their fingerprint plots are drawn by using cif file as input [36]. Each point on surface depends on two distances de and di, whereas de represents the distance from the point to the nearest nucleus external to the surface and di represents the distance to the nearest nucleus internal to the surface. The normalized contact distance dnorm derived from de and di and the equation is given below,

ACCEPTED MANUSCRIPT Where, rivdw and revdw are the Vanderwaals radii of the suitable atoms which are internal and external to the surface. The dnorm value is negative or positive when intermolecular contacts are shorter or longer than rvdw. When dnorm was mapped on the Hirshfeld surface, close intermolecular distances were analysed by three identical colored regions: red region stand for closer contacts (-dnorm value), blue region represents a longer contacts (+dnorm value) and white

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region corresponds to the distance of contacts (zero dnorm value). The two distances combined to form 2D fingerprint plot which explains the intermolecular contacts in the crystal structure [37].The 3D Hirshfeld surfaces of the compound was examined for the nature of the interactions. The 2D fingerprint plots revealed the contribution of those interactions in the

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crystal structure quantitatively, presenting the surfaces that have been mapped over a dnorm range of -0.744 to 1.488, di range of 0.654 to 2.596, de range of 0.653 to 2.570, curvedness range of -4.000 to 0.400, shape index range of -1.000-1.000 and elctrostatic potential range of -

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0.103 to 0.235 shown in figure 3(a-f). The intramolecular hydrogen bond distances of N1H1…O1, N1H1…O2, C5H5…O1 and O3H3A…O1 are 5.606 Å, 5.092 Å, 4.497 Å and 1.39 Å respectively. The intermolecular hydrogen bond distances of N2H2B-O4 is 2.217Å. These two types of interactions are predicted in figure 3(g-h). Figure 4a demonstrates the 2D fingerprint plot for H-H interaction and covered 43.09% area of Hirshfeld surface. The O-H

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interaction covers 37.2% portion of Hirshfeld surface and the spike at the bottom of two side area of fingerprint plot (figure 4b). The C-H, C-C, C-N, N-H and C-O interactions occupy 8.3%, 7.6%, 1.3%, 1.1% and 0.2% area of fingerprint plot respectively figure 4(c-g). The overall interaction contribution is plotted as a bar diagram figure 4h. Inter and intramolecular

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hydrogen bonding is a relatively strong, highly directional, and specific noncovalent interaction present in many organic molecules, and notably this nature is responsible for biological

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systems [38,39]. Here the theoretical investigation satisfy the experimental results. NMR Spectral Analysis The 1H NMR and

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C NMR data are shown in figure 5a and figure 5b respectively. The 1H

NMR spectrum of the representative compound (3AQ2CB) exhibits two singlets at δ 8.52 ppm and 7.24 ppm (Ar-CH).

One of the aromatic protons appears as doublet at 7.83ppm.

Moreover, other protons appear as multiplets at 7.40-7.31 ppm for three aromatic protons (ArH), multiplet appears at 7.60-7.52 ppm for four aromatic protons (ArH) and the multiplet at 7.75-7.72 ppm is for two aromatic protons (ArH).

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C NMR spectrum of a representative compound (3AQ2CB) one carbonyl carbon

(C=O) appears at 167.51 ppm and other carbons appear at 141.16, 141.07, 141.03, 140.96, 140.75, 138.76, 131.61, 128.94, 128.04, 127.22, 126.19, 126.14, 125.16, 124.10, 122.98 and 111.73ppm. FTIR Spectral Analysis

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The presence of leading infrared absorption band of donor and acceptor in the 3AQ2CB spectrum confirms the transfer of proton between 3AQ and 2CB during acid-base reaction and is shown in figure 6a [17]. Comparison between parent (3AQ and 2CB) and complex molecule (3AQ2CB) is shown in table S1 (Refer supplementary material). The FTIR spectra of 3AQ and

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2CB molecule are depicted in figure S1 (Refer supplementary material).

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Amino group vibration

The non-coordinated -NH2 stretching vibration band of 3AQ2CB complex appeared at lower wavenumber (blue shift) 3385cm-1 than their parent ligand 3AQ [13]. Classically, the N-H stretching vibration appears in the range of 3500-3000cm-1 [3]. The asymmetric N-H stretching vibration of 3AQ was assigned to 3325cm-1. In 3AQ2CB complex, the asymmetric and symmetric stretching vibrations of N-H group were shifted to 3319 cm-1 and 3213cm-1

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respectively [2] . The medium intensity peak at 2104 cm-1 was assigned to the N-H+ stretching vibration of protonated 3AQ. This confirmed the formation of an intermolecular N-H…O hydrogen bond [3]. Usually, the C-NH2 stretching vibration occurs in the region 1350-1375 cm-1 [14]. The medium intensity peak at 1354 cm-1 in FTIR spectrum of 3AQ2CB was

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assigned to C-NH2 vibration which was red shifted (1347 cm-1 for 3AQ). The deformation mode of NH2 group mostly appears in the region 1600-1650 cm-1 [40]. In 3AQ2CB compound,

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a weak intensity peak appeared at 1626 cm-1 was corresponding to this vibrational mode. Carbonyl Group Vibration The COO- stretching vibration was observed at 1609 cm-1 for ammonium phthalate crystal [41]. Jagadeesh et.al and Senthil et.al have reported that the strong intensity absorption of C=O stretching vibration appeared at 1685 cm-1 [42,43]. Also for 2CB, the strong broad intensity peak of C=O stretching vibration was observed at 1685cm-1. For 3AQ2CB, the vibrational band at 1626 cm-1 was due to the mixing of C=O and COO- stretching vibrations. Thus the proton transfer from carboxylic acid (COOH) to nitrogen atom in 3AQ was justified. For 3AQ2CB, a peak at 1250 cm-1 corresponding to C-O stretching vibration was blue shifted

ACCEPTED MANUSCRIPT (1278 cm-1 for 2CB alone) [44]. Hence, the peak occured at 1250 cm-1 for 3AQ2CB complex was due to the mixing of C-O and C-N stretching vibration. Hydroxyl Group Vibration There are two carboxyl groups in the 2CB molecule. After deprotonation, one of the carboxyl

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groups became carboxylate group and another carboxyl group remains unchanged. In lithium hydrogen phthalate dihydrate crystal structure, the O-H hydrogen bond was assigned at 3391 cm-1 [43]. The band originated at 3385 cm-1 was assigned to O-H stretching vibration of 3AQ2CB complex. However, this peak also indicated the -NH2 stretching vibration of complex

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molecule as mentioned in amino group vibrations. Therefore, the peak observed at 3385 cm-1 may be due to both O-H and -NH2 stretching vibrations. In high wave number region, the broadening of the peaks was observed due to the combination of COOH, N-H and O-H

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vibrations [41]. The OH out-of-plane bending vibration of 2CB molecule was noticed at 1068cm-1. In 3AQ2CB, the band appeared at 1040 cm-1 was corresponding to OH out-of-plane bending vibration of carboxylic acid and it was blue shifted [42]. From the FTIR spectrum, the shift in the vibration was observed due to the presence of strong hydrogen bonding interaction in the complex molecule via protonation. In 3AQ2CB spectrum, the significant shift of donor

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and acceptor in the lower or higher frequency region was due to the change in the charge density upon complex formation [12,16]. Aromatic Ring Vibration

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Typically, the C-H stretching vibration is vital in aromatic group and is observed in the region of 3000-3100 cm-1 [31,45]. The weak intensity peaks of 3AQ2CB noticed at 3057cm-1 was assigned to C-H asymmetric vibration of aromatic group which was red shifted (3043cm-1 for

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3AQ) [10] . The C-N stretching vibration bands are usually observed in the region 1335-1250 cm-1 and 1280-1180 cm-1. The observation of C-N stretching vibration is difficult task since it is masked due to the mixing of other vibrations [40]. The C-N stretching vibration was found at 1234 cm-1 and 1294 cm-1 for 3AQ compound. In 3AQ2CB the bands due to C-N stretching modes of vibration were appeared at 1250 cm-1 and 1288 cm-1, which were slightly shifted than their reactants [46]. The aromatic C-H inplane bending vibration gives rise to medium intensity peaks in the region 1300-1000 cm-1 [46]. The shifting of C-H inplane bending vibration was seen at 1163 cm-1. The out of plane bending vibration has been observed within the region of 1000-750 cm-1. A sharp intensity peak at 765 cm-1, 788 cm-1, 885 cm-1, 897 cm-1 and 959 cm-1 were designated to C-H out of plane bending vibration of complex molecule. In 3AQ2CB, the

ACCEPTED MANUSCRIPT deformation band of aromatic ring were noticed at 463 cm-1, 522 cm-1, 581 cm-1, 624 cm-1, 735 cm-1, 765 cm-1 and 788 cm-1. It is evidenced for the mixing of C-H out of plane bending and ring deformation mode originated at 765 cm-1 and 788 cm-1 [47]. Also, the C=C out of plane bending vibration was observed at 522 cm-1 for 3AQ2CB complex. Deva Anban et.al and Selvakumar et.al reported that the C=C stretching vibration was observed at 1575 cm-1, 1580

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cm-1, 1500 cm-1 and 1473 cm-1 [3,16]. The C=C stretching vibration of 3AQ2CB complex were shifted to lower wavenumber 1582 cm-1 and 1451 cm-1 when compared with 1585 cm-1 for 2CB alone and 1469 cm-1 for 3AQ alone respectively [48]. The C=N stretching mode of 3AQ2CB was mixed with C=C stretching and the peak appeared at 1585 cm-1.

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Raman Spectral Analysis

Figure 6b shows the Raman spectrum for the 3AQ2CB compound. The vibration range of N-H,

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O-H, C-H and aromatic ring were mentioned in FTIR analysis. The C-H stretching vibration appeared at 3052cm-1. The peak at 1473cm-1 was corresponding to the C=C stretching vibration. The vibration band originated at 1391cm-1 was due to the mixing of ring vibration and symmetric carboxylate stretching vibration. It also explained the proton transfer from 3aminoquinoline to 2-carboxybenzoicacid. The C-NH2 stretching vibration was seen at 1364cm. The band appeared at 1045cm-1 was attributed to C-OH stretching vibration. From this, it was

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concluded that the amino and hydroxyl group vibrations were appeared in both the FTIR and Raman spectrum. The bands at 1012cm-1, 768cm-1, 812cm-1 and 962cm-1 revealed the presence of C-H in-plane and C-H out-of-plane bending vibrations respectively. The deformation bands

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of aromatic ring were seen at 420cm-1, 459cm-1, 529cm-1 and 727cm-1. It was clearly evidenced that the mixing of C-H out of plane bending and ring deformation mode originated at 768cm-1 as already mentioned in FTIR analysis. Moreover, the band at 812cm-1 was arised due to the

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mixing of N-H and O-H out-of-plane bending vibration. Here, the protonated carbonyl stretching vibration was inactive in Raman spectrum but active in FTIR spectrum. UV-Vis Spectral Analysis Figure 7a shows the UV-Vis spectrum of 3AQ2CB compound. The presence of specific band indicated that the electron absorption was due to the charge transfer transition from the ground state to the first excited state (π-π* and n- π*). The absorption spectrum of 3AQ2CB revealed that the charge transition band originated on the longer wavelength side at 390nm and it was assigned to n- π* transition due to the promotion of electron from donor molecule AQ to acceptor molecule 2CB. There was no shift observed but the intensity of the charge transfer

ACCEPTED MANUSCRIPT peak was decreased when compared with the 3AQ. The presence of intermolecular charge transfer activity in the complex molecule was confirmed by this charge transfer peak [16]. The minimum intensity band observed at 321nm might be attributed to the excitation of π- electrons (π-π* transition) which was localized on the 3AQ ring [49]. Moreover, the π-π* transition of 3AQ2CB complex occured at 262nm was due to benzene moiety of acceptor molecule 2CB

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which was red shifted (241nm for 2CB alone) and this shift was due to the proton transfer from the acceptor 2CB to the donor molecule 3AQ. The UV-Vis spetrum of 3AQ and 2CB are shown in figure S2 (Refer supplementary material). Comparison of parent (3AQ and 2CB) and complex molecule (3AQ2CB) is shown in table S2(Refer supplementary material).

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TGA/DTA Analyses

The thermal stability of the grown crystal 3AQ2CB was evaluated by the TGA/DTA method

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and figure 7b shows the TGA/DTA graph for the synthesised material. The DTA curve of 3AQ2CB showed a sharp endothermic transition at 138ºC related to its melting point. This sharp endothermic peak explained the crystallinity and purity of the sample [50]. The curve inferred that, there was no phase transition below the melting point. It evidenced the absence of isothermic transition and absence of water molecule in the grown crystal [51,52]. The second broad endothermic peak at 167ºC denoted the decomposition of material. In TGA, the total

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weight loss of residue was observed in single stage in the temperature range of 138οc and 175οc which was due to decomposition [53]. The TGA curve revealed that the material was stable from ambient temperature to 1380C. TGA/DTA results concluded that the material was useful

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for any application up to 138οC. The TGA showed exactly the same changes shown by the DTA for title compound.

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Biological Application

Disc Diffusion Method

From the biological literature survey, the anti-bacterial activity of synthesized compound 3AQ2CB was assessed against selected gram positive bacteria such as Staphylococcus aureus (ATCC 29213), Bacillus cereus (ATCC 14579) and gram negative bacteria such as Serratia marcescens

(43862),

Pseudomonas

aeruginosa

(ATCC27853),

Escherichia

Coli

(ATCC25922) using standard disc diffusion assay. Various infections and disorders like skin infection, respiratory infection, food poisoning, nausea and vomiting were caused by the gram positive bacteria like Staphylococcus aureus and Bacillus cereus. Moreover, urinary tract

ACCEPTED MANUSCRIPT infections, wound infections, typhoid fever, haemolytic uremic syndrome and nosocomial infections were caused by the gram negative bacteria Serratia marcescens and Pseudomonas aeruginosa [54,55]. Hence the synthesized compound 3AQ2CB was dissolved in DMSO and sterile paper disc was impregnated with filter sterilized compounds. A Muller Hinton agar plate was prepared and the cultures grown overnight were swapped on the plates to make lawn of the

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bacterial cultures. The discs paper were placed on the agar plates and incubated at 30ºC for 24hrs. After 24hrs, the zone of inhibition was observed and measured around the disc shown in table 4. Among the various antibiotics, Pencillin G is one of the important standard antibiotics which were the first medication to be effective against many bacterial infections. The

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compound showed good activity against Staphylococcus aureus and Escherichia Coli compared with penicillin G antibiotic. The compound showed moderate activity against Bacillus cereus and Serratia marcescens compared with penicillin G antibiotic. The compound

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displayed zero activity against Pseudomonas aeruginosa compared with penicillin G antibiotic. Antifungal Activity

The compounds were evaluated against anti-fungal activity such as Aspergillus niger, Candida albicans (ATCC 10231) and Penicillium variance. The scrapings from a ripe (7-14

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days) fruiting culture of the test fungi Aspergillus niger, Candida albicans and Penicillium variance were added to sterile Erlenmeyer flasks containing 50 ± 1 ml of sterile water with few glass beads [56,57]. The flask was thoroughly shaked to bring the spores into suspension. This suspension was used as the inoculum. About 1.0±0.1 ml of inoculum were swabbed over the

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agar surface using the sterile cotton swab. The respective disc preloaded with 50µL of the supernatant was placed on the potato dextrose agar surface and the plates were incubated at

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28°C for 72 hours. The test was repeated thrice and the isolates exhibiting significant zones of inhibition against test fungus were chosen. Ketaconazole was used as a reference to evaluate the susceptibility of test organisms (table 4). The 3AQ2CB compound was tested against Aspergillus niger which exhibits zero activity. The compound 3AQ2CB has shown moderate activity against Candida albicans and good activity against Penicillium variance. Molecular docking studies In order to know the binding modes of the synthesized compound (3AQ2CB), the molecular docking study was carried out against enzymes Escherichia Coli and Penicillium variance. The crystal structures of E.coli (PDB code: 1BTL) [58]and Penicillin variance (PDB code: 2NB0) [59] were taken from the Protein Data Bank. Hetero atoms and water molecules in the

ACCEPTED MANUSCRIPT PDB file were removed and hydrogen atoms were added to the protein. Docking of the ligand was carried out using the AutoDock Tool 4.2 program. Ligand and receptor were added along with Gasteiger charges and polar hydrogen atoms using Auto Dock vina version 1.5.6. Auto Grid (grid space value 0.375 for all) was used to calculate the grid maps and a large grid was chosen to include a significant part of the receptor with a grid box size of 40 × 40 × 40 points.

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The affinity value for E.coli with the complex is -7.6(kcal/mol) and penicillin variance with the complex is -6.7(kcal/mol). The discovery studio software was used to visualize the attraction between the compound and protein. The compound containing O, N and six membered rings were bind to various amino acids of Escherichia Coli with minimum

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distances and summarized in table 2. Similarly the compound containing different functional atoms were bind with various amino acids of penicillium variance with various distances and shown in table 5. This theoretical modelling result also confirms the binding modes of

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compound with receptor.

Conclusion

The compound 3AQ2CB was synthesized and grown as single crystals by slow evaporation solution growth technique at room temperature. The densities of the grown crystals

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were calculated by sink and swim method which confirmed the new complex formation. The grown crystal was in monoclinic crystal system with P 21/n spacegroup. Hirshfeld surface analysis proposed that H-H interaction contributed more for structural stabilization of 3AQ2CB structure. The molecular structure of 3AQ2CB was established by 1H and

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C NMR spectral

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studies and it was confirmed by single crystal X-ray diffraction technique. The corresponding vibrational modes of various functional groups of 3AQ2CB have been assigned by FTIR and

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Raman spectral analysis. The presence of N-H…O and O-H…O hydrogen bonds in the molecular structure was evidenced from the shift in the wavenumber of fundamental bands such as N-H, C-H and C=O stretching vibration which enhanced the bioactivity of 3AQ2CB. The proton transfer from the anion to the cation was recognized by the UV-Vis absorption spectrum of 3AQ2CB and proved that the bioactivity of the compound was due to the proton transfer interaction within the molecule via hydrogen bonding interaction. TGA/DTA analysis revealed that the synthesized material had a good thermal stability up to 138ºC. The antibacterial activity and anti-fungal activitiy of 3AQ2CB compound was more effective against Escherichia Coli and Penicillium variance respectively. Also, the binding modes of 3AQ2CB compound were ascertained by molecular docking studies against Escherichia Coli

ACCEPTED MANUSCRIPT and Penicillium variance. From these results, it is concluded that the hydrogen bonding interactions are enough to prove that the 3AQ2CB complex is biologically active. References [1]

M.C. Mandewale, U.C. Patil, S. V. Shedge, U.R. Dappadwad, R.S. Yamgar, A review on quinoline hydrazone derivatives as a new class of potent antitubercular and anticancer agents, Beni-Suef Univ.

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Figure Captions

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doi:10.1371/journal.pone.0169920.

Figure 1: (a) ORTEP diagram with atom numbering scheme and (b) Packing diagram for

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3AQ2CB

Figure 2: (a) A molecular aggregations formed in 3AQ2CB showing chain C42 (11) and graph

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set S(7) motifs. Hydrogen bonds are shown in dashed lines Figure 3: Hirshfeld surfaces analysis mapped with (a) dnorm (b) di (c) de (d) curved index (e) shape index (f) electrostatic potential (g) Intramolecular (h) intermolecular hydrogen bonding with distance values (red and blue represents the closest contacts and most distant contacts) Figure 4: Fingerprint plots of (a) H-H (43.09%) (b) O-H (37.2%) (c) C-H (8.3%) (d) C-C (7.6%) (e) C-N (1.3%) (f) N-H (1.1%) (g) C-O (0.2%) and (h) bar diagram for overall interactions

ACCEPTED MANUSCRIPT Figure 5: (a) 1H NMR (300 MHz, DMSO) and (b) 13C NMR (75 MHz, CDCl3) for 3AQ2CB compound Figure 6: (a) FT-IR spectrum and (b) Raman spectrum for 3AQ2CB crystal

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Figure 7: (a) UV-Visible spectrum and (b) TGA/DTA curve for 3AQ2CB crystal Figure 8: Proposed binding mode for compound with E.coli (a) Overall view (b) Selected amino acid residue contact with compound (c) H-bond of the compound –protein complex and Proposed binding mode for compound with penicillium variance (d) Overall view (e) Particular

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amino acid residue contact with compound (f) H-bond of the compound –protein complex. Pink and green colour indicates donor and acceptor property for both E.coli and Penicillium variance. The active compound was shown as ball and stick in both E.coli and Penicillium

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variance. Table captions Table 1

Table 2

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Crystallographic Data and Structure Refinement for 3AQ2CB compounds

Table 3

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Selected bond length and bond angle for 3AQ2CB crystal

Hydrogen Bonding Geometry for 3AQ2CB crystal

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Table 5

Antibacterial and Antifungal Activities of 3AQ2CB Complex Table 6

Binding modes of compound with amino acid of E.coli and penicillium variance

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C17 H14 N2 O4 310.30

Temperature Wavelength Crystal system

293(2) K 0.71073 Å Monoclinic

Space group Unit cell dimensions

P 21/n a = 7.338(3) Å b = 25.383(12) Å c = 7.951(3) Å

Volume Z Density (calculated)

1469.3(8) Å3 4 1.403 Mg/m3 0.102 mm-1

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Absorption coefficient F(000) Crystal size Theta range for data collection

α= 90° β= 97.19(2)° γ= 90°

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Empirical formula Formula weight

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Table 1

0 ≤ h ≤ 8, -1 ≤ k ≤ 30, -9 ≤ l ≤ 9 2935 2590 [R(int) = 0.0631] 100.0 % Full-matrix least-squares on F2

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Index ranges Reflections collected Independent reflections Completeness to theta = 25.003°

648 0.20 x 0.20 x 0.20 mm3 2.704 to 25.003°.

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Refinement method Data / restraints / parameters Goodness-of-fit on F2 Final R indices [I>2sigma(I)]

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R indices (all data) Largest diff. peak and hole

2590 / 0 / 209 1.201 R1 = 0.0577, wR2 = 0.2076 R1 = 0.0804, wR2 = 0.2211 0.274 and -0.202 e.Å-3

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Connected atoms

Bond Length [Å]

O(3)-C(16) O(3)-H(3A) O(1)-C(17) N(1)-C(7)

1.271(5) 0.8200 1.262(4) 1.311(4)

C(1)-C(9) C(1)-C(2) C(1)-C(6) C(9)-C(8)

1.397(5) 1.414(5) 1.415(5) 1.375(5)

N(1)-C(6) N(1)-H(1) O(4)-C(16) N(2)-C(8)

1.364(4) 0.8600 1.224(5) 1.363(5)

C(10)-C(11) C(8)-C(7) C(5)-C(4) C(5)-C(6)

N(2)-H(2A) N(2)-H(2B) O(2)-C(17)

0.8600 0.8600 1.223(5)

C(13)-C(12) C(13)-C(14) C(14)-C(17)

C(15)-C(10) C(15)-C(14) C(15)-C(16) Connected atoms

1.390(5) 1.421(4) 1.505(5) Bond Angles[ο]

C(11)-C(12) C(2)-C(3) C(4)-C(3) Connected atoms

1.376(6) 1.354(6) 1.402(6) Bond Angles[ο]

C(16)-O(3)-H(3A) C(7)-N(1)-C(6)

109.5 124.0(3)

N(1)-C(6)-C(1) O(4)-C(16)-O(3)

116.9(3) 119.6(3)

C(7)-N(1)-H(1) C(6)-N(1)-H(1) C(8)-N(2)-H(2A) C(8)-N(2)-H(2B) H(2A)-N(2)-H(2B) N(2)-C(8)-C(9)

118.0 118.0 120.0 120.0 120.0 124.1(3)

O(4)-C(16)-C(15) O(3)-C(16)-C(15) N(1)-C(7)-C(8) N(1)-C(7)-H(7) O(2)-C(17)-O(1) O(2)-C(17)-C(14)

119.6(3) 120.8(3) 121.7(3) 119.2 120.8(4) 117.3(3)

N(2)-C(8)-C(7)

119.4(3)

O(1)-C(17)-C(14)

121.9(3)

N(1)-C(6)-C(5)

121.6(3)

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Bond Length [Å]

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Connected atoms

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Table 2

1.367(5) 1.404(5) 1.356(6) 1.394(5)

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1.367(5) 1.386(4) 1.515(5)

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Table 3 D-H [Å]

H…A [Å]

D…A [Å]

D...H.A [º]

O3-H3A…O1

0.820

1.554

2.373

175.86

N1-H1…O2 #1

0.860

1.866

2.646

N2-H2A…O4 #2

0.860

2.310

2.936

N2-H2B…O3#3

0.860

2.550

3.220

N2-H2B…O4#3

0.860

2.485

3.268

C7-H7…O3 #3

0.930

2.456

3.179

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D-H…A

150.11

129.88

135.47 151.78

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134.56

Table 4 Antibacterial Studies Pathogens

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aspergillus niger candida albicans Penicillium variance

Penicilin G (mm)

3AQ (mm)

3AQ2CB (mm)

11 12 4 8

11 10 4 10

6 12 13 13

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-

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Staphylococcus aureus Bacillus cereus Serratia marcescens Pseudomonas Escherichia Coli Antifungal Studies Pathogens

DMSO (mm)

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Symmetry equivalent positions for 3AQ2CB #1 x+1/2, -y+1/2, z-1/2 #2 -x, -y, -z+2 #3 x, y, z-1

DMSO (mm)

Ketaconazole (mm)

3AQ (mm)

3AQ2CB (mm)

-

6 10 8

4 7 9

11 12

Table 5

distance

Binding residue

2.33 & 2.77 2.37 & 2.34 5.6 4.82 2.02 & 2.68 2.79 2.95

SER70 & GLU166 ASN170 & GLU166 TYR105 VAL216 SER235 & ARG244 SER130 SER130

2.24 3.31 4.92 4.01 4.05

ALA1 ASP46 Lys42 ALA51 ASP46

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Binding atom of asynthesized compound E.coli N2 H2A N2 H2B C1-C6 C10-C15 O4 O3 O1 penicillium variance O3 O1 C10-15 C1-C6 C1-C6

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Figure 1

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Figure 2

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A proton transferred molecular complex 3AQ2CB was grown as crystal from slow evaporation solution technique.
The crystal structure was stabilized by N-H…O, O-H…O and C-H…O interactions.
These hydrogen bonding interactions lead to chain and self-motif.

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The biological activity of 3AQ2CB was studied.

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NMR, FTIR, Raman and UV-Vis studies were carried out for 3AQ2CB compound.