Cocrystals of pyrazinamide with p-toluenesulfonic and ferulic acids: DFT investigations and molecular docking studies

Accepted Manuscript Cocrystals of pyrazinamide with p-toluenesulfonic and ferulic acids: DFT investigations and molecular docking studies Jamelah S. Al-Otaibi, Y. Sheena Mary, Y. Shyma Mary, C. Yohannan Panicker, Renjith Thomas PII:

S0022-2860(18)30996-7

DOI:

10.1016/j.molstruc.2018.08.055

Reference:

MOLSTR 25576

To appear in:

Journal of Molecular Structure

Received Date: 25 June 2018 Revised Date:

12 August 2018

Accepted Date: 14 August 2018

Please cite this article as: J.S. Al-Otaibi, Y. Sheena Mary, Y. Shyma Mary, C.Y. Panicker, R. Thomas, Cocrystals of pyrazinamide with p-toluenesulfonic and ferulic acids: DFT investigations and molecular docking studies, Journal of Molecular Structure (2018), doi: 10.1016/j.molstruc.2018.08.055. 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.

AC C

EP

TE D

M AN U

SC

RI PT

ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT

Cocrystals of pyrazinamide with p-toluenesulfonic and ferulic acids: DFT investigations and molecular docking studies Jamelah S. Al-Otaibia, Y.Sheena Maryb*, Y.Shyma Maryb*, C.Yohannan Panickerb, Renjith a

RI PT

Thomasc

Department of Chemistry, College of Science, Princess Nourah bint Abdulrahman University,

Saudi Arabia b

Department of Physics, Fatima Mata National College (Autonomous), Kollam, Kerala, India

Department of Chemistry, St Berchmans College (Autonomous), Changanassery, Kerala, India

SC

c

M AN U

*author for correspondence :email: [email protected] Abstract

Cocrystals of pyrazinamide with p-toluenesulfonic acid (PZTSA) and ferulic acid (PZFER) are investigated by density functional calculations to find geometrical parameters, wavenumbers and different molecular properties. The vibrational modes associated with the phenyl and pyrazine rings have small changes during the cocrystal formation, while changes are associated with the

TE D

amide group of pyrazinamide, hydroxyl and carboxylic groups of ferulic acid and SO3 group of PZTSA. Using density functional theory method the molecular geometries of the co-crystals were optimized in the ground state and a comparison is made with the reported experimental data. The theoretically obtained wavenumbers are assigned by means of potential energy

EP

distribution. The downshift of different modes in the infrared spectrum is due to hydrogen bonding and this is supported by the strong hyper conjugative interactions given by natural bond

AC C

orbital analysis. HOMO is delocalized over the entire molecule except phenyl ring and methyl group and LUMO is delocalized over the entire molecule except C=ONH2 group for PZTSA while for PZFER, HOMO and LUMO are delocalized over the ferulic acid. From the MEP plot, electron rich regions are mainly localized over C=O and SO3 groups of PZTSA while for PZFER, all the oxygen atoms electron rich regions. The first hyperpolarizability of PZTSA and PZFER are 5.99 and 89.66 times that of urea. Different molecular properties like, global chemical descriptors, frontier molecular orbital analysis, nonlinear optical properties and natural bond orbital analysis are also discussed in the present work. The different functional groups in the title compounds are identified by configurations markers using the theoretical VCD spectra 1

ACCEPTED MANUSCRIPT

analysis. Light harvesting efficiency analysis shows that PZFER is suitable for photo sensitizers in DSSC's. Docking results suggest that the compounds might exhibit inhibitory activity against mycobacterium tuberculosis type II and the compounds can be developed as a new anti-TB drug. Keywords: DFT; cocrystals of pyrazinamide; FT-IR; Molecular docking. Introduction

RI PT

1.

For improving the physiochemical properties of pharmaceutical constituents cocrystallization is a good technique [1, 2]. With other solid state techniques, co-crystallization is a good technique because no ionisable groups are needed either for the conformer or for the drug

SC

and is used for the preparation of polymorphs, amorphous formulation and molecular salts [3]. The anti-TB pro-drug pyrazinamide is an amphiprotic molecule containing carboxylic acid and

M AN U

pyridine groups and form co-crystals with significant partner molecules. Electrostatic and steric compatibility problems between molecules of the combination occur and affect intermolecular interactions and supra molecular growth with the alteration of the carboxamide position [4]. Pyrazinamide co-crystals are the first-line drugs for tuberculosis, a nonsteroidal antiinflammatory material suggested by world health organization. It is an interesting pharmaceutical co-crystal in terms of combination drug perspective with known side effects in therapy [5]. With

TE D

similar TB drugs rifampicin, ethambutol and isoniazid, pyrazinamide is used during monotherapy and fixed dose combination. It is also an effective antiuricosuric drug used to preserve optimum uric acid levels in human blood serum [6]. Sarmah et al. [7] reported the single crystal and powder crystal XRD reports of cocrystals of pyrazinamide with p-

EP

toluenesulfonic and hydroxybenzoic acids. Shanmugam and Brahadeeswaran [8] reported the synthesis and spectroscopic studies of 4-methylanilium p-toluenesulfonate crystal and Kumar et

AC C

al. [9] reported the optical, thermal and vibrational study of benzotriazolium p-toluene sulfate crystal. Feluric acid is a phenolic compound seen in rice bran, barley, tomato, wheat and toasted coffee and possesses various pharmacological properties, like anti-carcinogenic, antihyperlipidemic, antioxidant and antimicrobial properties [10]. There is no DFT and FT-IR vibrational data analysis of the cocrystals of pyrazinamide with p-toluenesulfonic acid (PZTSA) and ferulic acid (PZFER) to our knowledge. 2.

Computational and experimental details The geometry optimization of all the compounds, (PZTSA and PZFER) (Fig.1) were

carried out using Gaussian09 series of program [11] by using the coordinates extracted from the 2

ACCEPTED MANUSCRIPT

corresponding cif files [7] at B3LYP/6-31G (6D, 7F) level of theory. The NLO properties, frontier molecular orbital analysis, molecular electrostatic potential and NBO analysis were also done at the same level of theory. All the positive values of wavenumbers confirmed that the optimized geometry corresponds to a true minimum for the three title compounds. Using the

RI PT

Gauge Invariant Atomic Orbitals implemented in Gaussian program package the VCD intensities were calculated with the magnetic field perturbation method [12] and a scaling factor of 0.9613 is used for scaling the theoretically obtained wavenumbers [13] and vibrational assignments are done with the aid of GAR2PED and Gaussview software [14,15]. FT-IR spectra (Fig.2) were

3.

Results and discussion

3.1

Geometrical parameters

M AN U

resolution of 2 cm-1 in the range 4000 to 400 cm-1.

SC

conducted on Perkin Elmer Spectrum One to identify wavenumbers in KBr pellet with a

The theoretically predicted geometrical parameters with experimental values are given in Table S1 (supplementary information). The C=O bond lengths in the C=ONH2 group deviate by 0.0047Å for PZTSA, and 0.0418Å for PZFER, from the XRD results and the reported values are 1.2365Å and 1.2311Å [16]. The C=O bond lengths (DFT/XRD) in the carboxylic group are

TE D

1.2610/1.2635Å (C14-O22) and 1.3492/1.2737Å (C14-O21) for PZFER [17]. The C-O bond lengths (DFT/XRD) of PZFER are C5-O24 = 1.3789/1.3529Å, C4-O23= 1.3971/1.3698Å and C15-O23=1.4525/1.4280Å and the reported values are in the range 1.3574/1.3492Å [18]. The pyrazine bond lengths of the title compounds are in agreement with literature [16]. The bond

EP

angles (DFT/XRD) around the carbon atom of carbonyl group of pyrazinamide of the title compounds, around C8 of PZTSA (O15-C8-C1 = 120.0/119.4°, O15-C8-N14 = 123.7/124.5°,

AC C

N14-C8-C1 = 114.2/115.7°) and around C34 of PZFER (O35-C34-C29 = 119.0/119.9°, O35C34-N36 = 124.5/124.3°, N36-C34-C29 = 116.5/115.9°) show the interaction of C=ONH2 group with the surrounding groups. The SO bond lengths (DFT/XRD) of PZTSA are S33-O31 = 1.4715/1.4465Å, S33-O32 = 1.4627/1.4683Å and the reported values are 1.4235Å and 1.4218Å [19]. For PZFER, all the dihedral angles are 180.0° or 0.0° which means the molecules has a planar structure but for PZTSA, the orientation is not planar. The SO3 group is tilted from the phenyl ring as is evident from the dihedral angles, C17-C16-S33-O30 (-87.9°), C17-C16-S33O31 (24.6°), C17-C16-S33-O32 (157.7°), C24-C16-S33-O30 (92.6°), C24-C16-S33-O32 (21.8°) and C24-C16-S33-O31 (-154.9°). The C=ONH2 group of PZTSA is slightly tilted from 3

ACCEPTED MANUSCRIPT

the pyrazine ring which is evident from the torsion angles, N13-C1-C8-O15 = -178.9°, N13-C1C8-N14 = 1.6°, C2-C1-C8-O15 = -3.3° and C2-C1-C8-N14 = 177.2°. In the case of PZTSA, pyrazinamide and p-toluenesulfonic acid molecules are in different planes as given by the dihedral angles, C4-O30-S33-C16 = 164.1°, C4-O30-S33-O31 = 49.6°, C4-O30-S33-O32 = -

RI PT

81.0°, O30-C4-C6-N13 = 98.9°, O30-C4-N12-C2 = -89.8°, C6-C4-O30-S33 = 157.1° and N12C4-O30-S33 = -83.5°. The root mean square deviations (between calculated and XRD values) for bond lengths and bond angles are respectively, 0.0606, 2.4143 for PZTSA and 0.0330, 1.6929 for PZFER. IR and VCD spectra

SC

3.2

The observed IR bands and calculated scaled wavenumbers with vibrational assignments are

M AN U

given in Table 1. Phenyl ring vibrations

The phenyl ring modes of the title compounds are assigned at: 3110, 3097, 3068 cm-1 (CH stretching modes) ((PZTSA), 1595, 1395 cm-1 (PZTSA), 1426, 1290 cm-1 (PZFER), (ring CC stretching modes), 1291, 1190, 1109, 1003 cm-1 (PZTSA), 1119 cm-1 ((PZFER), (in-plane CH deformation modes) and at 820 cm-1 (PZTSA), 944, 845 cm-1 ((PZFER) (out-of-plane CH

TE D

deformation modes) in the IR spectrum as expected [20]. The DFT calculations give these modes in the ranges, 3107-3069 cm-1 (PZTSA), 3118-3085 cm-1 ((PZFER), 1593-1305 cm-1 (PZTSA), 1585-1292 cm-1 (PZFER), 1292-995 cm-1 (PZTSA), 1266-1117 cm-1 ((PZFER) and at 940-801 cm-1 (PTSA), 940-822 cm-1 (PZFER)). The ring breathing mode of PZTSA is assigned at 788

EP

cm-1 in IR and at 790 cm-1 (DFT) and that of PZFER is assigned at 1008 cm-1 (DFT), 1015 cm-1 (IR) as expected [20-22]. The ring breathing mode of para substituted benzene is reported at 796, 784 cm-1 [23] and that of tri substituted benzene ring is reported at 1050 cm-1 in IR and at 1049

AC C

cm-1 theoretically [24] and at 1042 cm-1 in IR, 1046 cm-1 theoretically [25]. Pyrazine ring vibrations

The pyrazine ring stretching modes are assigned at 1617, 1130, 968, 912 cm-1 (PZTSA),

1174, 1045 cm-1, (PZFER) the IR spectrum, in the range 1612-911 cm-1 (PZTSA), 1554-933 (PZFER) [26]. The pyrazine ring stretching modes are reported at 1554, 1495, 1426 cm-1 in the IR spectrum, in the range 1548-984 cm-1 theoretically [27], at 1545, 1153, 1059, 985 cm-1 in the IR spectrum and in the range 1550-982 cm-1 theoretically [26] and at 1540, 1424 cm-1 in the IR spectrum and in the range 1546-1200 cm-1 theoretically [28]. The ring breathing mode of the 4

ACCEPTED MANUSCRIPT

pyrazine ring of PZTSA is observed at 968 cm-1 in the IR spectrum with a theoretical value of 973 cm-1 and that of PZFER is at 1031 (DFT), 1045 (IR) and is in agreement with reported literature [27, 29]. The pyrazine CH modes of the title compounds were assigned at 3135, 3045 cm-1 (IR), 3129, 3061, 3004 cm-1 (DFT) (PZTSA), at 3136 cm-1 (IR), 3135 cm-1, 3113 cm-1,

RI PT

3095 cm-1 (DFT) (PZFER) (stretching modes), 1314 cm-1 (IR), 1376, 1332, 1311 cm-1 (DFT) (PZTSA), 1458, 1370 (IR), 1460, 1372, 1281 cm-1 (DFT) (PZFER), (in-plane bending) and at 855 cm-1 (IR), 903, 863, 782 cm-1 (DFT) (PZTSA), 861 cm-1 ((IR), 977, 960, 861 cm-1 (DFT) (PZFER) (out-of-plane bending) [30].

SC

C=ONH2 modes

The vibration modes associated with NH2 group are expected in the regions, 3360-3540 cm-1 (stretching), 1580-1640 cm-1, 1100-1300 cm-1 and 585-710 cm-1 (deformation modes) [20].

M AN U

For the title compounds, the NH2 modes are assigned at 3333 cm-1 (IR), 3585, 3455 cm-1 (DFT) (PZTSA), 3432 cm-1 (IR), 3506, 3172 cm-1 (DFT) (PZFER) (stretching); 1540, 731 cm-1 (IR), 1557, 1279, 1061, 733 cm-1 (DFT) (PZTSA), 1661 cm-1 (IR), 1663, 1112, 703 cm-1 (DFT) (PZFER) (deformation) and the reported values are at 3550, 3470 cm-1 (IR), 3575, 3450 cm-1 (DFT) (stretching); 1540, 1245, 582 cm-1 (experimental), 1540, 1248, 588 cm-1 (DFT)

TE D

(deformation) [31] and the reported values of NH2 modes of similar derivatives are 3572, 3425, 1570, 1099, 744 cm-1 theoretically [16]. For PZTSA, N-H stretching mode red shift in the infrared spectrum is due to the formation of strong charge transfer from NH to the oxygen atom as is evident from the NBO analysis. The C=O stretching mode is observed in the region 1850-

EP

1550 cm-1 [32] and in the present case the carbonyl stretching modes are observed at 1689 cm-1 (IR), 1716 cm-1 (DFT) (PZTSA) and at 1600 cm-1 (IR), 1594 cm-1 (DFT) for PZFER [20]. For a

AC C

similar derivative the carbonyl stretching mode have significant downshift due to strong crystalline environment [7]. In the present case NBO analysis of the title compounds, give the following strong hyper conjugative interactions: N14→ π*(C8-O15), O15→σ*(C1-C8) and O15→σ*(C8-N14) with energies, 62.77, 20.14, 24.70 kcal/mol for PZTSA and C29→ π*(C34O35), N36→π*(C34-O35), O35 σ*→(C29-C34) with energies, 65.09, 87.26, 16.50 kcal/mol for PZFER and due to this strong hydrogen bonds are formed which produces the downshift of C=O stretching wavenumbers. NH and SO3 modes in PZTSA

5

ACCEPTED MANUSCRIPT

According to literature, the NH vibrations are expected in the region 3390 ± 60 cm-1 (stretching), 1500-1220 cm-1 and 790 ± 70 cm-1 (bending modes) [20, 33]. For the PZTSA, these modes were assigned at 3460 cm-1 (DFT) (stretching), 1497, 1204 cm-1 (IR), 1495, 1201, 658, 601 cm-1 (bending modes) (DFT) [31]. The stretching modes of SO3 are observed at 1265, 1098,

RI PT

1053 cm-1 (IR) and at 1258, 1105, 1052 cm-1 theoretically. The deformation bands of SO3 are observed at 502 cm-1 and 454 cm-1 in the IR and at 670, 545, 504, 455, 164 cm-1 theoretically. The SO3 stretching modes are reported at 1314, 1295, 1041 cm-1 experimentally, 1311, 1308, 1036 cm-1 theoretically by Anto et al. [19] and Marzotto et al. [34] reported the stretching of

SC

SO3 at 1300 cm-1 and 1150 cm-1 for sodium 5-sulfosalicylate dihydrate. The CS stretching mode is observed at 638 cm-1 in the IR spectrum and at 636 cm-1 theoretically for PZTSA [35]. Hydroxy group, Carboxylic group and methoxy modes of PZFER

M AN U

In the present work, the OH stretching modes are assigned at 3466 cm-1 (O20-H24) [20]. Experimentally IR bands are observed at 3275. The in-plane OH deformation [20] is expected in the region 1440±40 cm-1 and for the title compounds, these modes are assigned at, 1438 cm-1 (DFT). For the title compounds, the stretching of C-O of hydroxyl groups are assigned at 1226 cm-1 [36]. The C-O stretch and in-plane OH are reported at 1208 cm-1 and 1404 cm-1 [37]. The

TE D

C=O stretching modes are assigned at 1615 cm-1 (IR), 1609 cm-1 (DFT). The C14-O21 stretching mode associated with the carboxylic group is assigned at 1304 cm-1 (DFT), 1306 cm-1 (IR). The O21H19 stretching modes are observed experimentally at 2825 cm-1 while the DFT calculations give this mode at 2804 cm-1. In the present case NBO analysis of the title compounds, give the

EP

following strong hyper conjugative interactions:: O21→π*(C14-O22), O22→σ* (C14-O21) with energies, 56.09, 20.87 kcal/mol (carboxylic group) for PZFER and due to this strong hydrogen bonds are formed which produces the downshift of OH stretching wavenumber. Sebastian et al.

AC C

[38] reported the C=O stretching mode of ferulic acid at 1704 cm-1 in the IR spectrum,1207 cm-1 as C-O stretch and OH stretch at 3080 cm-1. The OH in-plane deformation of PZFER is assigned at 1420 cm-1. Ulahannan et al. [37] reported the C=O mode at 1634 cm-1, bending of OH at 1277 cm-1 and C-O stretch at 1337 cm-1 theoretically. The CH3 stretching vibrations are expected in the range 3050-2800 cm-1 [20, 36]. The methyl stretching modes are observed at 3070, 2998, 2932 cm-1 in the IR spectrum. The DFT calculations give these modes in the range 3064, 2999, 2926 cm-1. The CH3 deformations modes are assigned at 1473, 1160 cm-1 (IR), 1484, 1473, 1452, 1163, 1124 cm-1 (DFT) as expected in literature [20].The C-O-C stretching vibrations are 6

ACCEPTED MANUSCRIPT

expected in the range 1200-850 cm-1 [20, 39]. As expected, the C-O-C vibrations are assigned at 1186, 923 cm-1 theoretically, which is in agreement with the literature [40].The C-O stretching modes are reported at 1221, 978 cm-1 (DFT), 1219 cm-1 (IR) and at 1222 cm-1 (Raman) by Benzon et al. [41]. The root mean square deviations (between calculated and observed

RI PT

wavenumbers values) are respectively 6.40 and 5.57 for PZTSA and PZFER without considering the stretching wavenumbers of NH modes. VCD spectra

Vibrational circular dichroism (VCD) gives changes in right and left circularly polarized

SC

light through the molecules [23]. The stretching and bending modes generate VCD signals (Fig.S1- supporting material) and these are good markers of configuration identification. The VCD bands at 3585, 3460, 3004, 1716, 1568, 1258, 636 cm-1 (PZTSA), 2806, 1594, 1226, 993

M AN U

cm-1 (PZFER) which are the stretching modes, are good markers of configuration, showing left polarization while the stretching modes, 1359, 1105 cm-1 (PZTSA), 1381, 1304 cm-1 (PZFER) show right polarization. The bending modes showing left and right polarization are, 733 cm-1 (PZTSA), 1197 (FER) and 1495, 1311, 1201, 670, 567 cm-1 (PZTSA), 1163, 930 cm-1 (PZFER) respectively and good identifiers for assigning of absolute configuration. TD-DFT analysis and light harvesting efficiency

TE D

3.3

Electronic spectra was generated using Time Dependent Density Functional Theory using CAM-B3LYP functional with 6-31G(d) basis set. The theoretical UV spectra of the title compounds are given in Fig.S2 (supporting information). For PZTSA: Three major electronic

EP

transitions are observed in the complex at 278.03, 255.07 and 238.78 nm with oscillator strength of 0.077, 0.003 and 0.0003 respectively (Table S2-supporting information). The first transition

AC C

corresponds to HOMO to LUMO transition (59%) and HOMO to LUMO +1 (36 %) transition. The second represents HOMO-5 to LUMO (27%), HOMO-5 to LUMO+1 (23%), HOMO-1 to LUMO (17%) and HOMO-1 to LUMO+1 (21%) transition while, the last transition corresponds to HOMO-5 to LUMO (11%), HOMO-5 to LUMO+1 (11%), HOMO-1 to LUMO (17%) and HOMO-1 to LUMO+3 (49%). A large number of inner HOMO and outer LUMO orbitals are involved in the transitions, because of the less difference in their respective energies, as evident from DOS Fig.S3 (supporting information). In the case of PZFER, there are two significant electronic transitions at 308.04 nm and 287.56 nm with oscillator strength of 0.0045 and 0.8206 respectively (table S2). Second transition is the important one and it corresponds to HOMO to 7

ACCEPTED MANUSCRIPT

LUMO +1 transition (91%). (table S2). DOS spectrum of this complex clearly indicates well defined non overlapping HOMO's and LUMO's. Oscillator strength A corresponding to different transitions can be used as an indicator of light harvesting efficiency (LHE=1-10-A) of the suggested complex, which suggests its suitability to be used as a photo sensitizer in dye

RI PT

sensitized solar cells. As the first transition is the prominent transition for PZTSA, LHE corresponding to that transition is determined to be 0.164 (table S3-supplementary information). There is a very good LHE of 0.84 for the second transition corresponding to 287.56 nm of wavelength (table S3) for PZFER. Thus it can be concluded that the PZFER is having

3.4

SC

applications as photo sensitizers in DSSC's. Frontier molecular orbital analysis

M AN U

The HOMO-LUMO plot of the title compound is presented in Fig.3 and HOMO is delocalized over the entire molecule except phenyl ring and methyl group and LUMO is delocalized over the entire molecule except C=ONH2 group for PZTSA while for PZFER, HOMO and LUMO are delocalized over the ferulic acid. From the HOMO and LUMO energies, the ionization potential I=-EHOMO and electron affinity A=-ELUMO [42].The ionization potential, electron affinity and HOMO-LUMO energy gap are respectively, 7.940eV, 4.641eV and

TE D

3.299eV for PZTSA and 8.139eV, 5.559eV, 2.58eV for PZFER. The chemical descriptors are given by hardness η= (I-A)/2 =1.650 for PZTSA, =1.290 for PZFER, chemical potential µ = (I+A)/2 = -6.291 for PZTSA and -6.849 for PZFER and electrophilicity index ω = µ 2/2η = 11.993 for PZTSA and 18.182 for PZFER [43].

Molecular Electrostatic Potential map studies

EP

3.5

MEP plot is a visual representation of the most reactive sites in a molecule [44] and

AC C

mapped with rainbow color scheme (electron rich regions represent with red color, while poor electron regions represent with blue color). MEP and surface analysis diagram of title compounds showed in Fig.4, negative regions are mainly localized over C=O and SO3 groups of PZTSA while for PZFER, all the oxygen atoms electron rich regions. The NH2 groups are maximum positive regions with blue colour (which are most reactive sites for nucleophilic attack) for PZTSA. For PZFER carbonyl group and N atom of pyrazine are electrophilic while NH2 and hydrogen atom of OH are nucleophilic sites. 3.6

Nonlinear optical properties

8

ACCEPTED MANUSCRIPT

The energy of a molecular system is a function of the electric field and polarizability values will gives the NLO properties [27]. The computed values of dipole moment, polarizability, first order hyperpolarizability and second order hyperpolarizability values are: 3.5925 Debye, 2.601 × 10-23 esu, 2.218× 10-30 esu, -16.265 × 10-37 esu for PZTSA and 0.9329 esu, 33.176× 10-30 esu, -37.292 × 10-37

esu for PZFER and the NLO

RI PT

Debye, 3.110 × 10-23

properties are in agreement with that of reported pyrazine derivatives [27]. For the title compound energy gap is 3.299 eV for PZTSA and 2.58 for PZFER which is lower than that of urea and the first hyperpolarizability of PZTSA and PZFER are 5.99 and 89.66 times that of urea

3.7

SC

[45]. The first hyperpolarizability of ferulic acid is reported as 8.532× 10-30 esu [38]. Natural Bond Orbital Analysis

M AN U

The natural bond orbital (NBO) analysis was performed using NBO 3.1 version [46] as implemented in the Gaussian 09 software package. The strong intra-molecular hyper-conjugative interactions in the amide group are: N14→ π*(C8-O15), O15→σ*(C1-C8) and O15→σ*(C8N14) with energies, 62.77, 20.14, 24.70kcal/mol for PZTSA and C29→ π*(C34-O35), N36→π*(C34-O35), O35 σ*→(C29-C34) with energies, 65.09, 87.26, 16.50

kcal/mol for

PZFER. The interactions in the pyrazinamide ring are respectively, N12→ π*(C1-C2) and

TE D

σ*(C4-O30) with energies, 42.66, 22.04 for PZTSA and C29→π*(C25–N30) with energy, 73.41 kcal/mol for PZFER. For PTSA, SO3 group has the following interactions: O32→ σ*(O30-S33), O31→ σ*(O32-S33), O31→σ*(O30-S33) having energies, 31.78, 19.47 and 29.21 kcal/mol. The other strong interactions in PZFER are: O21→π*(C14-O22), O22→σ*(C12-C14), O22→σ*

EP

(C14-O21) with energies, 56.09, 15.96, 20.87 kcal/mol (carboxylic group), O23→π*C2-C4) with energy, 25.32 kcal/mol (methoxy group) and O24→π*(C5-C6) with energy, 28.10 kcal/mol (hydroxyl group).Almost 100% p-character was observed nearly in N12, N14, O15, O30, O31,

AC C

O32 for PZTSA and π bonding of C2-C4, C5-C6, C25-N30 and the lone pairs of O21, O22, O23, O24, C29, and N36 of PZFER. The important results are tabulated in tables S4 and S5 (supplementary information). 3.8

Molecular docking

Tuberculosis (TB) is the oldest documented infectious disease, which does not require any vector for transportation from one person to another [47]. The primary site of infection is the lungs, followed by dissemination via the circulatory and lymphatic system to secondary sites. The resurgence of TB is now one of the most serious public health concerns worldwide. Despite 9

ACCEPTED MANUSCRIPT

its global impact on world health, TB is considered a neglected disease, and no new anti-TB therapeutics have been introduced into the market over the last half-century. The last drug with a new mechanism of action approved (rifampicin) was discovered [48]. Therefore there is an urgent need for development of new drug leads to combat this chronic infectious disease. A

RI PT

series of pyrazine derivatives show in vitro against Mycobacterium tuberculosis H37Rv, Mycobacterium avium, Mycobacterium terrae, as well as against rifampicin and isoniazidresistance strains of Mycobacterium tuberculosis [49]. Based on the structure of a compound, PASS (Prediction of Activity Spectra) [50] is an online tool which predicts different types of

SC

activities as tabulated in Table 2. High resolution crystal structure of anti-tuberculosis protein mycobacterium tuberculosis type II was downloaded from the protein data bank website with

M AN U

PDB ID: 2Y71. All molecular docking calculations were performed on Auto Dock-Vina software [51-53]. The ligand PZTSA binds at the active site of the substrate by weak noncovalent interactions as detailed in Fig.5. Amino acids Asn12, Tyr24, Asn75, Ile102, Arg112 and Ser103 forms H-bond with the docked title compound. Tyr24 shows hydrophobic π-alkyl interaction with the methyl group attached with the phenyl ring. The ligand PZFER with the receptor interactions are shown in Fig.5. Amino acid His81, His101, Ile102, Asn75, Leu117,

TE D

Gly77 forms H-bond and Leu97, Ala121, Leu13, Ile102 shows π-alkyl interaction with docked ligand PZFER. Cys90 forms π-sulfur interaction with phenyl ring and His101 gives π-lone pair interaction with OH group. The docked ligands form stable complex with mycobacterium tuberculosis type II as in Fig.6. The binding affinity value of PZTSA and PZFER with receptor is

EP

-7.4kcal/mol and tabulated in Table 3. These preliminary results suggest that the compound might exhibit inhibitory activity against mycobacterium tuberculosis type II and the compounds

AC C

can be developed as a new anti-TB drug. However biological tests need to be done to validate the computational predictions. 4.

Conclusion

In the present work, DFT analysis of two cocrystals of pyrazinamide with p-

toluenesulfonic acid ferulic acid was investigated. The theoretically obtained wavenumbers are assigned by means of potential energy distribution and a good consistency between observed and calculated spectral data was found. The downshifts of different functional modes were due to hydrogen bonding and supported by natural bond orbital analysis. The most reactive electrophilic and nucleophilic sited are identified. The nonlinear optical properties are comparable with that of 10

ACCEPTED MANUSCRIPT

standard NLO material and hence these compounds are good objectives for further studies in NLO properties. The theoretically obtained geometrical parameters are in good agreement with the XRD results and the RMS errors are found. Light harvesting efficiency of the title compounds are discussed. The docked ligand, title compounds form a stable complex with

RI PT

mycobacterium tuberculosis type II and gives good binding affinities and the preliminary results suggest that the compound might exhibit inhibitory activity against mycobacterium tuberculosis type II. The title compounds can be developed as a new anti-TB drug. Acknowledgements

SC

The author, Jamelah S. Al-Otaibi, gratefully acknowledges the Princess Nourah bint Abdulrahman University, Deanship of Scientific Research. Authors are thankful to Ranjit

M AN U

Thakuria, Department of Chemistry, Gauhati University, Guwahati, Assam, India, for providing the IR spectral data. References [1]

S.H. Thorat, S.K. Sahu, R.G. Gonnade, Crystal structures of the pyrazinamide-paminobenzoic acid (1/1) cocrystal and the transamidation reaction product 4-(pyrazine-2carboxamido)benzoic acid in the molten state, Acta Cryst. Struct Chem. 71 (2015) 1010-

[2]

G. Bolla, A. Nangia, Pharmaceutical cocrystals: walking the talk, Chem. Commun. 52 (2016) 8342–8360.

[3]

TE D

1016.

N.K. Duggirala, M.L. Perry, O, Almarsson, M.J. Zaworotko, Pharmaceutical

[4]

EP

cocrystals: along the path to improved medicines, Chem. Commun. 52 (2016) 640–655. K.D. Prasad, S. Cherukuvada, R. Ganduri, L.D. Stephen, S. Perumalla, T.N.G. Row,

AC C

Differential Cocrystallization Behavior of Isomeric Pyridine Carboxamides toward Antitubercular Drug Pyrazinoic Acid, Cryst. Growth Des. 15 (2015) 858-866.

[5]

A.O.L. Evorat, R.A.E. Castro, T.M.R. Maria, M.T.S. Rosado, M.R.Silva, A.M. Beja, J.Canotilho, M.E.Eusebio, Pyrazinamide- Diflunisal: A New Dual-Drug Co-Crystal, Cryst. Growth Des. 11 (2011) 4780-4788.

[6]

K. Ichida, M. Hosoyamada, I. Hisatome, A. Enomoto, M. Hikita, H. Endou, T. Hosoya, Clinical and molecular analysis of patients with renal hypouricemia in Japan influence URAT1 gene on urinary urate excretion, J. Am. Soc. Nephrol. 15 (2004) 164– 173. 11

ACCEPTED MANUSCRIPT

[7]

K.K. Sarmah, T. Rajbongshi, S. Bhowmick, R. Thakuria, First-line antituberculosis drug, pyrazinamide, its pharmaceutically relevant cocrystals and a salt, Acta Cryst. B73 (2017) 1007-1016.

[8]

G. Shanmugam, S. Brahadeeswaran, Spectroscopic, thermal and mechanical studies on 4-

RI PT

methylanilium p-toluenesulfonate – a new organic NLO crystal, Spectrochim. Acta 95 (2012) 177-183. [9]

R.R. Kumar, P. Sathya, R. Gopalakrishnan, Structural, vibrational, thermal and optical

Proceedings, dx.doi.org/10.1063/1.4946559. [10]

S.Balakrishnan,

S.Manoharan,

A.Linsamary,

SC

studies of organic single crystal: benzotriazolium p-toluene sulfate, AIP Conference

K.Panjamurthy,

L.Vellaichamy,

ferulic

acid

M AN U

K.Vasudevan, Circadian time dependent chemopreventive efficacy of curcumin and in

7,12-dimethylbenz[a]anthracene-inducedhamster

buccal

pouch

carcinogenesis, E.J. Pharmacol. Ther. 1 (2008) 61-66. [11]

Gaussian 09, Revision B.01, M.J. Frisch, G.W. Trucks, H.B. Schlegel, G.E. Scuseria, M.A. Robb, J.R. Cheeseman, G. Scalmani, V. Barone, B. Mennucci, G.A. Petersson, H. Nakatsuji, M. Caricato, X. Li, H.P. Hratchian, A.F. Izmaylov, J. Bloino, G. Zheng, J.L.

TE D

Sonnenberg, M. Hada, M. Ehara, K. Toyota, R. Fukuda, J. Hasegawa, M. Ishida, T. Nakajima, Y. Honda, O. Kitao, H. Nakai, T. Vreven, J.A. Montgomery, Jr., J.E. Peralta, F. Ogliaro, M. Bearpark, J.J. Heyd, E. Brothers, K.N. Kudin, V.N. Staroverov, T. Keith, R. Kobayashi, J. Normand, K. Raghavachari, A. Rendell, J.C. Burant, S.S. Iyengar, J.

EP

Tomasi, M. Cossi, N. Rega, J.M. Millam, M. Klene, J.E. Knox, J.B. Cross, V. Bakken, C. Adamo, J. Jaramillo, R. Gomperts, R.E. Stratmann, O. Yazyev, A.J. Austin, R. Cammi,

AC C

C. Pomelli, J.W. Ochterski, R.L. Martin, K. Morokuma, V.G. Zakrzewski, G.A. Voth, P. Salvador, J.J. Dannenberg, S. Dapprich, A.D. Daniels, O. Farkas, J.B. Foresman, J.V. Ortiz, J. Cioslowski, D.J. Fox, Gaussian, Inc., Wallingford CT, 2010.

[12]

P. Stephens, Theory of vibrational circular dichroism, J. Phs. Chem. 89 (1985) 748752.

[13]

J.B. Foresman, P.A. Pittsburg in: E. Frisch (Ed.), Exploring Chemistry with Electronic Structure Methods: a Guide to Using Gaussian, 1996.

[14]

J.M.L. Martin, C. Van Alsenoy, GAR2PED, a Program to Obtain a Potential Energy Distribution from a Gaussian Archive Record, University of Antwerp, Belgium, 12

ACCEPTED MANUSCRIPT

2007. [15]

R. Dennington, T. Keith, J. Millam, Gaussview, Version 5, Semichem Inc., Shawnee Mission, KS, 2009. S. Beegum, Y.S. Mary, H.T. Varghese, C.Y. Panicker, S. Armakovic, S.J. Armakovic, J. Zitko, M. Dolezal, C. Van Alsenoy, Vibrational

spectroscopic analysis of

RI PT

[16]

cyanopyrazine-2carboxamide derivatives and investigation of their reactive properties by DFT calculations and molecular dynamics simulations, J. Mol. Struct. 1131 (2017) 1-15. [17]

Y.S. Mary, Y.S. Mary, C.Y. Panicker, S. Armakovic, S.J. Armakovic, B. Narayana, B.K.

SC

Sarojini, C. Van Alsenoy, Investigation of reactive and spectroscopic properties of oxobutanoic acid derivative: Combined spectroscopic, DFT, MD and docking study, J.

[18]

M AN U

Mol. Struct. 1148 (2017) 266-275.

A.S. Devi, V.V. Aswathy, Y.S. Mary, C.Y. Panicker, S. Armakovic, S.J. Armakovic, R. Ravindran, C. Van Alsenoy, Synthesis, XRD single crystal structure analysis, vibrational spectral analysis, molecular dynamics and molecular docking studies of 2-(3-methoxy-4hydroxyphenyl)benzothiazole, J. Mol. Struct. 1148 (2017) 282-292.

[19]

P.L. Anto, R.J. Anto, H.T. Varghese, C.Y. Panicker, D. Philip, G.F. S. Andrade, A.G.

TE D

Brolo, Spectroscopic investigations and computational study of sulfur trioxide-pyridine complex, J. Raman Spectrosc. 42 (2011) 1812-1819. [20]

N.P.G. Roeges, A Guide to the Complete Interpretation of Infrared Spectra of Organic Structures, John Wiley and Sons Inc., New York, 1994. K. Jalaja, M.A. Al-Alshaikh, Y.S. Mary, C.Y. Panicker, A.A. El-Emam, O. Temiz-

EP

[21]

Arpaci, C. Van Alsneoy, vibrational spectroscopic investigations and molecular docking

AC C

studies of biologically active 2-[4-(4-phenylbutanamido)phenyl]-5-ethylsulphonylbenzoxazole, J. Mol. Struct. 1148 (2017) 119-133.

[22]

G. Varsanyi, Assignments of vibrational spectra of seven hundred benzene derivatives, Wiley, New York, 1974.

[23]

A.S. Al-Tamimi, Y.S. Mary, H.M. Hassan, K.S. Resmi, A.A. El-Emam, B. Narayana, B.K. Sarojini, Study on the structure, vibrational analysis and molecular docking of fluorophenyl derivatives using FT-IR and density functional theory computations, J. Mol. Struct. 1164 (2018) 172-179.

13

ACCEPTED MANUSCRIPT

[24]

Y.S. Mary, C.Y. Panicker, T.S. Yamuna, M.S. Siddegowda, H.S. Yathirajan, A.A. AlSaadi, C. Van Alsenoy, Theoretical investigations on the molecular structure, vibrational spectral, HOMO-LUMO and NBO analysis of 9-[3-(dimethylamino)propyl]-2-trifluoromethyl-9H-thioxanthen-9-ol, Spectrochim. Acta 132 (2014) 491-501. Y.S. Mary C.Y. Panicker, P.L. Anto, M. Sapnakumari, B. Narayana, B.K.Sarojini,

RI PT

[25]

Molecular structure, FT-IR, NBO, HOMO and LUMO, MEP and first order

hyperpolarizability of (2E)-1-(2,4-dichlorophenyl)-3-(3,4,5-trimethoxyphenyl)prop-2en-1-one by HF and density functional methods, Spectrochim. Acta 135 (2015) 81-92. J. Lukose, C.Y. Panicker, P.S. Nayak, B. Narayana, B.K. Sarojini, C. Van Alsenoy, A.A.

SC

[26]

Al-Saadi, Synthesis, structural and vibrational investigation on 2-phenyl-N-(pyrazine-2-

M AN U

yl)acetamide combining XRD diffraction, FT-IR and NMR Spectroscopies with DFT calculations, Spectrochim. Acta 135 (2015) 608-616. [27]

AS. El-Azab, Y.S. Mary, A.A.M. Abdel-Aziz, P.B. Miniyar, S. Armakovic, S.J. Armakovic, Synthesis, spectroscopic analyses (FT-IR and NMR), vibrational study, chemical reactivity and molecular docking study and anti-tubercular activity of condensed oxadiazole and pyrazine derivatives, J. Mol. Struct. 1156 (2018) 657-674. S.H.R. Sebastian, M.A. Al-Alshaikh, A.A. El-Emam, C.Y. Panicker, J. Zitko, M.

TE D

[28]

Dolezal, C. Van Alsenoy, Spectroscopic quantum chemical studies, Fukui functions, in vitro antiviral activity and molecular docking of 5- chloro-N-(3-nitrophenyl)pyrazine-2carboxamide, J. Mol. Struct. 1119 (2016) 188-199. A.M.S. Al-Tamimi, Y.S. Mary, P.B. Miniyar, L.H. Al-Wahaibi, A.A. El-Emam, S.

EP

[29]

Armakovic, S.J. Armakovic, Synthesis, spectroscopic analyses, chemical reactivity and

AC C

molecular docking study and anti-tubercular activity of pyrazine condensed oxadiazole derivatives, J. Mol. Struct. 1164 (2018) 459-469.

[30]

P.K. Ranjith, E.S. Al-Abdullah, F.A.M. Al-Omary, A.A. El-Emam, P.L. Anto, Y.S. Mary, S. Armakovic, S.J. Armakovic, J. Zitko, M. Dolezal, C. Van Alsenoy, FT-Ir and

FT-Raman characterization and investigation of reactive properties of N-(3-iodo-4-

methylphenyl)pyrazine-2-carboxamide by molecular dynamics simulations and DFT calculations, J. Mol. Struct. 1136 (2017) 14-24. [31]

R.K. Muthy, Y.S. Mary, Y.S. Mary, C.Y. Panicker, V. Suneetha, S. Armakovic, S.J. Armakovic, C. Van Alsenoy, P.A. Suchetan, Synthesis, crystal structure analysis, spectral 14

ACCEPTED MANUSCRIPT

investigations, DFT computations and molecular dynamics and docking study of 4benzyl-5-oxomorpholine-3-carbamide, a potential bioactive agent, J. Mol. Struct. 1134 (2017) 25-39. [32]

G. Socrates, Infrared and Raman Characteristic Group Frequencies, Wiley,

[33]

RI PT

Middlesex, UK, 2001.

Y.S. Mary, C.Y. Panicker, H.T. Varghese, K. Raju, T.E. Bolelli, I. Yildiz,

C.M.

Granadeiro, H.I.S. Nogueiro, Vibrational spectroscopic studies and computational study of 4-fluoro-N-(2’-hydroxy-4’-nitrophenyl)phenyl-acetamide, J. Mol. Struct. 994 (2011)

[34]

SC

223-231.

A. Marzotto, D.A. Clemente, T. Gerola, G. Valle, Synthesis, molecular structure and

M AN U

reactivity of sodium-5-sulfosalicylate dehydrate and sodium[triaqua(5-sulfo salicylato) copper(II)]-2-hemihydrate, Polyhedron, 20 (2001) 1079-1087. [35]

B. Sureshkumar, Y.S. Mary, C.Y. Panicker, K.S. Resmi, S. Suma, S. Armakovic, S.J. Armakovic, C. Van Alsenoy, Spectroscopic analysis of 8-hydroxyquinoline-5-sulphonic acid investigation of its reactive properties by DFT and molecular dynamics simulations, J. Mol. Struct. 1150 (2017) 540-552.

N.B. Colthup, L.H. Daly, S.E. Wiberly, Introduction of Infrared and Raman

TE D

[36]

Spectroscopy, Academic Press, New York, 1975. [37]

R.T. Ulahannan, C.Y. Panicker, H.T. Varghese, C. Van Alsenoy, R. Musiol, J. Jampilek, P.L. Anto, Vibrational spectroscopic, 1H-NMR and quantum chemical computational

EP

study of 4-hydroxy-2-oxo-1,2-dihydroquinoline-8-carboxylic acid, Spectrochim. Acta 121 (2014) 445-456.

S. Sebastian, N. Sundaraganesan, S. Manoharan, Molecular structure, spectroscopic

AC C

[38]

studies and first order molecular hyperpolarizabilities of ferulic acid by density functional theory, Spectrochim. Acta 74 (2009) 312-323.

[39]

R.M. Silverstein, G.C. Bassler, T.C. Morril, Spectrometric Identification of Organic

Compounds, ed. 5, John Wiley and Sons Inc., Singapore, 1991.

[40]

A.S. El-Azab, Y.S. Mary, C.Y. Panicker, A.A.M. Abdel-Aziz, M.A. El-Sherbeny, C. Van alsenoy, DFT and experimental (FT-IT and FT-Raman) investigation of vibrational spectroscopy and molecular docking studies of 2-(4-oxo-3-phenethyl-3,4-

15

ACCEPTED MANUSCRIPT

dihydroquinazolin-2-ylthio)-N-(3,4,5-trimethoxyphenyl) acetamide, J. Mol. Struct. 1113 (2016) 133-145. [41]

K.B. Benzon, H.T. Varghese, C.Y. Panicker, K. Pradhan, B.K. Tiwary, A.K. Nanda, C. Van Alsenoy, Spectroscopic and theoretical characterization of 2-(4-methoxyphenyl)-4,5-

[42]

RI PT

dimethyl-1H-imidazole 3-oxide, Spectrochim. Acta 151 (2015) 965-979.

Y.S. Mary, H.T. Varghese, C.Y. Panicker, M. Girisha, B.K. Sagar, H.S. Yathirajan, A.A. Al-Saadi, C. Van Alsenoy, Vibrational spectra, HOMO, LUMO, NBO, MEP analysis and molecular docking study of 2,2-diphenyl-4-(piperidin-1-yl)butanamide, Spectrochim.

[43]

SC

Acta 150 (2015) 543-556.

R.G. Parr, R.G. Pearson, Absolute hardness: companion parameter to absolute

[44]

M AN U

electronegativity, J. Am. Chem.Soc. 105 (1983) 7512-7516.

C.S. Abrham, J.C. Prasana, S. Muthu, Quantum mechanical, spectroscopic and docking studies of 2-amino-3-bromo-5-nitropyridine by density functional method, Spectrochim. Acta 181 (2017) 153-163.

[45]

T.K. Kuruvilla, J.C. Prasana, S. Muthu, J. George, S.A. Mathew, Quantum mechanical and spectroscopic (FT-IR, FT-Raman) study, NBO analysis, HOMO-LUMO, first order

TE D

hyperpolarizability and molecular docking study of methyl[(3R)-3-(2-methylphenoxy)-3phenylpropyl]amine by density functional method,Spectrochim. Acta 188 (2018) 382393. [46]

E.D. Glendening, A.E. Reed, J.E. Carpenter, F.Weinhold, NBO Version 3.1, Gaussian

[47]

EP

Inc., Pittsburgh, PA, 2003.

A.K. Dutt, W.W. Stead, Epidemiology and Host Factors: Tuberculosis and

AC C

Nontuberculous Mycobacterial Infection, W.B. Saunders Company, Philadelphia, Pa, USA, 4th edition, 1999.

[48]

A. Koul, E. Arnoult, N. Lounis, J. Guillemont, K. Andries, The challenge of new drug discovery for tuberculosis, Nature, 469 (2011) 483-490.

[49]

M.A. Kravchenko, E.V. Verbitskiy, S.N. Skornyakov, P.A. Slepukhin, G.L. Rusinov, O.N. Chupakhin, V.N. Charushin, Synthesis and antitubercular evaluation on novel 1ethyl-5-(hetero)aryl-1,6-dihydropyrazine-2,3-dicarbonitriles

and

3-cyano-1-ethyl-5-

(hetero)aryl-2(1H)-pyrazinones, Anti-infective Agents 14 (2016) 139-144.

16

ACCEPTED MANUSCRIPT

[50]

A. Lagunin, A. Stepanchikova, D. Filimonov, V. Poroikov, PASS: prediction of activity spectra for biologically active substances, Bioinformatics 16 (2000) 747-748.

[51]

O.Trott, A. J. Olson, AutoDock Vina: Improving the speed and accuracy of docking with

(2010) 455-461. [52]

RI PT

a new scoring function, efficient optimization and multithreading, J. Comput. Chem. 31

B. Kramer, M. Rarey, T. Lengauer, Evaluation of the FlexX incremental construction algorithm for protein ligand docking, Proteins: Struct. Funct .Genet. 37 (1999) 228-241.

[5]

J.A.War,

K.Jalaja,

Y.S.Mary,

C.Y.Panicker,

S.Armakovic,

S.J.Armakovic,

SC

S.K.Srivastava, C. Van Alsenoy, Spectroscopic characterization of 1-[3-(1H-imidazol1yl)propyl]-3-phenylthiourea and assessment of reactive and optoelectronic properties

M AN U

employing DFT calculations and molecular dynamics simulations, J. Mol. Struct. 1129 (2017) 72-85.

Figure captions

Fig.1 Optimized geometries of (a) PZTSA (b) PZFER Fig.2 FT-IR spectra of (a) PZTSA (b) PZFER

TE D

Fig.3 HOMO-LUMO plots of (a) PZTSA (b) PZFER Fig.4 MEP plots of (a) PZTSA (b) PZFER

Fig.5 Ligands interactions (a) PZTSA (b) PZFER with the amino acids of mycobacterium tuberculosis type II

EP

Schematic for the ligands (a) PZTSA (b) PZFER at the active site of mycobacterium tuberculosis type II

AC C

Fig.6

17

ACCEPTED MANUSCRIPT

Table 1 Calculated scaled wavenumbers, observed IR bands and assignments of the title

Table 1.1

PZTSA IR

Assignmentsa

IRI

RA

υ(cm-1)

-

3585

66.46

75.47

-

υNH2(100)

3460

75.80

111.61

3333

υNH(100)

3455

55.22

132.40

3333

3129

0.72

66.03

3135

3107

1.58

120.87

3106

0.94

14.71

3070

11.32

110.68

3069

12.13

83.43

3061

11.25

103.59

3013

13.17

67.65

3004

9.45

2986

16.31

2930

19.35

1716

302.39

1612

78.76

1593

25.50

1568

1495

SC

υ(cm-1)

AC C

B3LYP/6-31G(d) (6D, 7F)

RI PT

compounds

υNH2(99)

M AN U

υCHPz(100)

υCHPh(92)

3097

υCHPh (95)

-

υCHPh(97)

3068

υCHPh(90)

3045

υCHPz(94)

-

υCH3(90)

TE D

3110

-

υCHPz(93)

94.82

-

υCH3(100)

228.70

2929

υCH3(95)

13.83

1689

υC=O(75)

58.75

1617

υPz(65), υPh(19)

108.65

1595

υPh(60), υPz(15)

1.04

4.29

-

υPh(58), υPz(18)

76.57

181.20

-

υPz(62), υPh(20)

196.10

8.24

1540

δNH2(55), υPh(17)

136.13

22.03

1497

δNH(50), υPh(10), υPz(13)

1483

5.80

2.49

-

υPh(49), δNH(14)

1461

12.65

17.31

-

δCH3(68), υPh(12)

1458

7.27

20.91

1458

δCH3(71), υPh(10)

1393

10.44

1.73

1395

υPh(54), δCH3(17)

1566 1557

EP

63.42

1

ACCEPTED MANUSCRIPT

0.41

41.23

-

δCH3(62), υPh(12)

1376

7.47

9.93

-

δCHPz(55), δCH3(20)

1359

199.68

54.87

-

υCN(44), δCHPz(12)

1332

32.83

14.89

-

δCHPz(57), υCN(13)

1311

29.28

67.85

1314

δCHPz(49), δCHPh(11)

1305

4.93

0.77

-

υPh(57), δCHPh(18)

1292

0.16

0.64

1291

δCHPh(58), υPh(10)

1279

6.21

9.91

-

δNH2(40), δCHPh(17)

1258

185.38

4.96

1265

υSO3(41), δNH2(20)

1201

84.20

5.21

1204

1192

2.29

11.60

1190

1172

3.27

3.45

1135

21.31

0.81

1106

48.57

14.30

1105

169.34

53.51

1061

2.26

10.95

1052

55.17

9.91

1040

3.31

1034

11.77

995

5.89

981

0.91

973

26.70

940

0.09

937

863

SC

RI PT

1386

δNHPz(40), δCHPz(18)

M AN U

δCHPh(51), δNHPz(21)

δCHPh(22), υPz(23)

1130

υPz(43), δCHPz(24)

1109

δCHPh(50), υPz(15)

1098

υSO3(44), δCHPh(21)

-

δNH2(39), υSO3(15)

1053

υSO3(40), δNH2(17)

-

υPz(52), υSO3(16)

0.20

1034

δCH3(58), υPz(20)

1.71

1003

δCHPh(52), δCH3(21)

1.90

-

δCH3(45), δCHPh(20)

8.83

968

υPz(40), δCH3(22)

0.28

-

γCHPh(62), τPh(14)

0.28

1.05

-

γCHPh(65), τPh(16)

12.32

6.48

912

υPz(44), τPh(20)

0.70

6.72

-

γCHPz(72), υPz(12)

10.24

35.35

855

γCHPz(68), τPz(11)

822

0.06

3.33

820

γCHPh(65), γCHPz(15)

801

1.85

4.07

-

γCHPh(75), γCHPz(11)

790

62.72

13.06

788

υPh(44), γCHPz(20)

782

19.69

59.50

-

γCHPz(70), γCHPh(13)

911 903

EP

2.58

AC C

TE D

1174

2

ACCEPTED MANUSCRIPT

17.33

12.44

-

δC=O(32), γCHPz(16)

733

45.32

38.11

731

δNH2(41), δC=O(19)

685

1.87

1.18

682

τPh(32), δNH2(17)

670

6.92

5.95

-

δSO3(28), τPh(21)

658

3.67

1.59

-

γNH(50), δSO3(12)

636

246.43

6.22

638

υCS(39), γNH(23)

626

14.29

31.19

-

δPz(24), δPh(27)

623

1.03

5.80

618

δPh(31), δPz(22)

592

17.62

13.18

-

τNH(42), δPh(12), δPz(13)

590

7.65

3.09

-

567

173.00

3.82

569

545

2.27

3.79

SC

RI PT

743

τNH2(39), τNH(14)

M AN U

δC=O(31) δSO3(19)

-

δSO3(28), δC=O(12), τNH2(13)

504

64.20

4.45

502

δSO3(25), τNH2(12),

τPh(27), δSO3(17), δC=O(12)

480

δPz(38), τNH(11)

488

38.98

14.37

482

6.54

4.24

455

8.90

435

12.21

399

0.19

392

20.05

369

3.40

352

2.99

316

AC C

-

TE D

δC=O(12)

299 263 261

454

δPh(22), δSO3(24)

1.09

433

δPh(27), τPz(30)

0.04

402

τPh(31), τNH(17)

0.27

-

τPz(27), τPh(27)

1.45

-

δPh(22), δPz(19), δNH2(18)

0.14

-

τPz(22), δCH3(24)

5.86

0.96

-

τCH3(25), τPh(20)

6.56

0.38

-

τCH3(18), τC=O(15), τPz(23)

39.24

4.35

-

τNH2(22), τCH3(11), τPh(14)

15.22

7.75

-

δCS(17), τNH2(11), τPz(13),

EP

2.47

τPh(11) 218

122.43

1.02

-

τNH2(21), τCS(10), τPz(18), τPh(15)

199

59.82

0.66

3

τPz(30), τNH2(18)

ACCEPTED MANUSCRIPT

21.25

1.34

-

τPz(16), τC=O(23)

164

9.21

3.93

-

τSO3(26), τNH2(12)

156

2.76

0.37

-

τSO3(21), τPh(30)

129

0.37

0.67

-

τPz(33), τPh(24)

82

0.17

0.76

-

τSO3(25), τC=O(20)

65

1.25

1.34

-

τSO3(19), τNH2(13)

55

0.71

3.15

-

τPh(25), τCH3(21)

41

0.19

0.49

-

τCH3(18), τSO3(12), τPz(14)

30

2.00

6.57

-

τPz(30), τSO3(14), τPh(15)

21

0.06

8.35

-

15

1.57

5.57

-

Table 1.2

PZFER

IRI

RA

3506

190.72

31.96

3466

121.46

230.80

3172

20.20

3135

0.06

3118

7.70

3115

11.67

3113

40.89

3104 3095

SC

τPh(23), τPz(26)

IR

Assignmentsa

υ(cm-1)

-

3432

υNH2(100)

3275

υO24H20(100)

-

υNH2(100)

87.49

3136

υCHPz(95)

198.77

-

υCHPh(98)

6.73

-

υCHPh(95)

266.79

-

υCHPz(94)

14.23

13.34

-

υCH(90)

2.19

89.31

-

υCHPz(93)

7.58

60.46

-

υCHPh(95)

18.04

133.78

3070

υCH3(90)

3055

1.47

28.49

3050

υCH(92)

2999

34.08

25.02

2998

υCH3(91)

2926

31.66

106.85

2932

υCH3(94)

2804

3004.36

560.96

2825

υO21H19(90)

1663

243.11

37.23

1661

δNH2(65)

3085 3064

EP

76.22

AC C

TE D

υ(cm-1)

τPh (35), τCH3(17)

M AN U

B3LYP/6-31G(d) (6D, 7F)

RI PT

187

4

ACCEPTED MANUSCRIPT

143.11

9.82

-

υC=C(60), δNH2(10)

1609

287.05

19.17

1615

υC14O22(59), υC34O35(18)

1594

475.53

14.45

1600

υC34O35(57), υC14O22(21)

1585

131.35

4.88

-

υPh(50), υC34O35(20)

1554

84.12

8.02

-

υPz(56), υPh(17)

1541

33.76

14.02

-

υPh(61), δCH3(14)

1507

188.32

1.41

1510

υPh(23), δCH3(17), υPz(16)

1501

8.72

26.27

-

υPz(54), δCH3(16)

1484

82.26

9.93

-

δCH3(75), υPz(11)

1473

10.79

29.57

1473

1460

74.69

14.04

1458

1452

10.99

78.43

1438

2.29

58.63

1427

239.40

1.99

1420

15.33

1.05

1381

5.96

10.00

1372

126.43

1.51

1330

43.33

1304

50.29

1292

56.11

1281

0.32

1266

229.49

1226 1202

SC

RI PT

1641

δCH3(68), υPz(10)

M AN U

δCHPz(64), δCH3(12) δCH3(72), δCHPz(10)

-

δO24H20(42), δCH3(18)

1426

υPh(45), δO24H20(10)

-

δO20H19(41), υPh(17)

-

υPh(55), δO20H19(15)

1370

δCHPz(40), υCN(37)

1328

δCH(49), υO14H21(15)

13.87

1306

δCH(20), υO14H21(43)

10.19

1290

υPh(48), υO14H21(17)

3.46

-

δCHPz(55), δCHPh(14)

55.41

1269

δCHPh(59), δCHPz(10)

13.61

2.43

-

υC5O24(44), δCHPh(12)

35.02

14.86

1204

υPz(24), υC5O24(18)

2.48

3.70

-

δCH(51), υPz(16)

4.36

2.79

-

δCH3(24), υCOC(39)

3.33

29.21

1174

υPz(44), υCOC(12)

1163

224.76

17.75

1160

δCH3(58), υPz(12)

1147

11.36

9.77

-

υPz(60), δCHPz(16)

1141

6.08

5.98

-

δCHPh(52), υPh(11)

1124

0.36

6.19

-

δCH3(60), δCHPh(17)

1197 1186 1177

EP

46.71

AC C

TE D

-

5

ACCEPTED MANUSCRIPT

28.97

14.11

1119

δCHPh(55), δNH2(14)

1112

8.75

10.89

-

δNH2(39), δCHPh(20)

1031

3.31

2.31

1045

υPz(44), δCHPz(19)

1008

48.36

5.05

1015

υPh(44), υPz(15)

1005

6.57

8.96

-

υPh(21), υPz(17), γCHPz(19)

993

30.93

11.35

-

υPz(40), υPh(18)

992

305.43

0.75

990

υPz(21), γCHPz(33)

977

1.39

0.72

-

γCHPz(78)

960

0.22

1.78

963

υCC(32), γCHPz(22)

960

0.02

2.75

958

940

5.67

4.47

944

930

6.86

0.11

923

4.72

0.25

885

5.04

16.29

861

8.71

0.70

859

35.80

2.40

822

3.08

4.78

799

20.10

796

0.99

771

9.42

736

5.13

711

0.04

703 691

SC

RI PT

1117

γCHPz(70)

M AN U

γCHPh(68)

γCH(73), γCHPh(11)

-

υCOC(39), γCH(14)

-

γCH(70), υCOC(11)

861

γCHPz(72), τPz(13)

845

γCHPh(79), τPh(12)

-

γCHPh(68), τPh(11)

800

δPh(35), δPz(28)

11.65

-

δPz(29), δPh(22)

4.15

778

δPz(30), δPh(16)

6.02

733

δPh(28 δPz(22)

0.09

-

τPh(30), δPh(14)

10.44

3.18

-

τNH2(39), τPh(12)

9.39

1.48

689

τPz(29), τNH2(16)

0.09

0.03

-

τPh(34), τPz(22)

16.38

7.53

663

τNH2(22), δC=O(18)

646

0.93

16.18

635

δC=O(27), τPh(14)

609

3.62

2.30

607

δPz(36), δC=O(11)

591

11.76

0.74

-

τPh(28), δPz(17)

564

11.13

0.78

570

δC=C(25), τPh(21)

553

6.79

6.42

-

δPh(30), δC=C(10)

678 661

EP

31.48

AC C

TE D

-

6

ACCEPTED MANUSCRIPT

96.23

3.42

520

δPz(28), δC=C(13)

513

16.06

3.75

-

τOH(27), δPz(20)

503

11.81

2.11

-

δPh(32), τOH(14)

491

5.50

0.67

485

δPh(35), δPz(23)

453

17.45

0.34

455

τPz(29), δPh(18)

443

3.64

0.58

441

τPh(30), τPz(23)

400

0.71

13.73

-

δC=O(20), τPh(26)

385

2.59

1.09

-

τPh(21), τPh(24)

384

2.36

0.53

-

τPz(32), δPh(16)

357

16.65

3.13

-

299

6.40

2.88

-

268

0.11

1.08

263

4.44

11.55

250

2.23

1.80

215

0.20

0.80

201

6.14

1.30

188

0.19

0.67

174

0.09

159

0.26

140

3.89

101

5.60

88

0.56

87

1.38

83

48

SC

RI PT

517

δPh(27), δPz(20)

M AN U

τOH(32) , δPh(22)

τPh(30), τOH(16)

-

τC=O(20), τPh(19)

-

τNH2(28), τPz(22)

-

τCH3(28), τPh(18)

-

τC=O(24), τCH3(12)

-

τCH3(20), τC=C(18)

-

τCH3(22), τPz(18)

3.06

-

τC=C(25), τPz(10)

2.74

-

τC=O(19), τC=C(17)

0.06

-

τNH2(19), τCH3(12)

1.37

-

δPz(31), τCH3(18)

0.76

-

τPh(20), τCH3(22)

3.39

1.24

-

τCH3(28), τNH2(11)

0.83

0.07

-

δPh(21), τPz(22)

0.07

0.37

-

τC=O(27), τNH2(24)

0.38

8.62

-

τPh(30), τPz(27)

31

2.11

0.15

-

δPh(29), τPz(30)

22

2.83

1.59

-

τPh(25), τPz(23)

12

1.39

0.36

-

τPh(35), τPz(32)

78 56

EP

2.30

AC C

TE D

-

7

ACCEPTED MANUSCRIPT

a

υ-stretching; δ-in-plane deformation; γ-out-of-plane deformation; τ-torsion; IRI-IR

AC C

EP

TE D

M AN U

SC

RI PT

intensity(KM/Mole) ; RA-Raman activity(Ǻ4/amu); Ph-phenyl ring; Pz-pyrazine ring;

8

ACCEPTED MANUSCRIPT Table 2 PASS prediction for the activity spectrum of the title compounds. Pa represents probability to be active and Pi represents probability to be inactive. Pa

Pi

Activity

0.650 0.005 Antituberculosic

RI PT

0.683 0.064 Mucomembranous protector 0.523 0.016 Antimycobacterial

0.575 0.072 Glycosylphosphatidylinositol phospholipase D inhibitor

0.507 0.010 Mannosyl-glycoprotein endo-beta-N-acetylglucosaminidase inhibitor

SC

0.487 0.005 1.2-alpha-L-fucosidase inhibitor 0.481 0.011 Glycine-tRNA ligase inhibitor 0.472 0.005 Antineoplastic enhancer

M AN U

0.484 0.022 Alanine-tRNA ligase inhibitor

0.479 0.019 Cyanoalaninenitrilase inhibitor 0.498 0.040 Endopeptidase So inhibitor 0.523 0.069 Omptin inhibitor

0.485 0.040 Sulfur reductase inhibitor

TE D

0.447 0.008 Antineoplastic (non-small cell lung cancer) 0.469 0.040 (S)-6-hydroxynicotine oxidase inhibitor

AC C

EP

0.480 0.052 Lipoprotein lipase inhibitor

1

ACCEPTED MANUSCRIPT

Table 3 The binding affinity values of different poses of the title compounds predicted by Autodock Vina

Distance from best mode (Å)

-

-

RMSD l.b.

RMSD u.b.

1

-7.4

0.000

0.000

2

-7.0

1.816

2.285

3

-6.7

3.883

6.093

4

-6.4

1.819

2.783

5

-6.3

5.916

8.420

6

-6.3

4.223

7

-6.1

3.638

8

-6.1

12.511

9

-5.9

4.460

PZFER

-

-

1

-7.4

2

-7.2

3

-7.1

4

-6.9

6 7 8 9

14.891 6.840

RMSD l.b.

RMSD u.b.

0.000

0.000

0.940

1.103

1.619

5.537

2.763

4.230

-6.8

2.322

5.900

-6.6

2.066

6.192

-6.4

1.853

2.615

-6.4

1.663

3.197

-5.9

3.840

5.143

AC C

5

6.042

Distance from best mode (Å)

EP

Mode Affinity (kcal/mol)

6.573

TE D

Table 3.2

M AN U

Mode Affinity (kcal/mol)

RI PT

PZTSA

SC

Table 3.1

1

AC C

EP

TE D

M AN U

SC

RI PT

ACCEPTED MANUSCRIPT

AC C

EP

TE D

M AN U

SC

RI PT

ACCEPTED MANUSCRIPT

AC C

EP

TE D

M AN U

SC

RI PT

ACCEPTED MANUSCRIPT

AC C

EP

TE D

M AN U

SC

RI PT

ACCEPTED MANUSCRIPT

AC C

EP

TE D

M AN U

SC

RI PT

ACCEPTED MANUSCRIPT

AC C

EP

TE D

M AN U

SC

RI PT

ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT

DFT analysis of cocrystals of pyrazinamide were reported

•

Most reactive sites are identified

•

Studied NLO properties, MEP and NBO

•

Molecular docking studies have been discussed

AC C

EP

TE D

M AN U

SC

RI PT

•