Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 135 (2015) 984–993

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Design, synthesis, computational calculation and biological evaluation of some novel 2-thiazolyl hydrazones R. Anbazhagan, K.R. Sankaran ⇑ Department of Chemistry, Annamalai University, Annamalainagar 608 002, Tamil Nadu, India

h i g h l i g h t s

g r a p h i c a l a b s t r a c t

 A novel series of thiazolyl hydrazones

2a–2f synthesized and characterized.  Molecular geometries of 2a–2f are

optimized and structural parameters were derived.  Frontier molecular orbital energies, MEP and NBO were analyzed.  Compounds 2c, 2e and 2f show excellent antimicrobial activity than reference drugs.

a r t i c l e

i n f o

Article history: Received 6 December 2013 Received in revised form 25 June 2014 Accepted 27 June 2014 Available online 4 August 2014 Keywords: Thiazolyl hydrazones NMR spectral DFT calculation NBO analysis Antimicrobial activity

a b s t r a c t In the present study a novel series of 1-(1-(4-isobutylphenyl)ethylidene)-2-(4-phenylthiazol-2-yl)hydrazine 2a and its derivatives 2b–2f have been synthesized by the cyclization of 1-(1-(4-isobutylphenyl)ethylidene)thiosemicarbazide with 2-bromoacetophenone/ 4-substituted 2-bromoacetophenones. The structures of the synthesized thiazolyl hydrazones 2a–2f were characterized by FT-IR, 1H, 13C NMR, 2D NMR and mass spectral techniques. The molecular geometries were also investigated theoretically using B3LYP functional with 6-311G(d,p) basis set. To explain the molecular properties energy gap (Eg), electronegativity (v), hardness (g), electrophilicity (x) and softness (S) were computed, natural bonding orbital (NBO) analysis and molecular electrostatic potential (MEP) were also performed at the same level of theory. All the synthesized thiazolyl hydrazones 2a–2f were screened for their in vitro antimicrobial activity against selected bacterial and fungal strains. The results showed that the heterocyclic thiazolyl hydrazone derivatives exhibit a promising selective inhibitory activity against various bacterial and fungal strains. Ó 2014 Elsevier B.V. All rights reserved.

Introduction Hydrazine and hydrazones have attracted considerable attention to organic and medicinal researchers for many years, because they exhibit diverse biological and pharmaceutical applications. Hydrazones have pronounced biological and pharmaceutical activity in medicinal chemistry, such as antimicrobial [1], antibacterial [2], antifungal [3], antiviral [4], antimalarial [5], antitumor [6], anticancer [7,8], anti-tubercular [9,10], anti-inflammatory [11],

⇑ Corresponding author. Tel.: +91 4144 238601; fax: +91 4144 238145. E-mail address: [email protected] (K.R. Sankaran). http://dx.doi.org/10.1016/j.saa.2014.06.160 1386-1425/Ó 2014 Elsevier B.V. All rights reserved.

anticonvulsant [12] and antiplatelet [13] activities. The 2-thaizoyl hydrazone derivatives are found to be associated with various biological activities such as anti-inflammatory [14,15], antiviral [16], antioxidant [17,18], antitumor [19], anticancer [20], antibacterial [21], antifungal [22], analgesic [23], anticonvulsant and neuroprotective activity [24]. Due to the developments in computational chemistry in the past decade, the research on the theoretical modeling of drug design, functional material design, etc. has become much more mature than ever. Many important chemical and physical properties of biological and chemical systems can be predicted from first principles using various computational techniques [25]. In recent years, density functional theory (DFT) has been a shooting star in theoretical

R. Anbazhagan, K.R. Sankaran / Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 135 (2015) 984–993

modeling. The development of better and better exchange–correlation functional has made it possible to calculate many molecular properties with accuracy comparable to traditionally correlated ab initio methods for larger chemical systems containing more than fourty atoms, at a more favourable computational cost [26]. A survey of the literature revealed that DFT has great accuracy in reproducing the experimental values for the geometry, dipole moment, vibrational frequency etc. [27–34]. In recent years, the high therapeutic properties of the thiazole related drugs have brought attention to the medicinal chemists to synthesize a large number of thiazoles and their derivatives. Hence, in the present study, a novel series of pharmaceutically active thiazole molecules incorporated with active hydrazone and isobutyl chain moieties are designed and synthesized. The synthesized 2,4-disubstituted thiazolyl hydrazone derivatives are characterized by FT-IR, 1D NMR (1H and 13C NMR), 2D (1H–1H COSY, 1H–13C COSY and HMBC) and mass spectral techniques. The molecular geometrical parameters, the energies of frontier molecular orbitals (HOMO, LUMO and their energy gap), MEP and NBO for the thiazolyl hydrazones 2a–2f are investigated using B3LYP functional with 6-311G(d,p) basis set. Further, the in vitro antimicrobial activities of all the synthesized thiazolyl hydrazones are studied against various Gram-positive, Gram-negative bacterial and fungal strains.

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hydrazine 2a and its derivatives 2b–2f were prepared according to the literature procedures [14,35]. General procedure for the synthesis of 1-(1-(4-isobutylphenyl) ethylidene) thiosemicarbazide (1) To a mixture of 40 -(2-methylpropyl)acetophenone (0.01 mol), thiosemicarbazide (0.01 mol) and con. HCl (1 mL) in methanol (15 mL) was refluxed for 2 h and then allowed to cool at room temperature. The solid product 1 collected was recrystallized from ethanol. 1-(1-(4-Isobutylphenyl)ethylidene)thiosemicarbazide (1) White micro crystals; Yield 92%; m.p. 138–140 °C; IR (KBr, cm1): 3376 (NH2), 3179 (NH), 3013, 2952, 2920 and 2863 (CAH), 1608 (C@N azomethine), 1083 (C@S). 1H NMR (400 MHz, DMSO-d6, ppm): d = 0.85 (d, 6.4 Hz, 6H, (CH3)2, 1.82 (m, 1H, CH), 2.27 (s, 3H, CH3), 2.45 (d, 6.8 Hz, 2H, CH2), 7.16 (d, 7.2 Hz, 2H, ArAH), 7.82 (d, 7.6 Hz, 2H, ArAH), 8.24 (bs, 1H, NH), 10.18 (s, 2H, NH2); 13C NMR (100 MHz, DMSO-d6, ppm): d = 13.9 (CH3), 22.1 (CH3)2, 29.6 (CH), 44.2 (CH2), 126.4 (Ar), 128.8 (Ar), 135.1 (Ar), 142.5 (Ar), 148.0 (C@N), 178.7 (C@S); GC–MS-CI (m/z): Calcd. for C13H19N3S: 249.3, Found: 247.0 [M2]. General procedure for the synthesis of 1-(1-(-isobutylphenyl)ethylidene)2-(4-phenylthiazol-2-yl)hydrazines (2a–f)

Experimental Chemistry The chemicals (40 -(2-methylpropyl)acetophenone, 2-bromo acetophenone and 4-substituted-2-bromo acetophenone) and reagents (con. HCl) were purchased from Sigma Aldrich (India) and Shasun Pharmaceuticals (Cuddalore, Tamil Nadu) and they are used without purification. The synthesized 2-thiazolyl hydrazones (Scheme 1) were purified by column chromatography using readymade silica gel and chloroform as the mobile phase/finally recrystallized from ethanol. All the melting points were calculated in open capillary tube melting point apparatus and are uncorrected. The IR spectra were recorded in potassium bromide (KBr) disc on a Nicolet Avatar 360 FT-IR spectrometer and the wave numbers are given in cm1. The 1H and 13C NMR and 2D NMR spectra were recorded at 400 and 100 MHz on a Bruker NMR spectrometer in CDCl3 while TMS was used as an internal standard and the chemical shift value (d) are given in parts per million (ppm). The mass spectra were performed using Varian Saturn 2200 GC–MS spectrometer. The 1-(1-(4-isobutylphenyl)ethylidene)thiosemicarbazide 1, 1-(1-(4-isobutylphenyl)ethylidene)-2-(4-phenylthiazol-2-yl)

A mixture of 1-(1-(4-isobutylphenyl)ethylidene) thiosemicarbazide (0.0025 mmol) and phenacyl bromide/substituted phenacyl bromide (0.0025 mol) in isopropanol (50 mL) was refluxed for 2–4 h. The solid product 2 a - 2f appeared during reflux were filtered after cooling and were purified by silica gel column chromatography (chloroform). 1-(1-(4-Isobutylphenyl)ethylidene)-2-(4-phenylthiazol-2-yl) hydrazine (2a) Dark brown solid; Yield 89%; m.p. 134–136 °C; IR (KBr, cm1): 3425 (NH), 3063, 3028, 2955, 2924 and 2865 (CAH), 1621 (C@N), 1573 (C@C), 1019 (CAS); 1H NMR (500 MHz, CDCl3, ppm): d = 0.95 (d, J = 6.5 Hz, 6H, (CH3)2), 1.92 (m, 1H, CH), 2.19 (s, 3H, CH3), 2.53 (d, J = 7.0 Hz, 2H, CH2), 6.93 (s, 1H, H5 thiazole), 7.20 (d, J = 8.5 Hz, 2H, ArAH), 7.32 (d, J = 7.5 Hz, 1H, ArAH), 7.41 (t, 2H, ArAH), 7.71 (d, J = 8.0 Hz, 2H, ArAH), 7.83 (d, J = 7.0 Hz, 2H, ArAH), 9.21 (bs, 1H, NH, D2O exch.); 13C NMR (100 MHz, CDCl3, ppm): d = 13.0, 22.4, 30.2, 45.2, 103.8, 125.7, 125.9, 127.7, 128.6, 129.2, 134.9, 135.3, 142.9, 146.3, 151.4 (C4AN), 169.7 (C2@N); MS-ESI (m/z): Calcd. for C21H23N3S: 349.4, Found: 349.2063 [M] +.

Scheme 1. Synthetic route of 2a–2f.

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1-(1-(4-Isobutylphenyl)ethylidene)-2-(4-(4-methoxyphenyl)thiazol2-yl)hydrazine (2b) Brown solid; Yield 78%; m.p. 130–132 °C; IR (KBr, cm1): 3442 (NH), 3052, 2955, 2921 and 2860 (CAH), 1609(C@N), 1560 (C@C), 1053 (CAS); 1H NMR (400 MHz, CDCl3, ppm): d = 0.91 (d, J = 6.8 Hz, 6H, (CH3)2), 1.88 (m, 1H, CH), 2.11 (s, 3H, CH3), 2.49 (d, J = 7.2 Hz, 2H, CH2), 3.77 (s, 3H, OCH3), 6.75 (s, 1H, H5 thiazole), 6.89 (d, J = 8.4 Hz, 2H, ArAH), 7.16 (d, J = 8.0 Hz, 2H, ArAH), 7.66 (d, J = 8.0 Hz, 2H, ArAH), 7.71 (d, J = 8.4 Hz, 2H, ArAH), 9.54 (bs, 1H, NH, NH, D2O exch.); 13C NMR (100 MHz, CDCl3, ppm): d = 13.1, 22.4, 30.2, 45.2, 55.3, 102.0, 114.0, 125.7, 127.2, 128.3, 129.3, 135.3, 142.8, 146.5, 151.1, 159.3 (C4AN), 169.9 (C2@N); MS-ESI (m/z): Calcd. for C22H25N3OS: 379.5, Found: 379.4799 [M] +. 2-(4-(4-Fluorophenyl)thiazol-2-yl)-1-(1-(4-isobutylphenyl) ethylidene)hydrazine (2c) Beige solid; Yield 80%; m.p. 142–144 °C; IR (KBr, cm1): 3349 (NH), 2960, 2921 and 2866 (CAH), 1616 (C@N), 1564 (C@C), 1094 (CAS); 1H NMR (400 MHz, CDCl3, ppm): d = 0.91 (d, J = 6.4 Hz, 6H, (CH3)2), 1.88 (m, 1H, CH), 2.17 (s, 3H, CH3), 2.50 (d, J = 7.2 Hz, 2H, CH2), 6.82 (s, 1H, H5 thiazole), 7.06 (t, 2H, ArAH), 7.17 (d, J = 8.4 Hz, 2H, ArAH), 7.68 (d, J = 8.0 Hz, 2H, ArAH), 7.75 (q, 2H, ArAH), 9.12 (bs, 1H, NH, D2O exch.); 13C NMR (100 MHz, CDCl3, ppm): d = 13.0, 22.4, 30.2, 45.2, 103.4, 115.5/115.7 (CAF), 125.7, 127.6/127.7 (C21 & C25), 129.3, 131.2/131.3 (C22 & C24), 135.2, 143.0, 146.4, 150.4, 161.2 (C4AN), 163.7, 169.7 (C2@N); MS-ESI (m/z): Calcd. for C21H22FN3S: 367.4, Found: 368.6776 [M] +. 2-(4-(4-Chlorophenyl)thiazol-2-yl)-1-(1-(4-isobutylphenyl) ethylidene)hydrazine (2d) Brown solid; Yield 81%; m.p. 140–142 °C; IR (KBr, cm1): 3347 (NH), 3019, 2957, 2921 and 2866 (CAH), 1610(C@N), 1563 (C@C), 1091 (CAS); 1H NMR (400 MHz, CDCl3, ppm): d = 0.95 (d, J = 6.4 Hz, 6H, (CH3)2), 1.92 (m, 1H, CH), 2.21 (s, 3H, CH3), 2.54 (d, J = 6.8 Hz, 2H, CH2), 6.91 (s, 1H, H5 thiazole), 7.21 (d, J = 8.0 Hz, 2H, ArAH), 7.38 (d, J = 8.0 Hz, 2H, ArAH), 7.75 (d, J = 8.4 Hz, 4H, ArAH), 9.31 (bs, 1H, NH, D2O exch.); 13C NMR (100 MHz, CDCl3, ppm): d = 13.1, 22.4, 30.2, 45.2, 104.2, 125.8, 127.2, 128.9, 129.3, 133.3, 133.5, 135.1, 143.1, 146.7, 150.1 (C4AN), 169.9 (C2@N); MS-ESI (m/z): Calcd. for C21H23ClN3S: 383.93, Found: 384.4278 [M] +. 2-(4-(4-Bromophenyl)thiazol-2-yl)-1-(1-(4-isobutylphenyl) ethylidene)hydrazine (2e) Dark brown solid; Yield 88%; m.p. 128–130 °C; IR (KBr, cm1): 3422 (NH), 3050, 2953, 2919 and 2865 (CAH), 1566 (C@N), 1511(C@C), 1055 (CAS); 1H NMR (400 MHz, CDCl3, ppm): d = 0.91 (d, J = 6.4 Hz, 6H, (CH3)2), 1.88 (m, 1H, CH), 2.15 (s, 3H, CH3), 2.50 (d, J = 7.2 Hz, 2H, CH2), 6.89 (s, 1H, H5 thiazole), 7.17 (d, J = 8.0 Hz, 2H, ArAH), 7.49 (d, J = 8.8 Hz, 2H, ArAH), 7.65 (q, 4H, ArAH), 9.20 (bs, 1H, NH, D2O exch.); 13C NMR (100 MHz, CDCl3, ppm): d = 13.1, 22.4, 30.2, 45,2, 104.4, 121.6, 125.8, 127.5, 129.3, 131.8, 133.8, 135.1, 143.0, 146.6, 150.3 (C4AN), 169.9 (C2@N); MS-ESI (m/z): Calcd. for C21H22BrN3S: 428.3, Found: 428.0847 [M]+.

143.2, 146.7, 149.6 (C4AN), 169.7 (C2@N); MS-ESI (m/z): Calcd. for C21H22N3SCN: 374.5, Found: 374.8604 [M] +. Computational methodology Computational calculations of the all thiazolyl hydrazones 2a–2f were performed using GaussView molecular visualized program [36] and Gaussian 03W package [37] on the personal computer [Processor (Intel(R) Core(TM)2 Duo CPU E7200 @ 2.53 DHz)]. The molecular structures of the all 2-thiazolyl hydrazones 2a–2f in the ground state were optimized by density functional theory (DFT) using B3LYP functional with 6-311G(d,p) basis set [38,39]. The geometrical parameters (bond lengths, bond angles, dihedral angles), frontier molecular orbital energies [EHOMO, ELUMO and their energy gap (Eg)], molecular electrostatic potential (MEP) and second order perturbation energies from natural bonding orbital (NBO) analysis of all molecules were derived from the optimized structures. The obtained optimized geometries, molecular orbital and electrostatic potential energy diagrams of the all molecules were visualized from GaussView molecular visualized program. Microbiological screening The entire novel synthesized 2-thiazolyl hydrazones 2a–2f were screened for in vitro antimicrobial activity against five bacterial strains viz. Gram-positive: Bacillus subtilis (ATCC-530), Staphylococcus aureus (ATCC-25930), Streptococcus pyogenes (ATCC 19615); Gram-negative: Escherichia coli (ATCC-26032) and Pseudomonas aeruginosa (ATCC-27853) and five fungal strains viz. Aspergillus flavus (ATCC-525), Aspergillus niger (ATCC-635), Penicillium chrysogenum (ATCC-10106), Trichoderma viride (ATCC-28020) and Fusarium oxysporum (ATCC-62506). Agar-disc diffusion technique is followed for the present study [40]. The stock solution of all the test compounds and reference drugs were prepared by dissolving them in dimethyl sulfoxide (DMSO) at 10 lg mL1. It was found that DMSO at the final concentration had no influence on the growth of the tested bacterial and fungal microorganisms. Ampicillin and Amphotericin-B were used as standard reference drugs against bacteria and fungi, respectively. The microbial suspensions were prepared in sterile saline (0.85% NaCl) with an optical density conforming to the McFarland standard 0.5 [150  106 CFU (colonyforming units mL1)]. Discs impregnated with known concentrations of the tested compounds were placed on a Muller-Hinton agar plate that had been inoculated or seeded uniformly over the entire plate with a culture of the bacterial and fungal to be tested. All the plates were incubated for 24–72 h at 37 °C. The DMSO was used as a negative control, whereas reference drugs were used as a positive control. The diameter of the zone of inhibition of growth (including the 5 mm diameter of the disc itself) was measured and compared with the reference drugs. Results and discussion Chemistry

2-(4-(4-Cyanophenyl)thiazol-2-yl)-1-(1-(4-isobutylphenyl) ethylidene)hydrazine (2f) Beige shine crystals; Yield 84%; m.p. 154–156 °C; IR (KBr, cm1): 3282 (NH), 2953, 2920 and 2865 (CAH), 1603 (C@N), 1566 (C@C), 1050 (CAS); 1H NMR (400 MHz, CDCl3, ppm): d = 400 MHz, CDCl3): d = 0.92 (d, J = 6.0 Hz, 6H, (CH3)2), 1.89 (m, 1H, CH), 2.24 (s, 3H, CH3), 2.50 (d, J = 6.8 Hz, 2H, CH2), 7.06 (s, 1H, H5 thiazole), 7.18 (d, J = 7.6 Hz, 2H, ArAH), 7.68 (t, J = 8.8 Hz, 4H, ArAH), 7.90 (d, J = 8.0 Hz, 2H, ArAH), 8.82 (bs, 1H, NH, D2O exch.); 13C NMR (100 MHz, CDCl3, ppm): d = 13.0, 22.4, 30.2, 45.2, 107.1, 110.8, 119.1, 125.8, 126.3, 129.3, 132.6, 134.9, 139.0,

The compounds 2a–2f were obtained in good yields (78–89%) by refluxing 40 -(2-methylpropyl) acetophenone thiosemicarbazone with 2-bromoacetophenone in isopropanol. The starting material 1 was synthesized by refluxing methanolic solution of equimolar amount of 40 -(2-methylpropyl) acetophenone and thiosemicarbazide in the presence of 4–5 drops of concentrated hydrochloric acid. All the synthesized thiazolyl hydrazones were characterized by FT-IR, 1H and 13C NMR, 2D NMR (1H–1H–COSY, 1H–13C–COSY and HMBC) and mass spectral analyses. The reaction pathway is summarized in Scheme 1.

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FT-IR spectral analysis of 2-thiazolyl hydrazones 2a–2f In the IR spectra of compounds 2a–2f, the less intense broad bands around 3442–3282 cm1 are assigned for mNAH group. The prominent two different types of C@N bonds are observed in the region 1621–1566 cm1. Moreover, the stretching frequencies in the region 3063–2860 and 1094–1019 cm1, confirm the presence of aliphatic and aromatic CAH and CAS functional groups, respectively.

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Besides, one less intense signal for cyano carbon (C26) is observed at 119.1 ppm. The signal at 107.1 ppm is due to the C5 carbon of thiazole moiety. Furthermore, there are four signals in the aliphatic region at 45.2, 30.2, 22.4 and 13.0 ppm observed and they are due to C16 (isobutyl methylene), C17 (isobutyl methine), C18 & C19 (isobutyl methyl) and C9 (methyl) carbons respectively. In the 13C NMR spectrum of compound 2c, the fluoro substituted phenyl ring carbon signals (C23, C21 & C25 and C22 & C24) are appeared as doublets at 115.5/115.7, 127.6/127.7 and 131.2/ 131.3 ppm due to the splitting by 19F nucleus [41,42].

1

H NMR spectral analysis of 2-(4-(4-cyanophenyl)thiazol-2-yl)-1-(1(4-isobutylphenyl)ethylidene)hydrazine 2f For thiazolyl hydrazone 2f, 1H–1H COSY, 1H–13C COSY and HMBC were also recorded and hence it can be used as a reference compound for discussion. The signals were assigned based on their positions, integrals, multiplicities and on comparison with those of signals of 1. 1H NMR spectrum of compound 2f (Fig. 1) shows the presence of two doublets at 0.92 (integral corresponds to six protons) and 2.50 ppm (integral corresponds to two protons) for the methyl and methylene protons of isobutyl moiety respectively. The multiplet appeared at 1.89 ppm is due to the methine proton (H17). One sharp singlet observed at 2.24 ppm is assigned to C9 methyl protons and another singlet at 7.06 ppm is due to the H5 thiazole ring proton. The aromatic protons generally appeared around 7.18–7.89 ppm. The spectrum reveals the presence of two doublets at 7.18 and 7.90 ppm, which are assigned to aromatic protons H12 & H14 and H21 & H25. A triplet at 7.68 ppm (integral corresponds to four protons) is assigned to aromatic protons H11 & H15 and H22 & H24. A broad singlet observed at 8.82 ppm is attributed to the NH proton. These assignments are confirmed from the correlations found in the 1H–1H COSY spectrum (Fig. 2). 13

C, NMR spectral analysis of compound 2f

13 C NMR spectrum of 2f is shown in Fig. 3. In 13C NMR spectrum, three less intense signals in the high frequency region [169.7, 146.7 and 149.6 ppm] are observed and they are assigned to azomethine carbon (C8 & C2) and C4 carbon of thiazole ring.

2D NMR and mass spectral analysis of compounds 2f In the 1H–13C COSY spectrum of compound 2f, the most upfield aliphatic carbon signal at 13.0, 22.4, 30.2 and 45.2 ppm show one bond correlation with the protons resonating at 2.24, 0.92, 1.89 and 2.50 ppm (Fig. 4). Hence, the above said carbon chemical shifts are unambiguously assigned to C9, (C18 & 19), C17 and C16 carbons respectively. Moreover, the signal at 107.1 ppm exhibits cross peak with the proton resonating at 7.06 ppm. So, the signal is conveniently assigned to the C5 carbon of thiazole ring. The signal at 129.3 ppm correlates with aromatic proton signal at 7.18 ppm and hence assigned to phenyl carbons C12 & C14. The correlation of signal at 126.3 ppm with protons at 7.90 ppm confirmed that the signal is due to aromatic carbons C21 & C25. The important thiazole ring carbon signals at 169.7 and 149.6 ppm do not show correlation with any proton which confirmed that they are due to the quaternary C2 and C4 carbons. In addition, the HMBC spectrum (Fig. 5) shows that the C5 thiazole proton at 7.06 ppm is in a-correlation with C4 (149.6 ppm), b-correlation with C2 (169.7 ppm) and C20 (139.0 ppm) carbons, which confirms the signal at 107.1 ppm is due to C5 carbon. All other aliphatic and aromatic protons and carbons of 2f gave their characteristic signals at the expected regions and they are listed in Table 1. The 2D NMR (1H–1H COSY, 1H–13C–COSY and HMBC) analysis of 2f confirmed its structure without ambiguity. The mass spectrum of 2f shows molecular ion peak at m/z = 379.4799 (M+) which is in good agreement with the molecular formula of C21H23N3S and confirms the formation of thiazolyl

Fig. 1. 1H NMR spectrum of 2f.

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Fig. 2. HOMOCOSY spectrum of 2f.

Fig. 3.

13

C NMR spectrum of 2f.

hydrazone. The high resolution mass spectrum (HRMS) of thiazolyl hydrazone 2f is given in Fig. S1 (See Supplementary data). Optimized geometries The optimized molecular geometries and geometrical parameters (bond lengths, bond angles and dihedral angles) of thiazolyl hydrazones 2a–2f were determined by DFT calculations using

B3LYP functional with 6-311G(d,p) basis set. The geometrical parameters obtained B3LYP functional with 6-311G(d,p) basis set is reliable and has good agreement with the experimental parameters [43]. The computed optimized molecular geometries of thiazolyl hydrazones (2a–2f) are shown in Fig. S2 (see Supplementary data) and the selected geometrical parameters are listed in Table S1 (see Supplementary data). The Table S1 reveals that C4AN3 (1.385–1.387 Å) bond lengths of 2a–f are greater than the

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Fig. 4. HSQC spectrum of 2f.

Fig. 5. HMBC spectrum of 2f.

C2AN3 (1.290–1.291 Å) bond lengths, because both are in chemically different environments, which also indicate that the C2AN3 bond has double bond character. In addition, the C2AS1 and C5AS1 bond lengths are almost similar (1.773–1.776 and 1.740– 1.744 Å) and the bond lengths of C5AC4 (1.366 Å) is higher than the bond lengths of C2AN3 (1.290–1.291 Å). The bond angles of

the thiazole ring S1AC2AN3, S1AC5AC4 and N3AC4AC5 are 114.9–115.1°, 110.6–110.7° and 115.3–115.0°, respectively. Also the dihedral angles C15AC10AC8AN7, C8AN7AN6AC2 H6AN6AC2AN3 and C5AC4AC20AC25 are (13.98)–(15.88)°, (179.4)–(179.9)° (177.0)–(178.9)° and (172.5)–(178.4)° respectively. The above observations clearly indicate that all the thiazolyl

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Table 1 Correlations in the HOMOCOSY, HSQC and HMBC spectra of 2f. 1

H NMR Chemical shifts (ppm)

Correlation in 1H-1H COSY H Chemical shifts (ppm)

Correlation in 1H-13C COSY 13 C Chemical shifts (ppm)

Correlation in HMBC 13 C Chemical shifts (ppm)

1.89 0.92, 2.50 – 1.89 – 7.68 7.90 7.18 7.68

22.4 30.2 13.0 45.2 107.1 129.3 132.6 125.8 126.3

30.2 (a), 45.2 (b) 22.4 (a), 45.2 (b) 146.7(a), 134.9 (b) 30.22 (a), 22.3 (b), 143.2 (a), 129.3 (b) 149.6 (a), 139.0 (b), 169.7 (b) 45.2 (b), 134.9 (b) 119.1 (b), 139.0 (b) 143.2 (b), 146.7 (b) 132.6 (a), 110.8 (b), 149.6 (b)

1

CH3 (18, 19) 0.92 H(17) 1.89 CH3 (9) 2.24 H(16) 2.50 H(5) 7.06 ArAH(12, 14) 7.18 ArAH(22, 24) 7.68 ArAH(11, 15) 7.68 ArAH(21, 25) 7.90

hydrazones are having almost same geometrical parameters and further reveals that the both phenyl rings and thiazole ring are in one plane. Molecular properties The frontier molecular orbitals play an important role in the electric and optical properties as well as chemical reactions. The HOMO is an electron donor represents the ability to donate an electron and LUMO represents the ability to accept an electron. The lowest energy gap of the molecule reveals the easier electron transfer from HOMO orbital to LUMO orbital. The lower LUMO– HOMO energy gap reflects the chemical reactivity, stability of the molecules and potential application of these molecules as NLO materials. The HOMO–LUMO orbital pictures of molecules 2a–2f are shown in Fig. S3 (see Supplementary data), Frontier energies energy gap electronegativity (v), hardness (g), electrophilicity (x) and softness (S) are listed in Table 2 [44]. Generally EHOMO and ELUMO of compounds containing electron donors are higher while acceptors are smaller compare to the parent compound. Electron releasing methoxy group increases the EHOMO and ELUMO whereas the other substituents (–F, –Cl, –Br, –CN) decrease the EHOMO and ELUMO. The trend in EHOMO and ELUMO is 2b > 2a > 2c > 2e > 2d > 2f and the decreasing order of energy gap is 2e > 2d > 2c > 2a > 2b > 2f. The smallest energy gap is seen for 2f where electron attracting CN group is present at the one end and electron releasing isobutyl group is present at other end. The LUMO energy level of 2a is 1.393 eV and the work function of aluminium is 5.1 eV. The electron injection energy is calculated to be 3.71 eV [ELUMO– (5.1)] from 2a to aluminium electrode (Table 2). To improve the electron injection capability it is necessary to lower the ELUMO level. The electron injection barrier decreases in the compounds having withdrawing substituents as follows: 2c (3.66) > 2e (3.61) > 2d (3.61) > 2f (3.22). However, the electron injection barrier for methoxy substituted compound 2b is (3.77). The hole injection energy is around 0.29 eV [= 5.1  EHOMO] from 2a to aluminium electrode and the order of other substituents are 2b (0.1) > 2c (0.35) > 2d (0.41) = 2e (0.41) > 2f (0.6 eV). To enhance the hole injection ability it is necessary to increase the EHOMO. Table 2 Molecular descriptors of 2a–2f (in eV) at the B3LYP functional with 6-311G(d,p) basis set. Compounds

2a 2b 2c 2d 2e 2f

Molecular descriptors (eV) EHOMO

ELUMO

Eg

v

g

x

S

5.385 5.203 5.445 5.510 5.507 5.700

1.393 1.328 1.445 1.491 1.486 1.880

3.992 3.875 4.000 4.019 4.021 3.820

3.389 3.266 3.445 3.501 3.497 3.790

1.996 1.938 2.000 2.009 2.011 1.910

2.877 2.752 2.967 3.049 3.040 3.760

0.998 0.969 1.000 1.004 1.005 0.955

The hole injection ability is decreased in the methoxy derivative 2b whereas higher in the other derivatives. The decreased injection barrier for electron revealed that the derivatives 2c–2f are better charge transporters than the parent molecule. Further, the LUMO energies of 2c–2f are low-lying than 2a indicating that 2c–2f would be thermodynamically more stable and charge transport cannot be quenched by losing the electron. However, in methoxy derivative 2b, the charge transporting capacity is less when compared to 2a. The electronegativity (v) and Electrophilicity (x) are smaller for 2b (donor group is methoxy) while larger for 2c–2f compared to 2a. Fig. S3 (see Supplementary data), illustrates that HOMO is distributed on entire molecule except isobutyl group while LUMO is delocalized on the molecule except isobutyl group and little contribution from phenyl ring attached to thiazolyl ring in parent compound 2a. In compounds 2c–2f also HOMOs are distributed on entire molecules except isobutyl group. In 2b, in addition to isobutyl group, methyl group of methoxy moiety is not contributed to the construction of HOMO orbital. In the construction of LUMO orbitals, contribution of aryl ring attached to thiazolyl ring is increased in the order 2b < 2a < 2d < 2e. However in 2f, the phenyl ring having isobutyl moiety is not involved in the construction of ELUMO orbital. In 2f, electron transfer occurs from phenyl ring having isobutyl moiety to aryl ring attached to thiazolyl ring. However in compounds 2a–2e charge transfer occurs from aryl ring attached to thiazolyl ring to the phenyl ring having isobutyl moiety. Reorganization energies Fig. S4 (see Supplementary data) represents the correlation between the Hammett constants and hole injection energy (h) [45]. The comparison of line slopes indicates that the electron withdrawing groups [EWDGs] exert positive correlation while electron donating methoxy group [EDG] has negative correlation. Similar tendency has been observed between the Hammett constants and electron injection energy (e). The computed hole injection energy of 2a–2f are smaller than the electron injection energy indicating these materials would be hole transport materials like the electron donating molecule 2b. The significant effect towards the lowering of (h) has been observed in the case of electron donating methoxy substituent 2b compared to the parent molecule whereas the higher (h) has been observed for the electron withdrawing substituents 2c–2f than the parent compound 2a. Here we have compared the (h) of novel molecules with already known materials to shed some light on the charge transport properties. The (h) of naphthalene is 0.186 eV which is commonly used as a hole transfer material. The (h) of electron donating methoxy substituent 2b revealed that it would be a better hole transport material comparable to naphthalene. Molecular electrostatic potential In the majority of the MEP, the maximum negative region is the preferred site by electrophilic attack which is indicated as red

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colour and the maximum positive region is indicated as blue colour. To predict the reactive site of electrophilic and nucleophilic attack for the thiazolyl hydrazones 2a–2f, MEPs are investigated and 3D images are given in Fig. S5 (see Supplementary data). The scale of increased potential is indicated by red < orange < yellow < green < blue. As seen from Fig. S5 (see Supplementary data), all the negative regions (red) are found to be around the sulphur atom of the thiazole ring in all the thiazolyl hydrazones 2a–2f, because the electron delocalization occurs from C25AC20 bonding orbital to C4AC5 antibonding orbitals; an exception being an electron donating methoxy substituted thiazolyl hydrazone 2b. In 2b, electron transfer occurs from C20AC21 to C4AN3 bond and delocalization energy is 9.70 kJ mol1 which indicates that the molecule 2b have maximum negative region (red) around the nitrogen atom of the thiazole ring. From the MEP pictures, the electrophilic attacking site value is determined to be –0.0017 kJ mol1 and the nucleophilic attacking sites (maximum positive regions) are found to be localized around C5AH5 and N6AH6 atoms and the maximum potential is found to be 0.0017 kJ mol1. Natural bonding orbital (NBO) analysis The NBO analyses provides an efficient method which investigates an intra and inter molecular interactions among the bonds and also provides a convenient basis for investigating charge transfer or conjugative interaction in the molecular system [46,47]. The larger the E(2) value, the more intensive is the interaction between electron donor and electron acceptor. This electron donating tendency reflects the greater extent of conjugation in the whole system. The results of second-order perturbation theory analysis of Fock Matrix of the 2-thiazolyl hydrazones 2a–2f based on the B3LYP/6-311G(d,p) level are presented in Table 3. NBO analysis revealed that the most important interactions of 2-thiazolyl hydrazones 2a–2f correspond to the transfer of electrons from LP(1)N6 to antibonding orbital of C2AN3 and antibonding orbital of C8AN7. The delocalization energies are found to be 206.4–199.03 and 121.29–116.06 kJ mol1 respectively. These values reveal that the delocalization towards the thiazole ring is a primary process rather than the delocalization towards the side chain C8AN7 moiety. Also, several other interactions, i.e. the lone pair to antibonding orbitals [LP(2)S1 to C2AN3], [LP(2)S1 to C5AC4] and [LP(1)N3 to

C2AS1] exhibit high stabilization energies [108.82–108.28, 76.15–72.05 and 73.39–72.80 kJ mol1 respectively]. Table 3 shows that delocalization of electrons occur from isobutyl attached phenyl ring to the side chain moiety. From the Table 3 it is noticed that the delocalization energy corresponding to the transfer of electrons from bonding orbital of C11AC10 to antibonding orbital of C8AN7 is higher (71.17 kJ mol1) than the reverse transfer (6.28 kJ mol1). In addition, the delocalization energy corresponding to the transfer of electrons from C8AN7 bonding orbital to N6AC2 antibonding orbital is higher (12.93 kJ mol1) than that of the reverse transfer [BD(N6AC2) to BD*(C8AN7) is 9.37 kJ mol1] which further confirms that the delocalization of electrons from C8 phenyl ring to side chain moiety (C8AN7AN6AC2). Further, electron transfer occurs from C4 phenyl ring to thiazole ring is confirmed from the high delocalization energies corresponding to the transfer of electrons from C20AC25 to C4AC5 (84.35– 82.01 kJ mol1) compared to the lower value for reverse transfer [C4AC5 to C20AC25 is 42.47–41.76 kJ mol1]. In the methoxy derivative 2b, the delocalization of electrons occurs in a different manner relative to other derivatives. The delocalization energies for the electron transfer from C20AC21 bonding orbital to C4AC5 antibonding orbital is 74.56 kJ mol1 and the reverse electron transfer from BD(C5AC4) to BD*(C20AC21) is 34.81 kJ mol1 in 2b. All the above delocalization energies reveal that the higher electron density is associated with the thiazole ring rather than the C8 and C4 phenyl rings. The extent of charge transfer from lone pair of electrons centred on N6 to antibonding orbital of C2AN3 bond (delocalization energy) follows the order 2f > 2d > 2e > 2c > 2a > 2b. This shows that charge transfer is easier in cyano derivative 2f which is in accordance with the smallest energy gap between HOMO and LUMO orbitals. Antimicrobial evaluation Antibacterial activity of all the synthesized 2-thiazolyl hydrazones 2a–2f were evaluated against Gram-positive (B. subtilis, S. aureus, S. pyogenes) and Gram-negative (E. coli, P. aeruginosa) bacteria where Ampicillin was used as the reference drug. Similarly, antifungal activities were evaluated against various fungal strains viz. A. flavus, A. niger, P. chrysogenum, T. viride, F. oxysporum. Here Amphotericin-B was used as the reference drug. Antibacterial

Table 3 Significant donor–acceptor interactions of 2a–2f and their second order perturbation energies. Donor NBO (i)

Acceptor NBO (j)

BD(2)C13AC12 BD(2)C11AC10 BD(2)C11AC10 BD(1)C8AN7 BD(1)C8AN7 BD(1)N6AC2 BD(2)C5AC4 BD(2)C2AN3 BD(1)N3AC4 BD(1)C20AC21 BD(2)C5AC4 BD(2)C20AC25 BD(2)C5AC4 BD(2)C20AC21 LP(1)N7 LP(1)N6 LP(1)N6 LP(2)S1 LP(2)S1 LP(1)N3

BD*(2)C11AC10 BD*(2)C15AC14 BD*(2)C8AN7 BD*(2)C11AC10 BD*(1)N6AC2 BD*(1)C8AN7 BD*(2)C2AN3 BD*(2)C5AC4 BD*(1)C20AC21 BD*(1)N3AC4 BD*(2)C20AC25 BD*(2)C5AC4 BD*(2)C20AC21 BD*(2)C5AC4 BD*(1)C8AC9 BD*(2)C8AN7 BD*(2)C2AN3 BD*(2)C2AN3 BD*(2)C5AC4 BD*(1)C2AS1

Compounds [E(2) kJ mol1] 2a

2b

2c

2d

2e

2f

91.46 79.33 71.17 6.28 12.93 9.37 36.02 81.76 – – 41.76 84.35 – – 46.74 119.75 199.24 108.32 73.03 73.39

91.33 79.33 69.96 7.70 13.05 9.37 35.81 81.55 8.200 9.70 – – 34.85 74.56 46.86 121.29 199.03 108.57 72.05 73.03

91.76 79.33 70.45 7.70 12.97 9.29 35.44 82.34 – – 41.71 83.89 – – 46.69 119.08 201.33 108.82 73.03 72.84

92.04 79.50 70.50 5.56 12.97 9.25 35.19 82.55 – – 42.13 82.01 – – 46.69 118.49 203.01 108.62 74.07 72.84

92.13 79.66 69.50 7.66 12.93 9.25 35.05 82.51 – – 42.47 82.42 – – 46.73 118.62 202.84 108.53 74.10 72.89

92.68 79.58 70.96 7.61 12.87 9.12 34.64 83.09 – – 41.74 84.25 – – 46.52 116.06 206.40 108.28 76.15 72.80

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Table 4 Antibacterial activity of 2a–2f against the pathological strain based on disc diffusion assay (mm). Compounds

Bacillus subtilis

Staphylococcus aureus

Streptococcus pyogenes

Escherichia coli

Pseudomonas aeruginosa

2a 2b 2c 2d 2e 2f Ampicillin

15 13 12 7 18 – 16

11 9 18 12 12 – 19

9 8 7 – 13 – 17

8 11 19 8 14 9 18

15 10 12 – 16 10 14

Table 5 Antifungal activity of 2a–2f against the pathological strain based on disc diffusion assay (mm). Compounds

Aspergillus flavus

Aspergillus niger

Penicillium chrysogenum

Trichoderma viride

Fusarium oxysporum

2a 2b 2c 2d 2e 2f Amphotericin-B

12 17 – – 11 10 14

15 17 – 21 – 24 20

24 14 19 21 22 25 17

10 – – 12 – 13 18

19 – 15 11 13 11 19

and antifungal activities are indicated by an inhibition zone surrounding the well containing compounds and were recorded if the zone of inhibition was above 5 mm. The antimicrobial activity results are summarized in Tables 4 and 5. Antibacterial activity As shown in Table 4, most of the compounds were active against Gram positive and Gram negative bacteria. A careful analysis of the data in Table 4 provides good antibacterial activity of some compounds. The test compounds with F and Br substituents at the para position of the phenyl ring (2c and 2e) expressed a moderate to good activity against most of the test pathogens. They inhibited Gram positive and Gram negative bacteria equally. Compounds 2a and 2e showed better activity against B. subtilis. Also compounds 2b and 2c have moderate activity and 2f is inactive against B. subtilis bacteria. Compound 2c exhibited better activity against S. aureus, compound 2a, 2d and 2e showed moderate activity and compound 2f is inactive against S. aureus. The lower activity against pathogenic bacteria S. pyogenes was observed for the compounds 2a–2e and inactive nature was observed for compound 2f. Compound 2c exhibited excellent activity and compounds 2b and 2e have moderate activity, whereas compounds 2a, 2d and 2f exhibit lower activity against E. coli. Compounds 2a and 2e showed very good activity against P. aeruginosa while compounds 2b, 2c and 2f exhibited moderate activity against the same pathogenic bacteria. Antifungal activity The data presented in Table 5 described the antifungal activity of the synthesized compounds. The introduction of OCH3, F, Cl, CN substituents on the phenyl ring exhibited moderate to good activity over some pathogenic fungi. Compound 2a showed better activity towards A. flavus, P. chrysogenum and F. oxysporum and moderate activity against A. niger and T. viride. Compounds 2b, 2d and 2f exhibited very good activity and compound 2a has moderate activity against A. niger whereas compounds 2a, 2c, 2d, 2e and 2f showed excellent activity against P. chrysogenum. The compounds 2a, 2d, 2f exhibited moderate activity against pathogenic fungi T. viride and compounds 2b, 2c and 2e are not active towards the same. Besides, compound 2a showed good activity and 2c, 2d, 2e and 2f have moderate activity against F. oxysporum. Structure activity relationship From the in vitro antimicrobial data, the preliminary structure activity relationship of the synthesized compounds 2a–2f was

studied. The introduction of various substitutes F, Cl, Br, CN and OCH3 on the phenyl ring significantly improves the antimicrobial activity. In general substituents CN, F, Cl and Br at the phenyl ring enhance the antimicrobial activity while OCH3 substituted compound and parent compound show moderate activity. A closer look into the structure activity relationship of these compounds revealed following points. The synthesized compounds 2a–2f exhibited moderate to good activity against five pathogenic bacteria B. subtilis, S. aureus, S. pyogenes, E. coli, P. aeruginosa and excellent antifumgal activity against five pathogenic fungi A. flavus, A. niger, P. chrysogenum, T. viride, F. oxysporum due to the presence of isobutyl chain, thiazole moiety, hydrazone and various substituents on the phenyl ring. The results also suggest that the combination of certain substituent on the phenyl ring is responsible for the antimicrobial activity. The halo substituent on the phenyl ring at the para position [compounds 2c and 2e] enhanced the antibacterial activity. The fluoro and bromo substituent on the phenyl rings exhibited very good antibacterial activity and the methoxy substituent on the phenyl ring exhibited moderate activity, while cyano substituent is inactive in the antibacterial activity for all pathogenic bacteria except E. coli and P. aeruginosa which showed moderate antibacterial activity. The thiazolyl hydrazones 2a–2f exhibited moderate to very good antifungal activity. The compounds 2d, 2e and 2f [Cl, Br, CN substituents at the para position of the phenyl ring] exhibited excellent antifungal activity against A. niger and P. chrysogenum and moderate antifungal activity with A. flavus, T. viride and F. oxysporum. Compared to compound 2a, compound 2c and 2e (with electron withdrawing fluoro and bromo substituents) are more potent antibacterial active compounds. Compounds 2d–2f exhibited excellent antifungal activity. The above conclusion reveals that the introduction of halogen and cyano substituent at the para position on the phenyl ring could increase antimicrobial activity. The antibacterial activity of these compounds was slightly enhanced in the following order F < Br whereas antifungal activity is of the order Cl < Br < CN which indicates that the halogen and cyano substituted compounds could be more antimicrobial active compounds among the synthesized compounds. Conclusion A series of novel 2-thiazolyl hydrazones 2a–2f were synthesized successfully and characterized by FT-IR, 1H, 13C NMR and 2D NMR and mass spectral techniques. The geometrical

R. Anbazhagan, K.R. Sankaran / Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 135 (2015) 984–993

parameters, molecular descriptors, MEP and NBO analyses of compounds 2a–2f have been calculated using density functional theory (DFT) with B3LYP functional with 6-311G(d,p) basis set. The theoretical geometrical parameter reveals that the both phenyl and thiazole rings were in same plane and the NBO reveals that the thiazole ring has been high electron density than the both phenyl rings for all substituents. Furthermore, antimicrobial activity screening against five pathogenic bacteria and five pathogenic fungi were done. Most of the compounds showed moderate to good activity towards bacteria as well as fungi strains. The presence of halogen and cyano substituents at the para position of phenyl ring i.e. compounds 2c–2f influenced antimicrobial activity to a considerable extent. The fluoro and bromo (2c and 2e) substituent on the phenyl rings exhibited very good antibacterial activity against some pathogenic bacteria. The chloro, bromo and cyano (2d, 2e and 2f) substituted compounds exhibited excellent antifungal activity against most of the pathogenic fungi. Acknowledgement We thank UGC BSR-SAP fellowship New Delhi for financial support and IIT Chennai for providing mass spectra of the compounds. Appendix A. Supplementary material Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.saa.2014.06.160. References [1] M.A.M.S. El-Sharief, S.Y. Abbas, K.A.M. El-Bayouki, E.W. El-Gammal, Eur. J. Med. Chem. 67 (2013) 263–268. [2] J. Capilla, C. Serena, F. Javier, T. Ortoneda, J. Guarro, Antimicrob. Agents Chemother. 47 (2003) 3976–3978. [3] C. Loncle, J.M. Brunel, N. Vidal, M. Dherbomez, Y. Letourneux, Eur. J. Med. Chem. 39 (2004) 1067–1071. [4] M.T. Abdel-Aal, W.A. El-sayed, E.H. El-ashry, Arch. Pharm. Chem. Life Sci. 339 (2006) 656–663. [5] A. Walcourt, M. Loyevsky, D.B. Lovejoy, V.R. Gordeuk, D.R. Richardson, Int. J. Biochem. Cell Biol. 36 (2004) 401–407. [6] G.E. Chavarria, M.R. Horsman, W.M. Arispe, G.D.K. Kumar, Shen-En Chen, T.E. Strecker, E.N. Parker, D.J. Chaplin, K.G. Pinney, Mary Lynn Trawick, Eur. J. Med. Chem. 58 (2012) 568–572. [7] L. Savini, L. Chiasserini, V. Travagli, C. Pellerano, E. Novellino, S. Consentino, M.B. Pisano, Eur. J. Med. Chem. 39 (2004) 113–122. [8] A. Bijev, Lett. Drug Des. Discov. 3 (2006) 506–512. [9] A. Imramovsky, S. Polanc, J. Vinsova, M. Kocevar, J. Jampitek, Z. Reckova, J.A. Kaustova, Bioorg. Med. Chem. Lett. 15 (2007) 2551–2559. [10] Y. Janin, Bioorg. Med. Chem. 15 (2007) 2479–2513. [11] S.M. Mohsin Ali, M. Jesmin, M. Abul Kalam Azad, M. Khairul Islam, R. Zahan, Asian. Pac. J. Trop. Biomed. 2 (2012) S1036–S1039. [12] J.R. Dimmock, S.C. Vasishtha, J.P. Stables, Eur. J. Med. Chem. 35 (2000) 241– 248. [13] G.A. Silva, L.M.M. Costa, F.C.F. Brito, A.L.P. Miranda, E.J. Barreiro, C.A.M. Fraga, Bioorg. Med. Chem. 12 (2004) 3149–3158. [14] M.H.M. Helal, M.A. Salem, M.S.A. El-Gaby, M. Aljahdali, Eur. J. Med. Chem. 65 (2013) 517–526.

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