Two novel imidazole derivatives - Combined

Journal of Molecular Structure 1173 (2018) 221e239

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Journal of Molecular Structure journal homepage: http://www.elsevier.com/locate/molstruc

Two novel imidazole derivatives e Combined experimental and computational study M. Smitha a, Y. Sheena Mary b, *, Mossaraf Hossain c, K.S. Resmi b, Stevan Armakovi c d, Sanja J. Armakovic e, Rani Pavithran a, Ashis Kumar Nanda c, C. Van Alsenoy f a

Department of Chemistry, University College, Trivandrum, Kerala, India Department of Physics, Fatima Mata National College, Kollam, Kerala, India Department of Chemistry, University of North Bengal, Siliguri, Darjeeling, India d University of Novi Sad, Faculty of Sciences, Department of Physics, Trg D. Obradovica 4, 21000, Novi Sad, Serbia e University of Novi Sad, Faculty of Sciences, Department of Chemistry, Biochemistry and Environmental Protection, Trg D. Obradovica 3, 21000, Novi Sad, Serbia f Department of Chemistry, University of Antwerp, Groenenborgerlaan 171, B-2020, Antwerp, Belgium b c

a r t i c l e i n f o

a b s t r a c t

Article history: Received 13 January 2018 Received in revised form 25 June 2018 Accepted 27 June 2018 Available online 29 June 2018

Two novel imidazole derivatives, 2-chloro-4,5-dimethyl-1-phenyl-1H-imidazole (C11H11ClN2)(PHENYLI) and 2-chloro-4,5-dimethyl-1-(o-tolyl)-1H-imidazole (C12H13ClN2) (TOLYLI), have been obtained by a procedure based on solvent-free synthesis pathway. Newly synthetized imidazole derivatives have been characterized experimentally by IR, FT-Raman and NMR techniques, while their reactive properties have been predicted on the basis of density functional theory (DFT) calculations and molecular dynamics (MD) simulations. The NLO behavior of the title compounds is greater than that of the standard NLO material urea. MEP analysis gives the most reactive sites in the molecules. TOLYLI compound reveals anti-bacterial activity against all four bacterial strain in both gram positive and gram negative bacteria and PHENYLI compound showed in gram positive and gram negative bacteria both with very good immense and has more sensitive. Interactions of these novel imidazole derivatives with selected protein have been computationally investigated by molecular docking procedure. The docking studies suggest that the compounds might exhibit inhibitory activity against APO-liver alcohol dehydrogenase inhibitor. © 2018 Elsevier B.V. All rights reserved.

Keywords: DFT Imidazole ALIE RDF Molecular docking

1. Introduction Ever since 1840s the discovery of imidazole, the development of research compounds like imidazole-based have been somewhat a speedily developing and increasingly active area due to their extensive potential applications in medicinal chemistry as drugs, man-made materials, artificial acceptors, agrochemicals, biomimetic catalysts, supramolecular ligands, and so on [1e5]. Various imidazole-based medicinal drugs have been playing a fundamental role for the treatment of different types of diseases and newly synthesized imidazole derivatives with biological importance are being actively exploited worldwide. In fact, imidazole moiety is commonly present in naturally occurring products and in the human metabolism set up as bioactive substances [6]. The imidazole

* Corresponding author. E-mail address: [email protected] (Y.S. Mary). https://doi.org/10.1016/j.molstruc.2018.06.110 0022-2860/© 2018 Elsevier B.V. All rights reserved.

scaffold is an important synthetic strategy in the drug discovery. Imidazole derivatives demonstrated analgesic, antimicrobial, antiinflammatory, antiviral, anti-tubercular, anti-diabetic and antimalarial and anticancer activity [7e13]. The vast therapeutic properties of the imidazole derivatives drugs have encouraged the chemists in the medicinal field to synthesize a huge number of novel chemotherapeutic agents. The complexity of developing the synthesis of many imidazole derivatives lies in the various facts, depending on reaction condition; it can normally enter the reaction in different forms such as the neutral, the conjugate acid and base, carbine and finally ylide (zwitterionic). Development of new methodologies for synthesis of imidazole derivatives is therefore of quite importance. In this purpose of investigating the reactivity of imidazole N-oxides to imidazole derivatives we have developed a protocol of introducing a halogen atom in the C-2 position of imidazole ring, based on the nucleophilic addition followed by cine-substitution. It should be pointed out that examples of halogenation of N-oxides in this way in the literature is very

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uncommon, all of them using either TsCl [14], PCl3, PCl5, or POCl3 [15]. Imidazole derivatives have a wide range of applications, while they are especially important for the development of novel pharmaceutical molecules. Additionally, imidazole ring is also recognized as an outstanding structural unit of ionic liquids [16e18]. Among many physical and chemical properties, ionic liquids owe their popularity due to the possibilities to finely adjust their properties, for which the C(2) position of imidazole is especially significant [19e22]. Since there are a large number of possible pharmaceutical molecules and ionic liquids, experimental studies for all possible structures are not feasible. Therefore, computational studies are used in order to narrow the window of prospective candidates through prediction of the most important reactive properties [23e31]. In this work a combination of DFT calculations and MD simulations have been used in order to understand in details reactive properties of novel imidazole derivatives. Global reactivity has been addressed by analysis of frontier molecular orbitals, while local reactivity properties have been addressed through analysis of molecular electrostatic potential (MEP), average local ionization energy (ALIE) and Fukui function surfaces. Since advanced oxidation processes are among the most important reactions for the removal of pharmaceutical molecules, in this work we have also investigated the sensitivity of title molecules towards the autoxidation mechanism by calculating the bond dissociation energies for hydrogen abstraction (H-BDE) [17,19,32e37]. Molecular dynamics simulations have been used in order to track the atoms of novel imidazole derivatives with the most important interactions with water. 2. Experimental details All the reagents used here such as diacetyl monoxime, paraformaldehyde, substituted aniline, oxalyl chloride, dimethylsulphoxide (DMSO‑d6), triethylamine and solvents were used as purchased from the commercial suppliers.

Bruker Advance 300 MHz spectrometer chemical shifts (d) in ppm reference as TMS with solvent used here dimethylsulphoxide (DMSO‑d6). Mass spectra were taken by ion spray technique on a MICROMASS QUATTRO II triple quadruple mass spectrometer. The FT-IR and FT-Raman spectra (Figs. 1 and 2) were recorded using DR/ Jasco FT-IR 6300 and Bruker RFS100/S spectrometer (Nd:YAG laser, 1064 nm excitation). Analytical thin-layer chromatography was performed using silica gel aluminium sheets (Merck, TLC silica gel 60 F254). Residue was purified by column chromatography on silica gel (60e120 mesh) as eluent petroleum ether and ethyl acetate mixture. Progress of reaction was monitored by thin layer chromatography. All the reaction was performed under solvent-free conditions with the help of agate mortar and pestle. 2.3. 2-Chloro-4, 5-dimethyl-1-phenyl-1H-imidazole (C11H11ClN2) (PHENYLI)

Yield 93%, white solid, mp 53e56 C, 1H NMR (300 MHz, DMSO‑d6), d, ppm: 7.60e7.53 (3H, m, AreH), 7.39e7.35 (2H, m, AreH), 2.09 (3H, s, -CH3), 1.92 (3H, s, -CH3). 13C NMR (75 MHz, DMSO‑d6), d, ppm: 135.5, 132.7, 130.1, 129.7, 128.3, 128.2, 126.1, 12.9 and 9.8. ESI MS (m/z) [MþH] þ: 207. 2.4. 2-Chloro-4, 5-dimethyl-1-o-tolyl-1H-imidazole(C12H13ClN2) (TOLYLI)

2.1. General procedure for preparation of substituted imidazole Noxide [38] The monoxime (1 mmol), aldehyde (1 mmol) and ammonium acetate (385 mg, 5 mmol) was ground in an agate mortar and pestle. The mixture was then heated in an oil bath with constant shaking at 115e120 C under solvent-free condition. A black solution resulted which was cooled when a black sticky precipitate formed. To the black precipitate was then added a small volume of diethyl ether when a brown precipitate separated. The precipitate was then thoroughly washed with ethyl acetate, dissolved in ethanol and crystallized by addition of water to yield pure products. Finally pure product was isolated by spectral investigation.

Yield 83%, white solid, mp 67e70 C, 1H NMR (300 MHz, DMSO‑d6), d, ppm: 7.50e7.27 (4H, m, AreH), 2.08 (3H, s, -CH3), 1.96 (3H, s, -CH3), 1.83 (3H, s, -CH3). 13C NMR (75 MHz, DMSO‑d6), d, ppm: 135.7, 133.8, 131.9, 131.1, 130.0, 128.3, 127.7, 127.3, 125.5, 16.6, 12.3 and 8.9. ESI MS (m/z) [MþH] þ: 221. 2.5. Material and method for antimicrobial activity

2.2. General procedure for preparation of chlorination at C-2 position of substituted imidazole 2-chloro-4,5-dimethyl-1-phenyl-1H-imidazole (PHENYLI) and 2-chloro-4,5-dimethyl-1-(o-tolyl)-1H-imidazole (TOLYLI) were synthesized via a mild and solvent-free strategy with imidazole Noxide (1 mmol), oxalyl chloride (2 mmol) and triethylamine (1.5 mmol) was ground into an intimate mixture in an agate mortar and pestle. The mixture was then stirrer at rate for 10 min under solvent-less condition. Then the reaction mixture was dissolved in dichlotomethane, washed with water and finally dried over Magnesium sulphate. Filtrate was subjected to chromatography on silica gel and petroleum ether/ethyl acetate mixture as eluent. Finally pure product was isolated by spectral investigation. NMR data (Fig. S1-supporting information) were recorded on

Minimum inhibitory concentration (MIC) is the lowest concentration of an antimicrobial that will inhibit the growth of a microorganism after overnight incubation. MIC determination of title compounds by employing a tube dilution method (most commonly method) in Mueller- Hinton broth, in accordance with the recommendations contained in the CLSI guidelines. Four bacterial strain 2 g positive (Staphylococcus Aureus MTCC1144, and Bacillus Subtilis MTCC1305) and 2 g negative (E.coli K12 MTCC1265 and Pseudomonas fluorescencs MTCC 103) were used. For MIC determination 3 ml Mueller-Hinton broth distributed in test tube and different concentration of compound which was dissolved in ethanol (10 mg/ml) added in test tube, with positive and negative control. 1% overnight growth bacterial culture was added in each test tube and incubated overnight at 37 C (MTCC1265, MTCC1305,


223

Fig. 1. FT-IR spectra of (a) 2-chloro-4,5-dimethyl-1-phenyl-1H-imidazole- experimental (PHENYLI), (b) 2-chloro-4,5-dimethyl-1-phenyl-1H-imidazole- theoretical (PHENYLI), (c) 2chloro-4,5-dimethyl-1-(o-tolyl)-1H-imidazole - experimental (TOLYLI) and), (d) 2-chloro-4,5-dimethyl-1-(o-tolyl)-1H-imidazole e theoretical (TOLYLI).

224


Fig. 2. FT-Raman spectra of (a) 2-chloro-4,5-dimethyl-1-phenyl-1H-imidazole- experimental (PHENYLI), (b) 2-chloro-4,5-dimethyl-1-phenyl-1H-imidazole- theoretical (PHENYLI), (c) 2-chloro-4,5-dimethyl-1-(o-tolyl)-1H-imidazole - experimental (TOLYLI) and), (d) 2-chloro-4,5-dimethyl-1-(o-tolyl)-1H-imidazole e theoretical (TOLYLI).

MTCC1144) and 25 C (MTCC103) for overnight. Bacterial growth was detected by optical density at 600 OD. MIC values were defined as the lowest concentration of each chemical compound, which completely inhibited microbial growth. The results were expressed in micrograms per milliliters.

3. Computational details In this work two software packages, Schrodinger Materials Science Suite 2017e2 (SMSS) and Gaussian09, have been extensively used in order to obtain detailed reactivity picture of the studied


molecules. Firstly, MicroModel program [39], as implemented in SMSS, was employed along with OPLS3 [40e43] force field in order to obtain all possible conformations of the investigated derivatives. Jaguar program [44e46] was further used in order to geometrically optimize obtained conformations at DFT level, using B3LYP [47] exchange-correlation functional and 6-31G(d,p) basis set. The lowest energy conformers were located and used for further computational studies, while their true ground states (Fig. 3) were confirmed by vibrational analysis at the same level of theory, which yielded only positive frequencies. Properties which were calculated further with Jaguar program encompassed MEP and ALIE surfaces, H-BDE and Fukui functions. MEP and ALIE have been calculated with 6e311þþG(d,p), Fukui functions with 6-31 þ G(d,p), while HBDE have been calculated with 6-311G(d,p) basis set. Different basis sets for different properties have been used according to the default settings and suggestions of the software developer. CeN bond energy scan has been performed in order to indicate conformational preference of the studied molecules, and the corresponding results have been provided in Fig. S2 of the supplementary materials. The quantum chemical calculations performed with Gaussian09 and Gaussview software packages [48,49] encompassed vibrational wavenumbers, NBO [50], frontier molecular orbitals and NLO properties. These properties have been obtained with molecular structures re-optimized at B3LYP/6e311þþG(5D,7F) level of theory, while the lowest energy conformers determined by Jaguar program have been used as initial structures. Using GAR2PED software [51], the potential energy distribution analysis is done to assign the theoretically obtained wavenumbers. The theoretically obtained wavenumbers are scaled by using a scaling factor of 0.9613 as reported in literature [52]. For molecular dynamics simulations (MD), a Desmond [39,41,53,54] program, as implemented in SMSS, with OPLS3 force field was used. MD simulation time was set to 10 ns and with cut off radius of 12 Å. The modeled system was of NPT ensemble, with pressure and temperature set to 1.0325 bar and 300 K, respectively. Simple point charge (SPC) model was used for the treatment of solvent, while the whole system was modeled by placing of one imidazole derivative molecule surrounded with ~3000 water molecules in a cubic box. When SMSS software package was used, its GUI called Maestro was used for creation of input files, visualization and analysis of results.

225

4. Results and discussion To developing of our process under a mild and greener synthetic protocol for the preparation of 2-chloro-4,5-dimethyl-1-phenyl1H-imidazole (PHENYLI) and 2-chloro-4,5-dimethyl-1-(o-tolyl)1H-imidazole (TOLYLI) under solvent-free strategy and room temperature condition for the conversion of excellent yields. The imidazole N-oxides which are usually used as starting compound are easily prepared under of our previously reported protocol [38] (Scheme 2-Fig.S3- supporting material). In our protocol we have used oxalyl chloride as a chlorinating agent and imidazole N-oxide (2:1), mixtures are crushed in a mortar and pestle in presence of a base (1.5 equivalent of the starting compound) under solvent-free condition (Scheme 1-Fig. S3-supporting material). In our biological examines, we have found the anti-bacterial activities against gram positive or gram negative bacteria. TOLYLI compound reveals anti-bacterial activity against all four bacterial strain in both gram positive and gram negative bacteria. Whereas PHENYLI compound showed in gram positive and gram negative bacteria both with very good immense and has more sensitive. MIC (mg/ml) values of the compounds are shown in Table 1.

4.1. Geometrical parameters The optimized structures and geometrical parameters of PHENYLI and TOLYLI are given in Fig. 3 and Table 2 and have C1 point group with 69 and 78 of freedom, respectively. The CeC bond lengths of the phenyl ring lie in the range 1.3983e1.3969 Å for PHENYLI and 1.4071e1.3953 Å for TOLYLI. For the title compounds, PHENYLI and TOLYLI, the bonds C13eN23 ¼ 1.3070 Å and Table 1 Anti-bacterial activity against gram positive and gram negative bacteria. -Compounds MIC(mg/ml) Bacillus

Staphylococcus Pseudomonas E.coli

e

Subtilis

Aureus

PHENYLI TOLYLI

(MTCC1305) (MTCC1144) 100 200 750 700

fluorescencs

K12(MTCC1265)

(MTCC 103) e 400

750 800

Fig. 3. Optimized geometries of (a) 2-chloro-4,5-dimethyl-1-phenyl-1H-imidazole (PHENYLI) and (b) 2-chloro-4,5-dimethyl-1-(o-tolyl)-1H-imidazole (TOLYLI).

226


Table 2 Optimized geometrical parameters (DFT) of the title compounds. 2-chloro-4,5-dimethyl-1-phenyl-1H-imidazole (PHENYLI) Bond lengths (Ǻ)rowhead C1eC2 1.3969 C2eC3 1.3976 C3eN11 1.4373 C5eC6 1.3983 N11eC12 1.4163 C12eC15 1.378 C14eH16 1.0892 C15eC19 1.4921 C19eH21 1.0906 C31eH33 1.0898 Bond angles ( )rowhead C2eC1eC6 120.1 C1eC2eC3 119.7 C2eC3eC4 120.5 C3eC4eC5 119.7 C4eC5eC6 120.1 C1eC6eC5 120.0 C3eN11eC12 126.3 N11eC12eC14 122.0 N11eC13eN23 113.1 C12eC14eH16 109.8 H16eC14eH17 107.6 C12eC15eC19 130.0 C15eC19eH20 111.0 H20eC19eH21 108.0 C13eN23eC15 105.6 Dihedral angles ( )rowhead C6eC1eC2eC3 0.1 C1eC2eC3eN11 179.4 C2eC3eN11eC12 89.7 C4eC3eN11eC13 90.3 C3eN11eC12eC14 0.0 C13eN11eC12eC15 0.0 C12eN11eC13eN23 0.0 N11eC12eC15eN23 0.0 N11eC13eN23eC15 0.0 C19eC15eN23eC13 180.0

C1eC6 C2eH8 C4eC5 C5eH10 N11eC13 C13eN23 C14eH17 C15eN23 C19eH22 C31eH34

1.3983 1.0815 1.3969 1.0817 1.3788 1.307 1.0933 1.408 1.0923 1.0912

C1eH7 C3eC4 C4eH9 C6eH25 C12eC14 C13eCl24 C14eH18 C19eH20 C31eH32

1.0817 1.3976 1.0815 1.0821 1.4924 1.7883 1.0933 1.0924 1.0859

C2eC1eH7 C1eC2eH8 C2eC3eN11 C3eC4eH9 C4eC5eH10 C1eC6eH25 C3eN11eC13 N11eC12eC15 N11eC13eCl24 C12eC14eH17 H16eC14eH18 C12eC15eN23 C15eC19eH21 H20eC19eH22

119.8 120.9 119.8 119.5 119.8 120.0 127.9 105.7 121.7 112.2 107.6 109.9 111.6 107.2

C6eC1eH7 C3eC2eH8 C4eC3eN11 C5eC4eH9 C6eC5eH10 C5eC6eH25 C12eN11eC13 C14eC12eC15 N23eC13eCl24 C12eC14eH18 H17eC14eH18 C19eC15eN23 C15eC19eH22 H21eC19eH22

120.2 119.5 119.8 120.9 120.2 120.0 105.7 132.3 125.2 112.2 107.3 120.2 110.9 108.0

C2eC1eC6eC5 C2eC3eC4eC5 C2eC3eN11eC13 C3eC4eC5eC6 C3eN11eC12eC15 C3eN11eC13eN23 C12eN11eC13eCl24 C14eC12eC15eC19 Cl24eC13eN23eC15

0.1 0.0 90.3 0.1 180.0 180.0 180.0 0.0 180.0

C1eC2eC3eC4 N11eC3eC4eC5 C4eC3eN11eC12 C4eC5eC6eC1 C13eN11eC12eC14 C3eN11eC13eCl24 N11eC12eC15eC19 C14eC12eC15eN23 C12eC15eN23eC13

0.0 179.4 89.7 0.1 180.0 0.0 180.0 180.0 0.0

1.4034 1.4071 1.4392 1.3971 1.4159 1.3784 1.0893 1.4922 1.0906 1.0899

C1eC6 C2eC25 C4eC5 C5eH9 N10eC12 C12eN22 C13eH16 C14eN22 C18eH21 C25eH28

1.3965 1.5098 1.3953 1.0816 1.3774 1.3074 1.0934 1.408 1.0925 1.0913

C1eH7 C3eC4 C4eH8 C6eH24 C11eC13 C12eCl23 C13eH17 C18eH19 C25eH26

1.0827 1.3972 1.0817 1.0821 1.4926 1.7894 1.0933 1.0922 1.0932

121.5 117.5 121.4 120.1 119.4 120.1 126.3 122.0 113.2 109.8 107.6 130.0 111.0 108.1 105.5 111.8 108.2

C2eC1eH7 C1eC2eC25 C2eC3eN10 C3eC4eH8 C4eC5eH9 C1eC6eH24 C3eN10eC12 N10eC11eC14 N10eC12eCl23 C11eC13eH16 H15eC13eH17 C11eC14eN22 C14eC18eH20 H19eC18eH21 C2eC25eH26 H26eC25eH27

118.9 121.1 119.7 119.1 120.1 119.8 128.0 105.8 121.7 112.2 107.6 109.9 111.6 107.2 111.2 107.7

C6eC1eH7 C3eC2eC25 C4eC3eN10 C5eC4eH8 C6eC5eH9 C5eC6eH24 C11eN10eC12 C13eC11eC14 N22eC12eCl23 C11eC13eH17 H16eC13eH17 C18eC14eN22 C14eC18eH21 H20eC18eH21 C2eC25eH27 H26eC25eH28

119.7 121.4 118.8 120.8 120.5 120.1 105.7 132.2 125.2 112.2 107.2 120.1 111.0 108.0 110.8 106.9

0.1 0.1 1.7 94.4 96.2

C6eC1eC2eC25 C1eC2eC3eN10 C2eC3eC4eC5 C2eC3eN10eC12 C3eC4eC5eC6

179.1 179.1 0.1 84.5 0.0

C2eC1eC6eC5 C25eC2eC3eC4 N10eC3eC4eC5 C4eC3eN10eC11 C4eC5eC6eC1

0.0 179.1 179.2 84.9 0.1

2-chloro-4,5-dimethyl-1-(o-tolyl)-1H-imidazole (TOLYLI) Bond lengths (Ǻ)rowhead C1eC2 C2eC3 C3eN10 C5eC6 N10eC11 C11eC14 C13eH15 C14eC18 C18eH20 C25eH27 Bond angles ( )rowhead C2eC1eC6 C1eC2eC3 C2eC3eC4 C3eC4eC5 C4eC5eC6 C1eC6eC5 C3eN10eC11 N10eC11eC13 N10eC12eN22 C11eC13eH15 H15eC13eH16 C11eC14eC18 C14eC18eH19 H19eC18eH20 C12eN22eC14 C2eC25eH28 H27eC25eH28 Dihedral angles ( )rowhead C6eC1eC2eC3 C1eC2eC3eC4 C25eC2eC3eN10 C2eC3eN10eC11 C4eC3eN10eC12


227

Table 2 (continued ) 2-chloro-4,5-dimethyl-1-(o-tolyl)-1H-imidazole (TOLYLI) C3eN10eC11eC13 C12eN10eC11eC14 C11eN10eC12eN22 N10eC11eC14eN22 N10eC12eN22eC14 C18eC14eN22eC12

1.1 0.0 0.1 0.0 0.1 179.7

C3eN10eC11eC14 C3eN10eC12eN22 C11eN10eC12eCl23 C13eC11eC14eC18 Cl23eC12eN22eC14

C12eN22 ¼ 1.3074 Å have some double bond characters. However, C13eN11 ¼1.3788 Å, C12eN11 ¼1.4163 Å, C15eN23 ¼ 1.4080 Å for PHENYLI and C12eN10 ¼ 1.3774 Å, C11eN10 ¼ 1.4159 Å, C14eN22 ¼ 1.4080 Å for TOLYLI [55]. The CeCl bond lengths are 1.7883 Å and 1.7894 Å for PHENYLI and TOLYLI. For PHENYLI, the bond angles around N11 are: C12eN11eC13 ¼ 105.7, C3eN11eC12 ¼ 126.3 , C13eN11eC3 ¼ 127.9 and for TOLYLI, the bond angles around N10 are: C11eN10eC12 ¼ 105.7, C11eN10eC3 ¼ 126.3 , C12eN10eC3 ¼ 128.0 and this asymmetry in angles reveal the interaction between phenyl ring and imidazole ring. Around C12 and C15 for PHENYLI, the bond angles are: N11eC12eC15 ¼ 105.7, N11eC12eC14 ¼ 122.0 , C15eC12eC14 ¼ 132.3 and C12eC15eN23 ¼ 109.9 , C12eC15eC19 ¼ 130.0 , N23eC15eC19 ¼ 120.3 and this asymmetry in angles reveal the interaction between the methyl groups and the imidazole group. The same interaction is also present in TOLYLI as given by the bond angles around C11 and C14 (N10eC11eC14 ¼ 105.8 , N10eC11eC13 ¼ 122.0 , C14eC11eC13 ¼ 132.2 and C11eC14eN22 ¼ 109.9 , C11eC14eC18 ¼ 130.0 , N22eC14eC18 ¼ 120.1 ). The phenyl ring and the imidazole ring are tilted from each other as is evident from the torsion angles: C2eC3e N11eC12 ¼ 89.8 , C2eC3eN11eC13 ¼ 90.2 , C4eC3e N11eC12 ¼ 89.8 , C4eC3eN11eC13 ¼ 90.2 for PHENYLI and C2eC3eN16eC17 ¼ 87.0 , C2eC3eN16eC18 ¼ 93.2 , C4eC3N16eC17 ¼ 92.6 , C4eC3eN16eC18 ¼ 87.2 for TOLYLI.

4.2. IR and Raman spectra The wavenumbers (theoretical, IR and Raman) and vibrational assignments of PHENYLI and TOLYLI are given in Table 3. The phenyl ring and imidazole rings are designated as PhI and PhII, respectively in the following discussion. Out of six phenyl ring stretching vibrations (yPh), the four modes near 1600 cm1, 1580 cm1, 1490 cm1 and 1440 cm1 are good group vibrations [56,57]. The sixth ring stretching vibration (ring breathing mode) is near 1000 cm1, in mono, 1,3-di and 1,3,5-trisubstituted benzenes. The yPh modes are assigned at 1576 cm1, 1561 cm1, 1483 cm1, 1438 cm1, 1279 cm1 for PHENYLI and at 1579 cm1, 1554 cm1, 1482 cm1, 1437 cm1, 1276 cm1 for TOLYLI, theoretically (B3LYP). Experimentally bands are observed at 1559 cm1, 1277 cm1 (IR), 1580 cm1, 1565 cm1, 1442 cm1, 1276 cm1 (Raman) for PHENYLI and at 1554 cm1, 1277 cm1 (IR), 1487 cm1 (Raman) for TOLYLI. The DFT calculations give ring breathing modes at 980 cm1 for PHENYLI and at 1031 cm1 for TOLYLI as expected [57] and reported values are at 1041 cm1 [58] and 1011 cm1 [59] and at 1020 cm1 [60]. DFT calculations give phenyl CeH deformations at 1320 cm1, 1168 cm1, 1164 cm1, 1063 cm1, 1017 cm1 for PHENYLI, 1281 cm1, 1165 cm1, 1109 cm1, 1031 cm1 for TOLYLI (in-plane) and at 990 cm1, 974 cm1, 924 cm1, 844 cm1, 787 cm1 for PHENYLI, 983 cm1, 945 cm1, 870 cm1, 740 cm1 for TOLYLI (outof-plane). Experimentally these modes are observed at: 1164 cm1, 1068 cm1 (IR), 1159 cm1 (Raman) for PHENYLI, 1164 cm1, 1099 cm1, 1033 cm1 (IR), 1288 cm1, 1163 cm1, 1030 cm1 (Raman) for TOLYLI (in-plane deformation) and at 992 cm1, 850 cm1, 790 cm1 (IR), 972 cm1, 923 cm1, 847 cm1, 788 cm1

179.1 179.1 180.0 0.2 180.0

C12eN10eC11eC13 C3eN10eC12eCl23 N10eC11eC14eC18 C13eC11eC14eN22 C11eC14eN22eC12

179.9 1.0 179.6 179.8 0.1

(Raman) for PHENYLI, 942 cm1, 865 cm1, 750 cm1 (IR), 745 cm1 (Raman) for TOLYLI (out-of-plane deformation). Expected values of yCH3 modes are in the range 3050e2800 cm1 [57,61], the observed values of PHENYLI are at 2955 cm1, 2910 cm1, 2875 cm1 (IR), 2990 cm1, 2955 cm1, 2914 cm1, 2880 cm1 (Raman) and for TOLYLI are at 2955 cm1, 2928 cm1, 2870 cm1 (IR), 2973 cm1, 2934 cm1, 2890 cm1 (Raman). The DFT calculations give these modes in the range 2989e2894 cm1 for PHENYLI and 2989-2894 cm1 for TOLYLI. Bending modes of CH3 are assigned at 1455 cm1, 1392 cm1, 1040 cm1 (IR), 1460 cm1, 1393 cm1,1038 cm1 (Raman), 1470-960 cm1 (DFT) for PHENYLI and 1455 cm1, 1390 cm1, 1065 cm1, 994 cm1 (IR), 1415 cm1, 1394 cm1, 1062 cm1, 1000 cm1, 966 cm1 (Raman), 1470962 cm1 (DFT) for TOLYLI as expected in literature [57]. The yC ¼ C and yC ¼ N modes are assigned at 1570 cm1, 1409 cm1 for PHENYLI and at 1569 cm1, 1409 cm1 for TOLYLI (DFT). The DFT calculations give yC-N modes at 1351 cm1, 1326 cm1, 1215 cm1, 1183 cm1 for PHENYLI and at 1346 cm1, 1326 cm1, 1216 cm1, 1180 cm1 for TOLYLI. The reported values of C]N stretching modes for a imidazole derivate are 1464 cm1 (DFT), 1462 cm1 (IR), 1464 cm1 (Raman) [62]. The presence of IR bands in the region 1700-2700 cm1 and their large broadening may be due hydrogen bonding in system [63]. The RMS errors of the observed Raman bands and IR bands are found to be 6.22 and 7.57 for PHENYLI and 4.24 and 9.77 for TOLYLI. The small difference between the calculated and experimental vibrational modes was that the experimental results belong to solid phase and theoretical calculations belong to gaseous phase.

4.3. NMR spectra PHENYLI: In 1H NMR spectrum of the title compound two types of signals of proton appears in the aromatic and aliphatic region. Normally aromatic proton appears in 7e8 ppm region. Here five aromatic proton of phenyl scaffold were seen as two proton doublet, two proton doublet of doublet and one proton triplet in region of 7.35e7.60 ppm. The signals due to six protons of two methyl groups on imidazole moiety appeared as singlet in the regions of 2.08 and 1.91 ppm. In 13C NMR spectrum of the title compound, there are nine types of carbon present. The signals appear in the region 9.85 and 12.97 ppm due to two non-aromatic carbon atoms. Signals due to seven carbon atoms on phenyl and imidazole moiety appeared between 126.09 and 135.47 ppm. TOLYLI: In 1H NMR spectrum of the given compound two types of signals of proton appears in the aromatic and aliphatic region. Here four aromatic proton of phenyl scaffold were seen as one proton doublet, one proton doublet of doublet, one proton doublet of doublet and one proton doublet in region of 7.26e7.50 ppm. The signals due to nine protons of three methyl groups on imidazole and phenyl moiety appeared as singlet in the regions of 2.11, 1.97 and 1.84 ppm. In 13C NMR spectrum of the title compound, there are twelve types of carbon present. The signals appear in the region 8.95, 12.32 and 16.63 ppm due to three non-aromatic carbon atoms. Signals due to nine carbon atoms on phenyl and imidazole moiety appeared between 125.49 and 135.75 ppm.

228


Table 3 Calculated scaled wavenumbers, observed IR, Raman bands and assignments of the title compounds. B3LYP/6e311þþG (5D, 7F)

IR

Raman

Assignmentsa

n(cm-1)

n(cm-1)

n(cm-1)

e

3105 e e 3053 e e e 2955 e 2910 2875 e e 1559 e e e e 1455 e e e 1392 1353 e e 1277 1220 1180 e 1164 e 1068 e 1040 e e 992 e e e 948 e 850 790 745 702 e 664 e 620 614 577 465 e e e e e e e e e e e e e e e

3076 e e 3053 3020 2990 e 2955 e 2914 2880 1580 e 1565 e e e e 1460 1442 e e 1393 1354 1327 e 1276 1220 1180 e 1159 1122 e e 1038 e e e 1000 972 e e 923 847 788 735 e e 659 e 620 612 e 458 e e 414 344 312 264 241 201 170 e e e e e e

yCHI(99) yCHI(100) yCHI(91) yCHI(99) yCHI(91) yasCH3(98) yasCH3(99) yasCH3(100) yasCH3(100) ysCH3(98) ysCH3(98) yPhI(52), dCHI(12) yPhII(C]C)(52), yCC(18) yPhI(68), dCHI(10) yPhI(45), dCHI(16) dasCH3(84) dasCH3(81) dasCH3(96) dasCH3(95) yPhI(52), dCHI(19) yPhII(C]N)(43), dsCH3(32) dsCH3(91) dsCH3(53), yPhII(C]N)(24) yPhII(CN)(42), yCN(31, yPhII(CN)(47), yCC(29) dCHI(81), yPhI(12) yPhI(86) yPhII(CN)(49), yPhI(19) yPhII(CN)(41), yCC(13), dCH3(13) dCHI(76), yPhI(10) dCHI(74), yPhI(16) dCH3(32), yPhII(CN)(21), yCC(13) dCHI(52), yPhI(22) dCH3(75) dCH3(88) dCHI(68), yPhI(16) dCH3(61) gCHI(80), tPhI(16) yPhI(64), gCHI(12) gCHI(90) dCH3(47), yPhII(CN)(17) yPhII(CN)(49), dPhII(32), dCH3(11) gCHI(74), tPhI(11) gCHI(100) gCHI(59), tPhI(25), gCN(17) tPhI(31), yCC(23) tPhI(28), gCHI(28), dPhI(12) tPhI(50), dPhI(12), gCHI(12) tPhII(55), gCCl(15) tPhII(61), gCC(29) dPhI(62),tPhII(18) dPhII(39), yCC(29), dPhI(23) tPhI(30), dCC(16), dCN(13) tPhI(38), dCC(22), gCN(19), dCCl(10) dCN(41), gCCl(13), gCC(11) tPhI(83) yCCl(61) dPhII(36), dPhI(31) gCC(67), gCCl(21) dCC(79) tPhI(46), dCC(18), dCN(11) gCC(49), tPhII(16), dCN(11) dCCl(56), dCC(13) gCCl(50), gCC(28), tPhII(11) tCH3(92) tCH3(82) gCN(42), dCN(41) gCN(75), dCN(11) tCN(76)

IRI RA 2-chloro-4,5-dimethyl-1-phenyl-1H-imidazole (PHENYLI)rowhead 3078 0.07 3.26 3069 0.19 0.02 3060 0.25 0.55 3051 0.05 1.18 3041 0.00 0.38 2989 0.24 0.85 2976 0.22 0.54 2953 0.19 1.10 2939 0.16 0.66 2901 0.43 3.40 2894 0.38 1.54 1576 0.19 0.52 1570 0.09 0.24 1561 0.03 0.11 1483 0.61 0.03 1470 0.03 0.07 1466 0.11 0.40 1464 0.20 0.14 1458 0.02 0.07 1438 0.04 0.01 1409 1.05 0.04 1408 0.16 0.17 1394 0.98 0.34 1351 0.54 0.59 1326 0.02 0.06 1320 0.00 0.01 1279 0.02 0.00 1215 0.85 0.05 1183 0.13 0.06 1168 0.02 0.04 1164 0.00 0.02 1125 0.05 0.06 1063 0.07 0.00 1059 0.01 0.00 1047 0.01 0.00 1017 0.04 0.02 1005 0.06 0.02 990 0.00 0.02 980 0.00 0.52 974 0.00 0.00 960 0.06 0.03 952 0.12 0.05 924 0.04 0.00 844 0.00 0.00 787 0.13 0.01 739 0.23 0.01 700 0.40 0.04 693 0.16 0.07 661 0.01 0.02 641 0.01 0.01 617 0.00 0.03 616 0.00 0.02 574 0.19 0.01 462 0.02 0.01 418 0.00 0.01 414 0.00 0.00 413 0.07 0.19 336 0.02 0.08 309 0.03 0.01 262 0.01 0.02 244 0.00 0.02 200 0.02 0.01 183 0.00 0.01 131 0.02 0.00 117 0.00 0.01 72 0.00 0.01 69 0.01 0.04 58 0.00 0.02 19 0.00 0.08


B3LYP/6e311þþG (5D, 7F)

n(cm-1)

IRI

RA

2-chloro-4,5-dimethyl-1-(o-tolyl)-1H-imidazole (TOLYLI)rowhead 3072 0.16 2.55 3059 0.28 0.70 3048 0.09 1.07 3036 0.04 0.51 2989 0.23 0.83 2983 0.23 0.53 2976 0.22 0.53 2958 0.13 0.50 2953 0.19 1.10 2939 0.16 0.61 2903 0.18 1.71 2901 0.44 3.34 2894 0.37 1.49 1579 0.02 0.33 1569 0.13 0.30 1554 0.01 0.20 1482 0.54 0.06 1470 0.04 0.06 1467 0.13 0.11 1467 0.05 0.26 1466 0.19 0.25 1464 0.17 0.04 1458 0.03 0.07 1437 0.11 0.03 1410 0.39 0.14 1409 0.56 0.09 1401 0.12 0.09 1393 1.07 0.32 1346 0.54 0.55 1326 0.02 0.06 1281 0.05 0.02 1276 0.03 0.04 1216 0.76 0.08 1189 0.17 0.08 1180 0.03 0.06 1165 0.01 0.04 1129 0.05 0.05 1109 0.04 0.01 1059 0.00 0.00 1052 0.06 0.00 1047 0.01 0.00 1031 0.04 0.16 996 0.05 0.14 985 0.01 0.04 983 0.00 0.00 962 0.07 0.02 955 0.04 0.01 945 0.12 0.01 870 0.00 0.00 792 0.00 0.09 780 0.17 0.00 740 0.46 0.01 719 0.06 0.01 682 0.04 0.13 661 0.02 0.01 640 0.01 0.01 620 0.00 0.02 581 0.08 0.01 545 0.01 0.08 489 0.05 0.00 455 0.00 0.03 447 0.04 0.01 411 0.07 0.16 359 0.00 0.05 317 0.02 0.03 294 0.02 0.02 275 0.01 0.03 259 0.02 0.00 194 0.02 0.01 185 0.02 0.01 164 0.01 0.01 135 0.00 0.00 125 0.01 0.00

229

IR

Raman

Assignmentsb

n(cm-1)

n(cm-1)

e

3105 3056 e e e e e e 2955 2928 e e 2870 e e 1554 e e e e e e 1455 e e e e 1390 1350 e e 1277 1220 e 1178 1164 e 1099 1065 e e 1033 994 e e e e 942 865 795 e 750 710 e 664 e 624 579 e 482 e e e e e e e e e e e e e

3078 3065 e e e e 2973 e e 2934 e e 2890 e 1567 e 1487 e e e e e e e 1415 e e 1394 1350 e 1288 e 1212 e e 1163 1125 e 1062 e e 1030 1000 e e 966 e e e e 783 745 710 e 660 e 624 e 540 493 e 446 412 363 e 296 e 262 e e 158 e e

yCHI(96) yCHI(99) yCHI(95) yCHI(97) yasCH3(99) yasCH3(96) yasCH3(98) yasCH3(99) yasCH3(99) yasCH3(100) ysCH3(99) ysCH3(98) ysCH3(98) yPhI(63), dCHI(15) yPhII(C]C)(57), yCC(20) yPhI(61), dCHI(14) yPhI(55), dCH3(16), dCHI(13) dasCH3(85) dasCH3(64) dasCH3(62) dasCH3(77) dasCH3(86) dasCH3(95) yPhI(51), dCHI(19) dsCH3(80) yPhII(C]N)(41), dsCH3(18) dsCH3(87) dsCH3(46), yPhII(C]N)(29) yPhII(CN)(29), yCN(28) yPhII(CN)(48), yCC(28) dCHI(53), yPhI(17) yPhI(64), dCHI(18) yPhII(CN)(46), dCHI(22) yCC(23), yPhII(CN)(22) yPhII(CN)(44), yCC(16) dCHI(81), yPhI(13) dCH3(23), yPhII(CN)(19), yCC(12) dCHI(57), yPhI(17), dCH3(16) dCH3(76) dCH3(66) dCH3(86) yPhI(44), dCHI(43) dCH3(51), dPhI(23), yPhI(11) dCH3(44), yPhI(15) gCHI(78), tPhI(12) dCH3(49), yPhII(CN)(14) gCHI(36), dPhII(15), dCH3(10) gCHI(55), dPhII(17) gCHI(83) dPhI(37), yCC(21) gCHI(29), tPhI(21), gCN(15) gCHI(66), yCC(14) tPhI(52), gCC(10) dPhI(46), yCC(10) tPhII(57), gCCl(16) tPhII(60), gCC(30) dPhII(35), dPhI(27),yCC(27) tPhI(41), dCC(13), dCN(11) dPhI(45), yCC(13), tPhII(10) tPhI(39), gCC(23), dCC(14) dCN(27), dCC(25) tPhI(55), gCC(12), gCN(11) yCCl(58) dCC(22), gCC(12), gCCl(11) gCC(36), gCCl(15) gCC(32), dCC(17) tPhI(27), gCC(17), dCC(10) dCC(77) gCC(19), tPhI(19), dCCl(18) tPhI(28), gCC(19), dCCl(10) tPhI(53), dCCl(23) tCH3(87) gCCl(39), gCC(25), tCH3(11), tPhII(11) (continued on next page)

230


Table 3 (continued ) B3LYP/6e311þþG (5D, 7F)

IR

Raman

Assignmentsb

n(cm-1)

IRI

RA

n(cm-1)

n(cm-1)

e

100 76 69 56 32

0.00 0.00 0.01 0.00 0.00

0.00 0.00 0.04 0.02 0.07

e e e e e

105 77 e e e

tCH3(86) tCH3(81) gCN(41), dCN(41) gCN(75), dCN(11) tCN(80)

a

y-stretching; d-in-plane deformation; g-out-of-plane deformation; t-torsion; IRI-IR intensity(KM/Mole); RA-Raman activity(Ǻ4/amu); PhI-phenyl ring; PhII-imidazole

ring. b y-stretching; d-in-plane deformation; g-out-of-plane deformation; t-torsion; as-asymmetric; s-symetric; IRI-IR intensity(KM/Mole); RA-Raman activity(Ǻ4/amu); PhIphenyl ring; PhII-imidazole ring.

4.4. Frontier molecular orbital analysis For the title compounds, the HOMO is delocalized over the entire molecule, except phenyl ring and the LUMO is delocalized over the phenyl ring only (Fig. 4). The chemical descriptors can be evaluated by using HOMO and LUMO orbital energies, EHOMO, and ELUMO as: ionization energy I ¼ -EHOMO, electron affinity A ¼ -ELUMO, hardness h ¼ (I-A)/2, electronegativity c ¼ (I þ A)/2, chemical potential m ¼ - (I þ A)/2 and electrophilicity (u ¼ m2/2h) [64]. The energies of the HOMO, LUMO orbital and energy gap for PHENYLI and TOLYLI are EHOMO ¼ 7.546eV, 7.557eV, ELUMO ¼ 4.584eV, 4.491eV, energy gap ¼ 2.962eV, 3.066eV. The various chemical descriptor for the title compounds are: I, A, h, m, c and u are 7.546eV, 4.584eV, 1.481eV, 6.065eV, 6.065eV, 12.41eV for PHENYLI and 7.557eV, 4.491eV, 1.533eV, 6.024eV, 6.024eV, 11.836eV for TOLYLI. All the descriptors are not different and substitution change in the title compounds does not affect these values. 4.5. MEP and ALIE surfaces and Fukui functions MEP is a valuable tool to visualize the reactive sites in a

compound and is useful in biological studies as well as hydrogen bonding interactions [65]. Optimized molecular structure was used for generation of MEP surface plots of the title compounds and mapped with rainbow color scheme (electron reach regions represent with red color, while electron poor regions represent with blue color). MEP and surface analysis diagram of PHENYLI and TOLYLI are shown in Fig. 5, negative regions are mainly localized over N23 of PHENYLI and N22 of TOLYLI and it is represent with red color in rainbow color scheme (electrophilic) while the maximum positive regions are localized over hydrogen atoms as well as phenyl rings, it is represent with blue color for PHENYLI and TOLYLI (nucleophilic), respectively. Sensitivity of certain pharmaceutical molecules towards electrophilic and nucleophilic attacks is frequently evaluated by calculating the MEP and ALIE values. These quantum molecular descriptors have been frequently used in order to address local reactive properties of molecular systems [31,34,37,66e72]. While MEP descriptor is used somewhat more frequently, ALIE descriptor is more suitable for determination of sensitivity towards electrophilic attacks. Both descriptors in this work have been visualized by their mapping to the electron density surface, as provided in Fig. 5. The values of MEP and ALIE descriptors indicate very similar reactivity of both imidazole

Fig. 4. HOMO-LUMO plots of (a) 2-chloro-4,5-dimethyl-1-phenyl-1H-imidazole (PHENYLI) and (b) 2-chloro-4,5-dimethyl-1-(o-tolyl)-1H-imidazole (TOLYLI).


231

Fig. 5. MEP and ALIE surfaces of investigated imidazole derivatives a) PHENYLI and b) TOLYLI.

derivatives. Concerning the lowest MEP values, they are practically having the same values, while the maximal MEP value is slightly (around 1 kcal/mol) higher in the case of PHENYLI imidazole derivative. The lowest ALIE values are also practically identical, while the maximal value is, again as in the case of MEP, slightly higher in the case of PHENYLI imidazole derivative. Localization of red color for both MEP and ALIE descriptors, which identifies the molecule sites with the lowest values, indicates that the nitrogen atom is the

most sensitive towards electrophilic attacks. Additionally, the ALIE descriptor also recognizes near vicinity of an imidazole ring to be also sensitive towards the electrophilic attacks. The values of Fukui functions as mapped to the electron density surface were also used as local reactivity descriptors in this study. Namely, the Fukui functions were calculated according to the finite difference approximation, as incorporated in the Jaguar program, according to the following equations:

Fig. 6. Fukui functions with their maximal and minimal values of a) PHENYLI and b) TOLYLI imidazole derivatives.

232


Table 4 Second order perturbation theory analysis of Fock matrix in NBO basis corresponding to the intra-molecular bonds of the title compound. Donor

Type

ED/e

Acceptor

2-chloro-4,5-dimethyl-1-phenyl-1H-imidazole (PHENYLI)rowhead C2eC3 s 1.975 C1eC2 e e C3eC4 e e

e

e

C3eN11

e

e

e

N11eC12

e C2eC3

e

e

N11eC13

p

e

e

1.675 e

C1eC6 C4eC5

e

e

e

N11eC12

e C3eC4

e

e

N11eC13

s

e

e

1.975 e

C2eC3 C3eN11

e

e

e

C4eC5

e

e

e

N11eC12

e C12eC15

e

e

N11eC13

s

e

e

1.978 e

C3eN11 N11eC12

e

e

e

C12eC14

e

e

e

C13 eCl24

e

e

e

C15eC19

e C13eN23

p s

1.848

C13eN23

e

e

1.986 e

C3eN11 N11eC13

e

e

e

C15eC19

e

e

e

C15eN23

e

p

1.893

C12eC15

e C3eN11

e

e

C13eN23

s

e

e

1.984 e

C1eC2 C2eC3

e

e

e

C3eC4

e

e

e

C4eC5

e

e

e

N11eC12

e

e

e

N11eC13

e

e

e

C12eC15

e N11eC13

e

e

C13eN23

s

e

e

1.982 e

C2eC3 C3eN11

e

e

e

N11eC12

e

e

e

C12eC14

e C12eC14

e

e

C13eN23

s

e

e

1.985 e

N11eC12 N11eC13

e

e

e

C12eC15

e C13eCl24

e

e

C15eN23

s

1.988 e

N11eC12 C15eN23

e

e C15eC19

s

e

e

1.984 e

N11eC12 C12eC15

e

e

e

C13eN23

e LPN11

e

e

C15eN23

s

e

e

1.597 e

C2eC3 C3eC4

e

e

e

C12eC15

e LPN23

e

e

C13eN23

s

e

e

1.914 e

C3eN11 N11eC13

e

e

e

C12eC14

e

e

e

C12eC15

e

e

e

C13eCl24

e LPCl24

e

e

C15eC19

s

e

e

1.993 e

N11eC13 C13eN23

p

1.962

N11eC13

Type

ED/e

E(2)a

E(j)-E(i)b

F(i,j)c

s* s* s* s* s* p* p* s* s* s* s* s* s* s* s* s* s* s* s* s* s* s* s* s* p* p* s* s* s* s* s* s* s* s* p* s* s* s* s* s* s* s* s* s* s* s* s* s* s* s* s* p* p* s* s* s* s* s* s* s* s* s*

0.014 0.026

2.45 3.70

1.28 1.27

0.050 0.061

0.039

1.07

1.10

0.031

0.036

0.90

1.13

0.029

0.065

0.96

1.14

0.030

0.323 0.320

18.75 20.52

0.29 0.29

0.066 0.069

0.036

2.70

0.68

0.041

0.065

2.93

0.70

0.043

0.026 0.039

3.70 1.07

1.27 1.10

0.061 0.031

0.014

2.45

1.28

0.050

0.036

0.91

1.13

0.029

0.065

0.96

1.14

0.030

0.039 0.036

4. 36 0.63

1.09 1.12

0.062 0.024

0.017

3.31

1.14

0.055

0.059

0.99

0.82

0.026

0.018

2.73

1.15

0.050

0.020

13.92

0.26

0.058

0.039 0.065

3.27 0.90

1.23 1.28

0.057 0.031

0.018

3.77

1.30

0.063

0.022

0.58

1.31

0.025

0.301

17.10

0.36

0.074

0.407

0.67

0.31

0.014

0.014 0.026

1.40 1.08

1.35 1.34

0.039 0.034

0.026

1.08

1.34

0.034

0.014

1.40

1.35

0.039

0.036

1.81

1.20

0.042

0.065

1.99

1.21

0.044

0.030

0.70

1.40

0.028

0.020

1.08

1.35

0.034

0.364 0.039

0.99 2.70

0.83 1.20

0.028 0.051

0.036

1.48

1.23

0.038

0.017

3.26

1.25

0.057

0.020

0.67

1.38

0.027

0.036 0.065

0.56 2.00

1.06 1.08

0.022 0.042

0.030

3.83

1.26

0.062

0.022

1.32

1.11

0.034

0.036 0.022

1.93 2.25

1.11 1.16

0.042 0.046

0.036 0.030

1.71 3.26

1.04 1.24

0.038 0.057

0.020

1.72

1.20

0.041

0.022

0.66

1.09

0.024

0.026 0.026

5.60 5.60

0.82 0.82

0.067 0.067

0.301

28.00

0.31

0.085

0.407

48.13

0.26

0.102

0.039 0.065

0.62 9.96

0.73 0.78

0.019 0.079

0.017

0.50

0.78

0.018

0.030

5.38

0.96

0.065

0.059

1.82

0.46

0.026

0.018

0.90

0.80

0.024

0.065 0.020

1.01 1.44

1.34 1.48

0.033 0.041

0.065

6.56

0.74

0.063


233

Table 4 (continued ) Donor

Type

ED/e

Acceptor

e e C13eN23 e n 1.938 C13eN23 e 2-chloro-4,5-dimethyl-1-(o-tolyl)-1H-imidazole (TOLYLI)rowhead C2eC3 s 1.971 C1eC2 e e C2eC25 e e

e

e

C3eC4

e

e

e

C3eN10

e

e

e

N10eC11

e C3eC4

e

e

N10eC12

s

e

e

1.974 e

C2eC3 C2eC25

e

e

e

C3eN10

e

e

e

C4eC5

e

e

e

N10eC11

e C3eC4

e

e

N10eC12

p

e

e

1.686 e

C1eC2 C5eC6

e

e

e

N10eC11

e C11eC14

e

e

N10eC12

s

e

e

1.978 e

C3eN10 N10eC11

e

e

e

C11eC13

e

e

e

C12 eCl23

e

e

e

C14eC18

e C12eN22

p s

1.848

C12eN22

e

e

1.986 e

C3eN10 N10eC12

e

e

e

C14eC18

e

e

e

C14eN22

e

p

1.892

C11eC14

e C3eN10

e

e

C12eN22

s e

1.984 e

C1eC2 C2eC3

e

e

C3eC4

e

e

C4eC5

e

e

N10eC11

e

e

N10eC12

e

e

C11eC14

s e

e 1.982 e

C12eN22 C3eC4 C3eN10

e

e

N10eC11

e

e

C11eC13

e

e

C12eN22

s e

1.985 e

N10eC11 N10eC12

e

e

C11eC14

e

e

C14eN22

s e

1.988 e

N10eC11 C14eN22

s

1.985

N10eC11 C11eC14

e

e

C12eN22

e

e

C14eN22

s e

1.593 e

C2eC3 C3eC4

e

e

C11eC14

e

e

C12eN22

s e

1.915 e

C3eN10 N10eC12

e

e

C11eC13

e

e

C11eC14

e

e

C12eCl23

N10eC12

C11eC13

C12eCl23 C14eC18

e

LPN10

LPN22

Type

ED/e

E(2)a

E(j)-E(i)b

F(i,j)c

s* p*

0.020

4.93

0.88

0.059

0.407

13.58

0.32

0.065

s* s* s* s* s* s* s* s* s* s* s* s* p* p* s* s* s* s* s* s* s* p* s* s* s* s* p* p* s* s* s* s* s* s* s* s* p* s* s* s* s* s* s* s* s* s* s* s* s* s* s* s* s* p* p* s* s* s* s* s*

0.021 0.014

2.94 1.67

1.27 1.12

0.055 0.039

0.024

3.83

1.27

0.062

0.039

1.15

1.09

0.032

0.037

1.04

1.12

0.030

0.064

0.85

1.14

0.028

0.034 0.014

4.26 2.88

1.27 1.12

0.066 0.051

0.039

1.03

1.09

0.030

0.014

2.53

1.28

0.051

0.037

0.80

1.12

0.027

0.064

1.12

1.14

0.032

0.330 0.329

20.89 17.93

0.29 0.29

0.070 0.065

0.037

2.72

0.68

0.041

0.064

2.99

0.69

0.044

0.039 0.037

4. 30 0.63

1.09 1.12

0.061 0.024

0.017

3.31

1.14

0.055

0.059

1.01

0.81

0.026

0.018

2.74

1.15

0.050

0.409

13.86

0.26

0.058

0.039 0.064

3.24 0.92

1.24 1.28

0.057 0.031

0.018

3.78

1.30

0.063

0.022

0.58

1.31

0.025

0.302

17.14

0.36

0.074

0.409

0.67

0.31

0.014

0.021 0.034

1.62 1.24

1.35 1.34

0.042 0.037

0.024

1.08

1.34

0.034

0.014

1.44

1.35

0.039

0.037

1.83

1.20

0.042

0.064

2.02

1.21

0.045

0.030

0.71

1.39

0.028

0.020 0.366 0.039

1.12 0.94 2.77

1.35 0.84 1.20

0.035 0.028 0.052

0.037

1.51

1.23

0.039

0.017

3.29

1.25

0.057

0.020

0.69

1.38

0.028

0.037 0.064

0.57 2.00

1.06 1.08

0.022 0.042

0.030

3.82

1.26

0.062

0.022

1.32

1.11

0.034

0.037 0.022

1.94 2.24

1.11 1.16

0.042 0.046

0.037 0.030

1.72 3.26

1.05 1.24

0.038 0.057

0.020

1.72

1.20

0.041

0.022

0.66

1.09

0.024

0.034 0.024

5.68 5.20

0.82 0.82

0.067 0.065

0.302

28.04

0.31

0.085

0.409

49.54

0.26

0.102

0.038 0.064

0.62 9.94

0.74 0.78

0.019 0.079

0.017

0.50

0.78

0.018

0.030

5.38

0.96

0.065

0.059

1.82

0.46

0.026

(continued on next page)

234


Table 4 (continued ) Donor

Type

LPCl23

ED/e

s* s* s* s* s* p*

0.018 0.064 0.020 0.064 0.020

e

C14eC18

1.993 e

N10eC12 C12eN22

1.962 e

N10eC12 C12eN22

1.938

C12eN22

p

c

ED/e

s

e n b

Type

e e

a

Acceptor

0.409

E(2)a

E(j)-E(i)b

F(i,j)c

0.90

0.80

0.024

1.02 1.41

1.35 1.48

0.034 0.041

6.44 4.95

0.75 0.88

0.062 0.059

13.42

0.32

0.065

E(2) means energy difference of hyper-conjugative interactions (stabilization energy in kJ/mol). Energy difference (a.u.) between donor and acceptor i and j NBO orbitals. F(i,j) is the Fock matrix elements (a.u.) between i and j NBO orbitals.

fþ ¼

rNþd ðrÞ

rN ðrÞ

;

(1)

rNd ðrÞ rN ðrÞ f ¼ ; d

(2)

d

where N is the number of electrons in the reference state of molecule anddis fraction of electron which default value is set to be 0.01 [73]. Fukui functions with corresponding values mapped to the electron density surface are presented in Fig. 6. In general, Fukui function provides information how electron density changes with the addition or removal of the charge. The location of purple color in case of the Fukui fþ function identifies molecule sites where electron density increased after the addition of charge. On the other side, the location of red color in case of the Fukui fe function identifies molecule sites where electron density decreased after the removal of charge. It can be seen in Fig. 6 in case of Fukui fþ function that both imidazole derivatives are characterized with blue-topurple color above the benzene ring, indicating molecule area where electron density increased after the charge addition. On the other hand, regarding the Fukui fe function, the area connecting benzene and imidazole ring is marked with red color in case of both derivatives, indicating molecule sites where electron density decreased after the removal of charge.

4.6. Nonlinear optical properties The calculated dipole moment and polarizability of PHENYLI and TOLYLI are 5.148 Debye,2.192 1023 and 4.875 Debye, 2.365 1023 esu. The first order hyperpolarizabilities are 1.860 1030 and 1.959 1030 esu for PHENYLI and TOLYLI which are comparable with the reported values of similar derivates [55,62] and these values are 14.31 and 15.07 times that of the standard NLO material urea [74]. The theoretically predicted second order hyperpolarizabilities are 7.305 1037 esu for PHENYLI and 11.399 1037 esu for TOLYLI. Analysis of organic molecules having conjugated p-electron systems and large hyperpolarizability using IR and Raman spectroscopies has evolved as a subject of research [75,76]. In the absence of inversion symmetry, the strongest band in the Raman spectrum is weak in the IR spectrum and vice versa in most cases. But the intra molecular charge transfer from donor to acceptor group through a single-double bond conjugated path can induce large variations of both the molecular dipole moment and the polarizability, making IR and Raman activities strong at the same time. By analyzing the vibrational modes in the IR and Raman spectrum, it is observed that the phenyl ring stretching bands at 1559 cm1, 1353 cm1, 1277 cm1, 1220 cm1, 1180 cm1 for PHENYLI, 1350 cm1, 1220 cm1, 1033 cm1 for TOLYLI observed in IR spectrum have their

counterparts in the Raman spectrum at 1565 cm1, 1354 cm1, 1276 cm1, 1220 cm1, 1180 cm1 for PHENYLI, 1394 cm1, 1350 cm1, 1212 cm1, 1030 cm1 for TOLYLI, respectively and their intensities in IR and Raman spectra are comparable, which leads to the nonlinear optical behavior of the title compounds [77]. Hence the title compounds and its derivatives are good objects for further studies of nonlinear optical properties. 4.7. Natural bond orbital analysis For PHENYLI, the strong intra-molecular hyper-conjugative interactions are:, C13eN23 from N11 of n1(N11)/p*(C13eN23), N11eC13 from N23 of n1(N23)/s*(N11eC13), N11eC13 from Cl24 of n2(Cl24)/ s*(N11eC13), C13eN23 from Cl24 of n3(Cl24)/p*(C13eN23) with electron densities, 0.407, 0.065, 0.065, 0.407e and stabilization energies, 48.13, 9.96, 6.56 and 13.58 kcal/mol. The natural hybrid orbital with higher energy and low occupation number is n2(Cl24) with energy 0.314a.u, p-character, 99.96% and occupation number 1.962 whereas the orbital with lower energy and high occupation number is n1(Cl24) with energy 0.912a.u, p-character 15.91% and occupation number 1.993. Thus, a very close to pure p-type lone pair orbital participates in the electron donation to the p*(C13eN23) orbital for n1(N11)/p*(C13eN23) and n3(Cl24)/p*(C13eN23), s*(N11eC13) orbital for n1(N23)/s*(N11eC13) and n2(Cl24)/ s*(N11eC13) interaction in the compound. For TOLYLI, the strong intra-molecular hyper-conjugative interactions are: C12eN22 from N10 of n1(N10)/p*(C12eN22), N10eC12 from N22 of n1(N22)/s*(N10eC12), N10eC12 from Cl23 of n2(Cl23)/ s*(N10eC12), C12eN22 from Cl23 of n3(Cl23)/p*(C12eN22) with electron densities, 0.409, 0.064, 0.064, 0.409e and stabilization energies, 49.54, 9.94, 6.44 and 13.42 kcal/mol. The natural hybrid orbital with higher energy and low occupation number is n2(Cl23) with energy 0.315a.u, p-character, 99.98% and occupation number 1.962 whereas the orbital with lower energy and high occupation number is n1(Cl23) with energy 0.914a.u, p-character 15.91% and occupation number 1.993. Thus, a very close to pure p-type lone pair orbital participates in the electron donation to the p*(C12eN22) orbital for n1(N10)/p*(C12eN22), and n3(Cl23)/p*(C12eN22), s*(N10eC12) orbital for n1(N22)/s*(N10eC12) and n2(Cl23)/ s*(N10eC12) interaction in the compound. The results are tabulated in Tables 4 and 5. 4.8. Reactive and degradation properties based on autoxidation and hydrolysis The importance of oxidation reactions is closely related with their ability to degrade, and in that way remove, organic pollutants, especially various pharmaceutical pollutants [78]. By using DFT calculations of the H-BDE values, one is able to computationally evaluate sensitivity of target molecule(s) without tedious experimental procedure related to measurements of bond dissociation


energies [78e80]. Molecule sites for which H-BDE take values between 70 and 85 kcal/mol [81,82] are regarded as sites sensitive towards the autoxidation mechanism. Molecule sites whose H-BDE values are somewhere between 85 and 90 kcal/mol might also indicate sensitivity towards the autoxidation mechanism, however, they should be taken with caution [82]. While it might be logical that values of H-BDE lower than 70 kcal/mol are desired for autoxidation mechanism, this is not the case [23,81,83]. For investigated imidazole derivatives, H-BDE values have been presented in Fig. 7. Both imidazole derivatives have H-BDE values very close to the upper border level of 90 kcal/mol. Namely, H-BDE values for hydrogen atoms belonging to same methyl group of both derivatives are in the range between 90 and 91 kcal/mol. Although these values are formally higher than the upper border level, they might indicate certain sensitivity towards autoxidation mechanism. Other methyl groups have H-BDE values in range between 94 and 95 kcal/mol, while remaining hydrogen atoms have H-BDE values in range between very high values of 117 and 119 kcal/mol. Using MD simulations in this work we were able to identify atoms of imidazole derivatives PHENYLI and TOLYLI with relatively significant interactions with water molecules. After obtaining information about trajectories, radial distribution functions (RDF) have been calculated. The RDF of atoms with the relatively important interactions with water molecules have been presented in Fig. 8. RDF results of both imidazole derivatives indicate very similar stability in water. For both derivatives, the nitrogen atom belonging to imidazole ring has the strongest interactions with water molecules, according to the distance of the maximal g(r) value. Also, for both molecules there are several carbon atoms with significantly higher maximal g(r) values, which are however located at higher distances. It can be also seen in Fig. 8 that TOLYLI derivative has one atom more with relatively significant (corresponding to the additional methyl group) interactions with water molecules. 4.9. Molecular docking Based on the structure of a compound, PASS (Prediction of Activity Spectra for Substances) [84] and the activities given by PASS analysis (Table 6) are 0.816 for PHENYLI and 0.765 for TOLYLI. Antioxidants have been widely used as food additives to provide protection against oxidative degradation of foods. They may play an important contributory role in the treatment of many degenerative or chronic diseases, such as atherosclerosis, braindys function, immune system decline and cancer, since considerable experimental evidence, links the production of reactive oxygen species to the initiation and/or progression of thosepathologies [85]. The series of structurally diverse 1-Aryl-2,3-diphenyl imidazole [86] and 2,4,5-Triarylimidazole are promising anti-oxidants [87]. Taurine protects the integrity of the hepatic tissue by stabilizing the reactive oxygen species mediated lipid peroxidation and protein carbonyl formation. Taurine must prove to be efficacious as an antioxidant [88] and possess a protective action against drug induced toxicity [89,90]. Thus we have to design these two compounds are new antioxidant drugs. High resolution crystal structure of Taurine dehydrogenase inhibitor as APO-liver alcohol dehydrogenase inhibitor was downloaded from the protein data bank website (PDB ID: 5ADH). All molecular docking calculations were performed on Auto Dock-Vina software and as reported in literature [91e93]. Amino acids Ile 250 forms p-sigma with phenyl ring and p-alkyl interaction with imidazole ring. Ile 224 form alkyl interaction with methyl group and Pro 243 forms p-alkyl interaction with imidazole ring. These are the non-covalent interaction of the ligands PHENYLI and TOLYLI with the substrate and are detailed in Fig. 9. The docked ligands form stable complexes with dehydrogenase inhibitor which gives binding affinity value of 5.3 kcal/

235

Table 5 NBO results showing the formation of Lewis and non-Lewis orbital. Bond(A-B)

ED/ea

EDA%

EDB%

NBO

s%

2-chloro-4,5-dimethyl-1-phenyl-1H-imidazole (PHENYLI)rowhead sC2-C3 1.975 49.10 50.90 0.7007(sp1.89) Cþ 34.59 0.711 e e 0.7135(sp1.72) C 36.75 pC2-C3 1.675 47.22 52.78 0.6871(sp1.00) Cþ 0.00 0.266 e e 0.7265(sp1.00) C 0.00 sC3-C4 1.975 50.90 49.10 0.7135(sp1.72) Cþ 36.75 0.711 e e 0.7007(sp1.89) C 34.59 sC12-C15 1.978 51.01 48.99 0.7142(sp1.61) Cþ 38.23 0.704 e e 0.6999(sp1.71) C 36.93 pC12-C15 1.848 51.03 48.97 0.7143(sp1.00) Cþ 0.00 0.253 e e 0.6998(sp1.00) C 0.00 sC13-N23 1.986 41.40 58.60 0.6434(sp1.58) Cþ 38.73 0.849 e e 0.7655(sp1.77) N 35.98 pC13-N23 1.893 43.90 56.10 0.6625(sp1.00) Cþ 0.00 0.307 e e 0.7490(sp1.00) N 0.00 sC3-N11 1.984 37.21 62.79 0.6100(sp2.78) Cþ 26.43 0.784 e e 0.7924(sp1.90) N 34.48 sN11-C13 1.982 63.78 36.22 0.7986(sp2.09) Nþ 32.39 0.814 e e 0.6018(sp1.90) C 34.39 sC12-C14 1.985 50.78 49.22 0.7126(sp1.71) Cþ 36.85 0.646 e e 0.7016(sp2.57)C 28.02 sC13-Cl24 1.988 45.85 54.15 0.6771(sp2.72) Cþ 26.83 0.697 e e 0.7359 (sp5.19)Cl 16.07 sC15-C19 1.984 50.65 49.35 0.7117(sp1.78)Cþ 35.92 0.628 e e 0.7025(sp2.52)C 28.36 n1N11 1.597 e e sp1.00 0.00 0.257 e e e e n1N23 1.914 e e sp2.04 32.89 0.349 e e e e n1Cl24 1.993 e e sp0.19 84.10 0.912 e e e n2Cl24 1.962 e e sp99.99 0.04 0.314 e e e n3Cl24 1.938 e e sp1.00 0.00 0.316 e e e Bond(A-B)

ED/ea

EDA%

EDB%

NBO

s%

2-chloro-4,5-dimethyl-1-(o-tolyl)-1H-imidazole 9TOLYLI)rowhead sC2-C3 1.971 49.74 50.26 0.7053(sp1.97) Cþ 33.63 0.703 e e 0.7089(sp1.70) C 37.01 sC3-C4 1.974 51.01 48.99 0.7142(sp1.70) Cþ 37.02 0.707 e e 0.6999(sp1.89) C 34.64 pC3-C4 1.686 53.30 46.70 0.7301(sp1.00) Cþ 0.00 0.262 e e 0.6834(sp1.00) C 0.00 sC11-C14 1.978 51.01 48.99 0.7142(sp1.62) Cþ 38.20 0.704 e e 0.7000(sp1.71) C 36.95 pC11-C14 1.848 51.10 48.90 0.7149(sp1.00) Cþ 0.00 0.254 e e 0.6993(sp1.00) C 0.00 sC12-N22 1.986 41.40 58.60 0.6435(sp1.58) Cþ 38.73 0.849 e e 0.7655(sp1.77) N 35.97 pC12-N22 1.892 43.91 56.09 0.6626(sp1.00) Cþ 0.00 0.307 e e 0.7489(sp1.00) N 0.00 sC3-N10 1.984 37.01 62.99 0.6084(sp2.86) Cþ 25.89 0.779 e e 0.7937(sp1.89) N 34.58 sN10-C12 1.982 63.75 36.25 0.7984(sp2.09) Nþ 32.38 0.815 e e 0.6021(sp1.89) C 34.50 sC11-C13 1.985 50.79 49.21 0.7127(sp1.71) Cþ 36.83 0.646 e e 0.7015(sp2.57)C 28.03 sC12-Cl23 1.988 45.75 54.25 0.6764(sp2.74) Cþ 26.71 0.697 e e 0.7365(sp5.19)Cl 16.09 sC14-C18 1.985 50.65 49.35 0.7117(sp1.78)Cþ 35.91 0.628 e e 0.7025(sp2.52)C 28.37 n1N10 1.593 e e sp1.00 0.01 0.256 e e e e n1N22 1.915 e e sp2.03 32.91 0.350 e e e e n1Cl23 1.993 e e sp0.19 84.09 0.914 e e e e n2Cl23 1.962 e e sp99.99 0.02 0.315 e e e e n3Cl23 1.938 e e sp1.00 0.00 –0.317 e e e e a

ED/e in a. u.

p% 65.41 63.25 100.0 100.0 63.25 65.41 61.77 63.07 100.0 100.0 61.27 64.03 100.0 100.0 73.57 65.52 67.61 65.61 63.15 71.98 73.17 83.93 64.07 71.64 100.0 e 67.11 15.91 99.96 100.0 e p% 66.37 62.99 62.98 65.36 99.99 100.0 61.80 63.06 100.0 100.0 61.27 64.03 100.0 100.0 74.11 65.42 67.62 65.50 63.17 71.97 73.28 83.91 64.09 71.64 99.99 e 67.09 e 15.91 e 99.98 e 100.0 e

236


Fig. 7. H-BDE values of a) PHENYLI and b) TOLYLI imidazole derivatives.

Table 6 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

2-chloro-4,5-dimethyl-1-phenyl-1H-imidazole (PHENYLI)rowhead 0.841 0.004 Cell adhesion molecule inhibitor 0.816 0.010 Taurine dehydrogenase inhibitor 0.782 0.004 CYP2A8 substrate 0.782 0.016 Glycosylphosphatidylinositol phospholipase D inhibitor 0.750 0.010 IgA-specific serine endopeptidase inhibitor 0.751 0.019 NADPH peroxidase inhibitor 0.718 0.004 CYP2C9 inhibitor 0.722 0.023 Glutamylendopeptidase II inhibitor 0.708 0.010 3-Hydroxybenzoate 6-monooxygenase inhibitor 0.713 0.020 5-O-(4-coumaroyl)-D-quinate 30 -monooxygenase inhibitor 0.736 0.055 Ubiquinol-cytochrome-c reductase inhibitor 0.696 0.027 Nicotinic alpha2beta2 receptor antagonist 0.686 0.017 Phthalate 4.5-dioxygenase inhibitor 2-chloro-4,5-dimethyl-1-(o-tolyl)-1H-imidazole (TOLYLI)rowhead 0.765 0.019 Taurine dehydrogenase inhibitor 0.710 0.005 Cell adhesion molecule inhibitor 0.724 0.022 Glutamylendopeptidase II inhibitor 0.705 0.007 CYP2A8 substrate 0.689 0.004 CYP2C9 inhibitor 0.689 0.038 Glycosylphosphatidylinositol phospholipase D inhibitor 0.663 0.021 Alkane 1-monooxygenase inhibitor 0.701 0.068 Ubiquinol-cytochrome-c reductase inhibitor 0.643 0.016 3-Hydroxybenzoate 6-monooxygenase inhibitor 0.656 0.032 5-O-(4-coumaroyl)-D-quinate 30 -monooxygenase inhibitor 0.606 0.004 CYP3A4 inhibitor 0.657 0.066 CYP2J substrate 0.617 0.026 Phosphatidylcholine-retinol O-acyltransferase inhibitor

5. Conclusion

Fig. 8. Representative RDFs of a) PHENYLI and d) TOLYLI molecules.

mol for both the compounds. These binding affinity values of different poses of ligands with same protein are tabulated in Table 7. These preliminary results suggest that the compounds might exhibit inhibitory activity against APO-liver alcohol dehydrogenase inhibitor (Fig. 10).

The vibrational spectra of two imidazole derivatives are reported theoretically and experimentally. The vibrational wavenumbers are assigned with the help of potential energy distribution analysis. Using frontier molecular orbital analysis the charge transfer within the molecules are discussed. Both MEP and ALIE descriptors identified nitrogen atom belonging to imidazole ring to be sensitive towards electrophilic attacks. Additionally, ALIE descriptor identified region above imidazole ring to be sensitive towards electrophilic attacks. According to Fukui functions, benzene ring could also be important reactive site, to the change in electron density after addition and removal of charge. Hydrogen atoms of one methyl group connected to imidazole ring have H-BDE values higher than, but very close to, 90 kcal/mol, indicating that these derivatives might be sensitive towards the autoxidation mechanism. MD simulations revealed very similar g(r) curves, with


237

Fig. 9. The detailed interaction of ligand a) PHENYLI and d) TOLYLI with the amino acids of APO-liver alcohol dehydrogenase inhibitor.

Table 7 The binding affinity values of different poses of the title compounds predicted by Autodock Vina. Mode Affinity (kcal/mol)

Distance from best mode (Å)

2-chloro-4,5-dimethyl-1-phenyl-1H-imidazole (PHENYLI)rowhead e e

RMSD l.b.

RMSD u.b.

0.000 1.856 2.089 17.335 17.070 15.843 13.029 12.078 2.639

0.000 2.653 4.868 18.793 19.030 17.124 14.498 13.253 3.712

1 2 3 4 5 6 7 8 9

5.3 5.2 5.0 4.9 4.9 4.9 4.8 4.7 4.7

2-chloro-4,5-dimethyl-1-(o-tolyl)-1H-imidazole (TOLYLI)rowhead e e 1 2 3 4 5 6 7 8 9

5.3 5.2 5.0 5.0 4.9 4.9 4.9 4.9 4.8

RMSD l.b.

RMSD u.b.

0.000 1.857 2.095 1.731 2.064 17.337 15.841 17.112 2.270

0.000 2.652 4.865 2.197 5.062 18.796 17.121 19.008 4.966

Fig. 10. The docked ligand a) PHENYLI and d) TOLYLI with the active site of APO-liver alcohol dehydrogenase inhibitor.

nitrogen atom of imidazole ring having the strongest interactions with water molecules. The docked ligands form stable complexes

with dehydrogenase inhibitor and exhibits inhibitory activity against APO-liver alcohol dehydrogenase inhibitor.

238


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