In this paper we have reported synthesis evaluation imidazole by solvent free multi component scaffolds (NEAT Reaction) by simple and very effective protocol. The compounds were confirmed by 1H NMR, Mass and I.R spectral studies. The theoretical interpretations of synthesized compounds with optimized by 6-311 + + G(d, p) basic set and different parameters using Gaussion-09 software .The PASS web-based application gave predicts the biological activity spectrum of a compound based on structure. It is useful to estimate the probable biological activity profile. The analysis shows that compound 6b shows high activity for Antieczematic and Gluconate 2-dehydrogenase (acceptor) inhibitor (Pa > 0.07). The bioactivity against Etiella zinkenella was evaluated. The result obtained showed a significant (P < 0.06) larvicidal activity with Lethal concentration (LC50) = 0.22 ppm for compound 6d at concentration ranging between 0.02–0.08 ppm.
Research Article
Synthesis, Characterization, Computational Studies, Microbial Activity, Larvicidal Activity and Theoretical Biological Potential of various Imidazole Scaffolds
https://doi.org/10.21203/rs.3.rs-4983422/v1
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Imidazoles
Neat reaction
PASS predication
DFT studies
Molecular Electrostatic Potential
Mulliken Charges
Antimicrobial activity
Larvicidal activity.
Imidazoles are important class of organic compounds which contains nitrogen in five membered heterocyclic ring that possess three carbons, two nitrogen and four hydrogen atom. It contains nitrogen at C1 and C3 position [1, 2]. Due to its biological active moiety, Imidazole is used in various pharmaceuticals and natural products [3] antiviral, antibacterial, anti-inflammatory and anti-fungal [4, 5].It has been used in the synthesis of various types of drug such as Zolpidem, Alpidem, Saripidem and Necopidem [6]. Hence Imidazole scaffolds are reported to possess high physiologically and pharmacologically activity in treatment of several diseases [7]. It is the basic core of some natural products such as histidine, purine, histamine and DNA based structures [8]. Apart from this some fused imidazoles possess photo physical properties and hence are widely used as organic conductors, photovoltaic cell and organic light emitting diodes [9, 10].
Imidazoles act as good donar and acceptor of hydrogen bond interactions making it relatively acidic [11]. There are several approaches for the synthesis of substituted imidazoles by condensation [12], ring cyclization [13], oxidation conversion [14], solid face analysis [15], flash vacuum pyrolysis [16], microreactor [17] and ionic liquid promoted technique [18]. In most cases, tri and tetra-substituted imidazoles are synthesized by three or four components of cyclo-condensation of 1,2-diketones, ammonium acetate with aldehydes, and anilines using a variety of different catalysts under efficient green method or solvent-based conditions [19]. Some of the well-known methods for the synthesis of substituted imidazoles are Van Leusen [20], Debus-Radziszewski [21], Marckwald [22], and Wallach [23].
In the present study we have extended our work by reporting facile and easy synthesis of new Imidazole scaffolds by reaction of Knoevenagel product [24–27] ( We have named the reaction as Rayate-Gaware Condensation reaction after the name of authors) with thioacetamide in ethylene diamine using solvent free condition (NEAT reaction). Most reactions involve harsh conditions and costly starting materials. But we have performed the synthesis simply at room temperature with good yield. The synthesis routes have been reported by P. Dash et.al [28]. We have modified the reported method for better result. The synthesized scaffolds were characterized by different characterization techniques such as 1H NMR, IR, UV and Mass spectrometry.
The Density functional theory (DFT) is a computational quantum-mechanical (QM) modeling method used in physics, chemistry and material science to the electronic structures. Due to this computational quantum chemistry, synthesized compound have been carried out structural information about Mulliken atomic charge, Molecular orbital theory, Frontier molecular orbital of the compounds by using Density functional theory DFT/B3LYP method/functional with the 6-311G++ (d, p) as basis set with the of Gaussian 09 software [29–31]. The experimental approach study the molecular properties like optimized molecular structure, bond length, bond angle Mulliken atomic charges, Total energy, Highest Occupied Molecular Orbital (HOMO)- Lowest Unoccupied Molecular Orbital (LUMO) energies, etc.[32].
The antimicrobial activity of Imidazole scaffolds were tested on different bacteria such as E. coli P.vulgaris and P.aeuruginosa. Result showed that Imidazole scaffolds possess good antimicrobial activity against P.vulgaris.
The synthesized Imidazole scaffolds were tested against Etiellia zinckenella larvae showed good Larvicidal activity with Lethal concentration (LC50) = 0.22 ppm for concentration ranging between 0.02–0.08 ppm showing promising candidate for various larvicidal applications.
PASS Analysis (Prediction of Activity Spectra for Substances) is a software designed compounds as this tool for evaluating the biological potential of molecule. PASS online provide the list of predictable activities with new proprietary compounds and novel activities. The potential biological properties of the selected compounds were investigated through the PASS web server (Lagunin et al., 2000). The PASS tool allows us to explore the possible biological properties of compounds, based on their chemical formula. It uses 2D molecular fragments known as multilevel neighbors of atoms (MNA) descriptors which suggest that the biological activity of a chemical compound is the function of its molecular structure [33, 34]. It gives the prediction score for biological properties on the ratio of ‘probability to be active (Pa)’ and ‘probability to be inactive (Pi)’. A higher Pa means the biological property is having more probability for a compound.
We have purchased all the required chemicals S. D. Fine, Merck and Loba Chemicals Pvt. Ltd. Melting point apparatus was used to determine the melting point of the solid compounds and were uncorrected. IR spectrum was recorded on Shimadzu FTIR spectrometer. 1H NMR was recorded on Bruker Advance II (400 MHz) using tetramethyl silane as the internal standard using DMSO and CDCl3 as solvents. Analytical TLC was performed on pre-coated alumina sheet and the products were visualized by UV light.
Table 1: Synthesis of (E)-ethyl 2-(4, 5-dihydro-1H-imidazol-2-yl)-3-arylacrylate with thioacetamide in ethylenediamine under solvent free condition
3.1 Computational Study
3.1.1 Structure Analysis
The optimized structure of represented molecule (6b) obtained from Gauss View program 5.0 is shown in Fig. 1. The structure consists of imidazole ring and aryl ring. The DFT calculations predict the planarity of aryl ring and the imidazole ring is tilt from the plane. This shows the non-planarity of the molecule. The molecule possesses C1 point group symmetry. The structural parameters like bond lengths and bond angles for the optimized molecule have been computed by the DFT/B3LYP method with the 6-311G++ (d, p) as basis set.
Table 2 Theoretical Bond Length (Å) obtained from DFF/B3LYP method 6-311 + + G (d,p) basis set of (E)-ethyl 2-(4,5-dihydro-1H-imidazol-2-yl)-3-(4-methoxyphenyl)acrylate (6b)
| Bond Lengths(Å) | B3LYP/6-311 + G(d,p) | Bond Lengths(Å) | B3LYP/6-311 + G(d,p) |
|---|---|---|---|
| C1-C2 | 1.3505 | C14-C18 | 1.3982 |
| C1-C4 | 1.4915 | C14-H19 | 1.0815 |
| C1-C21 | 1.4902 | C16-C18 | 1.4028 |
| C2-H3 | 1.0853 | C16-H20 | 1.0834 |
| C2-C11 | 1.4616 | C18-O38 | 1.3594 |
| C4-N31 | 1.2796 | C21-O22 | 1.2099 |
| C4-N32 | 1.3912 | C21-O23 | 1.3553 |
| C5-C6 | 1.5521 | O23-C24 | 1.4472 |
| C5-H7 | 1.098 | C24-C25 | 1.5152 |
| C5-H8 | 1.0912 | C24-H26 | 1.0926 |
| C5-N32 | 1.4697 | C24-H27 | 1.0923 |
| C6-H9 | 1.0919 | C25-H28 | 1.0934 |
| C6-H10 | 1.0957 | C25-H29 | 1.0926 |
| C6-N31 | 1.4768 | C25-H30 | 1.0924 |
| C11-C12 | 1.4034 | N32-H33 | 1.0098 |
| C11-C13 | 1.4111 | C34-H35 | 1.0885 |
| C12-C14 | 1.3919 | C34-H36 | 1.0949 |
| C12-N15 | 1.0851 | C34-H37 | 1.095 |
| C13-C16 | 1.3825 | C34-O38 | 1.4232 |
| C13-H17 | 1.0816 |
| Bond angles(o) | B3LYP/6-311 + G(d,p) | Bond angles(o) | B3LYP/6-311 + G(d,p) |
|---|---|---|---|
| C2-C1-C4 | 125.0557 | C18-C16-H20 | 118.4202 |
| C2-C1-C21 | 121.0084 | C14-C18-C16 | 119.4674 |
| C4-C1-C21 | 113.8905 | C14-C18-O38 | 124.6701 |
| C1-C2-H3 | 115.1773 | C16-C18-O38 | 115.8585 |
| C1-C2-C11 | 130.7101 | C1-C21-O22 | 123.9043 |
| H3-C2-C11 | 114.0969 | C1-C21-O23 | 113.2126 |
| C1-C4-N31 | 124.4019 | O22-C21-O23 | 122.8823 |
| C1-C4-N32 | 118.9501 | C21-O23-C24 | 116.0512 |
| N31-C4-N32 | 116.5691 | O23-C24-C25 | 107.6096 |
| C6-C5-H7 | 111.8099 | O23-C24-H26 | 108.7374 |
| C6-C5-H8 | 113.0895 | O23-C24-H27 | 108.632 |
| C6-C5-N32 | 100.3756 | C25-C24-H26 | 112.0443 |
| H7-C5-H8 | 108.7186 | C25-C24-H27 | 112.0208 |
| H7-C5-N32 | 111.1714 | H26-C24-H27 | 107.7086 |
| H8-C5-N32 | 111.5354 | C24-C25-H28 | 109.626 |
| C5-C6-H9 | 113.0552 | C24-C25-H29 | 111.1257 |
| C5-C6-H10 | 111.1165 | C24-C25-H30 | 111.0201 |
| C5-C6-N31 | 105.7429 | H28-C25-H29 | 108.2091 |
| H9-C6-H10 | 107.6655 | H28-C25-H30 | 108.2505 |
| H9-C6-N31 | 110.8007 | H29-C25-H30 | 108.5186 |
| H10-C6-N31 | 108.3968 | C4-N31-C6 | 106.2533 |
| C2-C11-C12 | 117.8452 | C4-N32-C5 | 106.6014 |
| C2-C11-C13 | 124.7661 | C4-N32-H33 | 118.3777 |
| C12-C11-C13 | 117.3749 | C5-N32-H33 | 119.7500 |
| C11-C12-C14 | 122.1427 | H35-C34-H36 | 109.3635 |
| C11-C12-H15 | 119.1129 | H35-C34-H37 | 109.3601 |
| C14-C12-H15 | 118.7423 | H35-C34-O38 | 105.7729 |
| C11-C13-C16 | 121.0563 | H36-C34-H37 | 109.6013 |
| C11-C13-H17 | 119.5973 | H36-C34-O38 | 111.3178 |
| C16-C13-H17 | 119.2989 | H37-C34-O38 | 111.3293 |
| C12-C14-C18 | 119.3491 | C18-O38-C34 | 118.8328 |
| C12-C14-H19 | 119.411 | ||
| C18-C14-H19 | 121.2375 | ||
| C13-C16-C18 | 120.5799 | ||
| C13-C16-H20 | 120.9927 |
The theoretical bond length (Å) and bond angle from DFF/B3LYP method 6-311 + + G(d, p) basis set of (E)-ethyl 2-(4,5-dihydro-1H-imidazol-2-yl)-3-(4-methoxyphenyl)acrylate (6b) are presented in Table 2 and Table 3 respectively. The olefinic carbon - carbon bond length is 1.3505 Å while bond length of C = N in imidazole ring is 1.2796 Å. The carbon and oxygen in carbonyl group of ester is 1.2099 Å. The carbon and oxygen in methoxy group of ester have bond length is 1.4472 Å while the carbon and oxygen in methoxy group attached to aryl ring is 1.4232 Å. The increase in bond length of carbon and oxygen in methoxy group of ester can be attributed to involvent in conjugation with olefinic carbon-carbon double bond. The theoretical bond angle is in range between 100o to 125o respectively. The decrease in the bond angle is due to five membered imidazole ring which have angle strain effect. The theoretical bond angle of O22-C21-O23 and C18-O38-C34 are 122.8823o and 118.8328o respectively, in O22-C21-O23 is 122.8823 and 106.2533o in C4-N31-C6.
3.1.2 Frontier Molecular Orbital analysis
The Frontier orbitals HOMO, LUMO plays important role to determine reactivity, stability of the molecule. EHOMO and ELUMO are linked to electron donating and electron accepting potential respectively. The red colour in HOMO and LUMO molecular orbital diagram indicates negative potential while green colour indicates positive potential. Orbitals containing electrons are termed as HOMO and considered to have highest in energy while orbitals with no electron are LUMO with lowest energy. The smaller the energy gap between HOMO and LUMO, the greater is the stability of molecule. The chemical reactivity of molecule is directly governed by the charge density of HOMO and LUMO energy surfaces. The HOMO acts as electron donar since its outermost orbital contain electron while LUMO acts as electron deficient or acceptor of electrons. This clearly indicates the HOMO-LUMO energy gap plays important role in kinetic stability of unsaturated systems. The increase in the HOMO-LUMO energy gap leads to decrease in polarizability, flexibility and electron transport in a molecule. The EHOMO and ELUMO are essential in determining ionization enthalpy and electron affinity respectively. Higher Value of EHOMO determines nucleophilic power while lower value of ELUMO represents the electrophilic character of any compound. The pictorial illustration of the frontier molecular orbital is shown in Fig. 2. The HOMO is observed mainly in imidazole ring whereas LUMO is distributed in aryl and olefinic carbons respectively. The lower HOMO LUMO energy gap shows the undeniable charge transfer interactions taking place in molecule.
| Compound | Etotal (a. u.) | EHOMO (eV) | ELUMO (eV) | ΔE (eV) | I (eV) | A (eV) |
|---|---|---|---|---|---|---|
| (E)-ethyl 2-(4,5-dihydro-1H-imidazol-2-yl)-3-phenylacrylate (6a) | -803.28 | -5.9699 | -1.8768 | 4.0931 | 5.9699 | 1.8768 |
| (E)-ethyl 2-(4,5-dihydro-1H-imidazol-2-yl)-3-(4-methoxyphenyl)acrylate (6b) | -917.84 | -6.0339 | -1.8813 | 4.1525 | 6.0339 | 1.8813 |
| ethyl 2-(4,5-dihydro-1H-imidazol-2-yl)-3-(2-hydroxyphenyl)acrylate (6c) | -878.53 | -6.0436 | -1.9295 | 4.1141 | 6.0436 | 1.9295 |
| (2E,4E)-ethyl 2-(4,5-dihydro-1H-imidazol-2-yl)-5-phenylpenta-2,4-dienoate (6d) | -880.72 | -5.8093 | -2.5358 | 3.2735 | 5.8093 | 2.5358 |
| (E)-ethyl 2-(4,5-dihydro-1H-imidazol-2-yl)-3-(4-nitrophenyl)acrylate (6e) | -1007.85 | -6.4339 | -3.1850 | 3.2488 | 6.4339 | 3.1850 |
| (E)-ethyl 3-(4-chlorophenyl)-2-(4,5-dihydro-1H-imidazol-2-yl)acrylate (6f) | -1262.91 | -6.1601 | -2.3271 | 3.8330 | 6.1601 | 2. 3271 |
| I = − EHOMO and A = − ELUMO; A: electron affinity; I: ionization potential | ||||||
All Global descriptors are shown in Table 4. The values are calculated from molecular parameters using Koopman’s theorem [35, 36]. The donar acceptor phenomenon of a chemical system can be easily predicted with the aid of η and σ parameters. A large energy gap indicates a hard molecule and small gap indicates soft molecule. Therefore there is presence of extra polarizability in comparison to the hard molecules. The absolute hardness and global softness corresponds to the gap between EHOMO and ELUMO and is related to the stability of the chemical structure. The ionization potential of an electron is determine by its chemical potential and is also associated with electronegativity.
| Compound | χ (eV) | η (eV) | σ (eV− 1) | ω (eV) | µ (eV) | ∆Nmax (eV) | Dipole moment (Debye) |
|---|---|---|---|---|---|---|---|
| 6a | 3.923 | 2.046 | 0.488 | 3.760 | -3.923 | 1.917 | 3.9896 |
| 6b | 3.957 | 2.076 | 0.481 | 3.771 | -3.957 | 1.906 | 5.8397 |
| 6c | 3.986 | 2.057 | 0.486 | 3.863 | -3.986 | 1.938 | 5.2375 |
| 6d | 4.172 | 1.636 | 0.610 | 5.318 | -4.172 | 2.549 | 2.1758 |
| 6e | 4.809 | 1.624 | 0.615 | 7.119 | -4.809 | 2.961 | 5.1102 |
| 6f | 4.243 | 1.916 | 0.521 | 4.698 | -4.243 | 2.214 | 2.7172 |
| χ = (I + A)/2; ɳ = (I − A)/2; σ = 1/ɳ; ω = µ2/ 2 η; µ = −χ; ΔNmax = − µ /ɳ | |||||||
| 6a: (E)-ethyl 2-(4,5-dihydro-1H-imidazol-2-yl)-3-phenylacrylate; 6b: (E)-ethyl 2-(4,5-dihydro-1H-imidazol-2-yl)-3-(4-methoxyphenyl)acrylate; 6c: ethyl 2-(4,5-dihydro-1H-imidazol-2-yl)-3-(2-hydroxyphenyl)acrylate; 6d: (2E,4E)-ethyl 2-(4,5-dihydro-1H-imidazol-2-yl)-5-phenylpenta-2,4-dienoate; 6e: (E)-ethyl 2-(4,5-dihydro-1H-imidazol-2-yl)-3-(4-nitrophenyl)acrylate; 6f: (E)-ethyl 3-(4-chlorophenyl)-2-(4,5-dihydro-1H-imidazol-2-yl)acrylate | |||||||
As the µ increases, the capability of a molecule to lose electron also increases. The chemical hardness and chemical potential are main factors of the general reactivity of the molecule and are principal components of charge transfer.
A good nucleophile has lower value of ω, while good electrophile has higher value. The electrophilicity ω scale permitted the grouping of organic molecules as strong electrophiles with ω > 1.5 eV, moderate electrophiles with 0.8 < ω < 1.5 eV, and very weaker electrophiles with ω < 0.8 eV [37]. Our reported work shows that the molecules having higher value of ω are good electrophile. The donor and accepted electron charge behavior of molecules can be computed by a maximum amount of electronic charge (ΔNmax). The ΔNmax value for (E)-ethyl 2-(4,5-dihydro-1H-imidazol-2-yl)-3-(4-nitrophenyl)acrylate (6e) is 2.961, which is higher than other molecules. The ionization potential (I) and electron affinity (A) values are also greater as compared to other molecules reported in this. Moreover, molecule lower energy gap (ΔE = 3.2488) which indicates the electron movement within the molecule is faster.
3.1.3 Molecular Electrostatic potential
Molecular Electrostatic Potential (MEP) is three dimensional representation of the charge distribution of molecules. The MEP diagram for represented molecule (E)-ethyl 2-(4, 5-dihydro-1H-imidazol-2-yl)-3-(4-methoxyphenyl) acrylate (6b) plotted by employing 6-311 + + G(d, p) basis set is represented in Fig. 3. Molecular Electrostatic Potential has fruitfully effective to study the molecular interactions. In modern science it is effectively connected to biological and chemical scaffolds. Nucleophilic and electrophilic sites, solvent effects, hydrogen bonding interactions and other important effects can be determined by the use of a molecular electrostatic potential. MEP is primarily used to find out the reactive sites of molecules which empower to anticipate how one molecule can interact with other molecules. The different values of the electrostatic potential at the surface of the molecule are represented by distinct colors. The red and yellow regions correspond to the region of high electron density and are associated with electrophilic reactivity. On the other hand, the blue parts represent low electron density and susceptible to nucleophilic reactivity and green colors represent regions of zero potential, respectively. The electrophilic and nucleophilic sites give idea about the region from where the compound can interact. The MEP suggests, in title molecule the aryl ring connected to imidazole ring is highly prone towards electrophilic attack and carbonyl system is reactive towards nucleophilic attack.
3.1.4 Vibrational assignments, Mulliken atomic charges, and thermodynamic properties
(E)-ethyl 2-(4,5-dihydro-1H-imidazol-2-yl)-3-(4-methoxyphenyl)acrylate (6b) has 38 atoms and therefore has 108 fundamental modes of vibration as per 3N-6 formula. The theoretical and observed FT-IR spectrum is shown in Figs. 4 and 5 respectively. It is found that all 108 fundamental modes are active. The harmonic-vibrational frequencies for molecule are calculated at the B3LYP level using basis set 6-311 + + G(d, p) and are represented in Table 6. The DFT hybrid B3LYP method overestimates the frequency values and hence a scaling factor of 0.9631 is used to scale up the frequencies obtained by B3LYP level using basis set 6-311 + + g(d, p) calculations. The comparison between observed and scaled frequencies obtained from B3LYP level using basis set 6-311 + + G(d, p) has good agreement with each other. (E)-ethyl 2-(4,5-dihydro-1H-imidazol-2-yl)-3-(4-methoxyphenyl)acrylate (6b) has ester carbonyl group, olefinic C = C, aromatic ring, Imidazole ring, methoxy group as main functional group. Aromatic hydrocarbons show absorption in region 1692 − 1542 cm-1 and 1500 − 1425 cm-1. Additionally they also show –CH stretching at 3112 cm-1 and in the plane bending occurs at 1313 − 1198 cm-1. The observed values of carbonyl ester, methoxy group are found to be 1663 cm-1 and 1029 cm-1 while scaled frequencies are 1691 cm-1 and 1017 cm-1 respectively. The olefinic C = C stretching scaled frequencies occurs at 1595.6 cm-1 and is observed at 1508 cm-1. In our present work observed frequencies and computed frequencies are ideally matching with the expected frequencies.
| Mode | Computed Scaled Frequencies (cm-1) | IR intensity (km) mole-1 | Experimental Frequencies (cm-1) | Assignments |
|---|---|---|---|---|
| 108 | 3474 | 15.66 | 3342.64 | N-H str. (2o amine) |
| 107 | 3090 | 14.83 | 3099.61 | Ar-H str. (sym) |
| 102 | 3022 | 21.07 | - | Ar-H str. (asym) |
| 101 | 2997 | 39.13 | - | CH str (asym) -CH3 |
| 100 | 2986 | 30.62 | 2981.95 | CH -str (asym) -CH3 |
| 99 | 2971 | 36.86 | - | CH -str (asym) -CH2 |
| 97 | 2960 | 39.67 | - | CH -str (asym) -CH2 |
| 96 | 2956 | 33.80 | - | CH -str (asym) -OCH3 |
| 95 | 2938 | 19.39 | - | CH -str (asym) -CH2 |
| 94 | 2922 | 19.17 | - | CH -str (asym) -CH3 |
| 93 | 2911 | 46.64 | - | CH -str (asym) -CH3 |
| 92 | 2897 | 68.91 | - | CH str (asym) -CH3 |
| 91 | 2879 | 48.22 | - | CH -str (asym)-CH2 |
| 90 | 1691 | 414.39 | 1653.00 | C = O str. (sym) |
| 89 | 1629 | 87.19 | 1606.70 | Aromatic C = C str. (sym) |
| 88 | 1595 | 41.45 | 1508.33 | C = C str. (olefin) |
| 87 | 1582 | 293.74 | - | Aromatic C = C str. (sym) |
| 86 | 1538 | 46.13 | Aromatic C = C str (asym) | |
| 85 | 1484 | 130.05 | - | Aromatic C = C roc. (sym) |
| 82 | 1447 | 39.45 | - | CH- def. (sym) |
| 76 | 1411 | 61.77 | - | NH-wag. (2o amine) |
| 75 | 1372 | 60.74 | 1367.53 | Aromatic CH = CH roc. (sym) |
| 71 | 1298 | 29.1 | 1315.45 | Aromatic C = C roc. (sym) |
| 70 | 1289 | 21.61 | - | Aromatic C = C roc. (sym) |
| 68 | 1264 | 32.99 | 1269.16 | CH -roc (sym)-CH2 |
| 66 | 1236 | 409.9 | - | Aromatic C = C str. (sym) |
| 65 | 1208 | 325.55 | - | C = O-C str. (sym) (carbonyl) |
| 63 | 1193 | 185.87 | 1192.01 | CH2 twis. (asym) |
| 62 | 1170 | 184.64 | - | N-H str.(sym) |
| 60 | 1154 | 30.58 | - | CH-twis. (asym) |
| 59 | 1153 | 391.52 | - | Aromatic CH = CH wag. (sym) |
| 56 | 1100 | 47.54 | 1126.43 | Aromatic CH = CH roc. (sym) |
| 54 | 1065 | 16.24 | - | C-C -roc (sym)-CH2 |
| 53 | 1035 | 256.86 | 1029.99 | CH2-O str. (sym) |
| 52 | 1017 | 74.29 | 1018.41 | O-CH3 str. (sym) |
| 50 | 987 | 12.63 | - | Aromatic CH = CH roc. (sym) |
| 47 | 952 | 25.74 | 950.91 | CH2-N str. (sym) . |
| 41 | 841 | 13.86 | 840.96 | Aromatic C-CH str.(sym) |
| str: stretching; sym:symmetric; Asym:Asymmetric; roc:rocking; twis: twisting; wag: wagging; def: deformation | ||||
Mulliken atomic charges are based on the electron density. The charge distribution plays important role in quantum mechanical calculations for the molecular framework. The Mulliken atomic charges for (E)-ethyl 2-(4, 5-dihydro-1H-imidazol-2-yl)-3-(4-methoxyphenyl) acrylate (6b) are calculated by the DFT/B3LYP method with 6-311 + + G(d, p) basis set in the gaseous phase and are reported in Table 7. The Mulliken atomic charges on carbon either exhibit positive or negative value. All hydrogen atoms have a net positive charge. H33 have gained maximum positive value due to electronegative atom (N 32).They act as acceptor atom. Therefore H33 is more acidic than other hydrogen atoms. Besides all oxygen atom of the optimized compound show negative charge which act as donar atom.
| Atom | Charge | Atom | Charge |
|---|---|---|---|
| 1 C | 0.431392 | 20 H | 0.202988 |
| 2 C | -0.275786 | 21 C | -0.665921 |
| 3 H | 0.205075 | 22 O | -0.221798 |
| 4 C | -0.363210 | 23 O | -0.057768 |
| 5 C | -0.172249 | 24 C | 0.060643 |
| 6 C | -0.222672 | 25 C | -0.603419 |
| 7 H | 0.144062 | 26 H | 0.182914 |
| 8 H | 0.169995 | 27 H | 0.185594 |
| 9 H | 0.157331 | 28 H | 0.145934 |
| 10 H | 0.169767 | 29 H | 0.148277 |
| 11 C | 1.014039 | 30 H | 0.158294 |
| 12 C | 0.062624 | 31 N | 0.028437 |
| 13 C | -0.735575 | 32 N | 0.081119 |
| 14 C | 0.005662 | 33 H | 0.232670 |
| 15 H | 0.163502 | 34 C | -0.322056 |
| 16 C | -0.436604 | 35 H | 0.183179 |
| 17 H | 0.142887 | 36 H | 0.156204 |
| 18 C | -0.545281 | 37 H | 0.154674 |
| 19 H | 0.179442 | 38 O | -0.144366 |
Based on vibrational investigation, the various thermodynamic properties were computed from the theoretical harmonic frequencies and reported in Table 8. All the thermodynamic information uncovered in this would be useful for further examination and can be used to compute the other thermodynamic energies according to relationships of thermodynamic functions.
| Parameter | 6a | 6b | 6c | 6d | 6e | 6f |
|---|---|---|---|---|---|---|
| Total E (Thermal) Kcal mol− 1. | 185.572 | 207.507 | 188.992 | 208.169 | 188.665 | 180.660 |
| Translational | 0.889 | 0.889 | 0.889 | 0.889 | 0.889 | 0.889 |
| Rotational | 0.889 | 0.889 | 0.889 | 0.889 | 0.889 | 0.889 |
| Vibrational | 183.795 | 205.730 | 187.214 | 206.392 | 186.887 | 178.883 |
| Total (Cv) Cal mol− 1 Kelvin− 1 | 62.912 | 72.143 | 67.524 | 70.333 | 71.596 | 66.018 |
| Translational | 2.981 | 2.981 | 2.981 | 2.981 | 2.981 | 2.981 |
| Rotational | 2.981 | 2.981 | 2.981 | 2.981 | 2.981 | 2.981 |
| Vibrational | 56.950 | 66.182 | 61.563 | 64.372 | 65.634 | 60.056 |
| Total Entropy (S) Cal mol− 1 Kelvin− 1 | 139.341 | 115.314 | 142.974 | 147.665 | 152.482 | 142.062 |
| Translational | 42.378 | 42.724 | 42.568 | 42.680 | 42.883 | 42.767 |
| Rotational | 33.664 | 34.592 | 33.912 | 34.915 | 34.886 | 34.694 |
| Vibrational | 63.299 | 42.724 | 66.494 | 70.070 | 74.713 | 64.601 |
| Zero Point vibrational energy (Kcal mol− 1) | 174.856 | 195.15011 | 177.553 | 196.310 | 176.325 | 169.4339 |
| Rotational constant (GHz) | 0.49688 0.29705 0.19790 | 0.44534 0.18426 0.13677 | 0.4288 0.2862 0.1862 | 0.436010 0.161268 0.118327 | 0.44999 0.15632 0.12139 | 0.44933 0.17670 0.13047 |
| E (RB3LYP) (a.u.) | -803.2688 | -917.8406 | -878.5302 | -880.7225 | -1007.8453 | -1262.9108 |
| Dipole Moment (D) | 3.9896 | 5.8397 | 5.2375 | 2.1758 | 5.1102 | 2.7172 |
| 6a: (E)-ethyl 2-(4,5-dihydro-1H-imidazol-2-yl)-3-phenylacrylate; 6b: (E)-ethyl 2-(4,5-dihydro-1H-imidazol-2-yl)-3-(4-methoxyphenyl)acrylate; 6c: ethyl 2-(4,5-dihydro-1H-imidazol-2-yl)-3-(2-hydroxyphenyl)acrylate; 6d: (2E,4E)-ethyl 2-(4,5-dihydro-1H-imidazol-2-yl)-5-phenylpenta-2,4-dienoate; 6e: (E)-ethyl 2-(4,5-dihydro-1H-imidazol-2-yl)-3-(4-nitrophenyl)acrylate; 6f: (E)-ethyl 3-(4-chlorophenyl)-2-(4,5-dihydro-1H-imidazol-2-yl)acrylate | ||||||
The antibacterial activities of imidazole scaffolds (6a-6f) were examined for E. coli, P.vulgaris and P.aeuruginosa respectively using Disc diffusion method on Agar plate [Kirby-Bauer Disk Diffusion Susceptibility Test Protocol] [38–40] using Mueller-Hinton agar as media. Antimicrobial susceptibility of the compound was checked by observing a clear zone around the discs, indicating inhibition of growth of the test organisms by the compounds. Antimicrobial screening is summarized in Table No 9 for Imidazole scaffolds (6a-6f) and are shown below
| Compound Name | Organisms used and results | ||
|---|---|---|---|
| E. coli | P.vulgaris | P.aeuruginosa | |
| (E)-ethyl 2-(4,5-dihydro-1H-imidazol-2-yl)-3-phenylacrylate (6a) | - | + | - |
| (E)-ethyl 2-(4,5-dihydro-1H-imidazol-2-yl)-3(4-methoxyphenyl)acrylate (6b) | - | - | - |
| ethyl 2-(4,5-dihydro-1H-imidazol-2-yl)-3-(2-hydroxyphenyl)acrylate (6c) | - | - | - |
| (2E,4E)-ethyl 2-(4,5-dihydro-1H-imidazol-2-yl)-5-phenylpenta-2,4-dienoate (6d) | - | + | - |
| (E)-ethyl 2-(4,5-dihydro-1H-imidazol-2-yl)-3-(4-nitrophenyl)acrylate (6e) | - | + | - |
| (E)-ethyl 3-(4-chlorophenyl)-2-(4,5-dihydro-1H-imidazol-2-yl)acrylate (6f) | - | - | - |
+ indicates the organism is sensitive to the compound;- sign indicates the compound does not have antibacterial activity
From the above table it is clear compound 6a, 6d and 6e are found to be sensitive towards P.vulgaris bacteria while 6b, 6c and 6f showed no antibacterial activity. This shows substituent plays an important role in showing the antibacterial activity. All the compounds were having no bacterial activity towards E. coli and P.aeuruginosa respectively. From our data, it is clear that synthesized derivatives can be used as an antimicrobial agent against P.vulgaris only.
The toxicity of compounds 6a, 6b, 6c, 6d, 6e and 6f against Etiella zinkenella was evaluated and results with calculated half lethal dose (LC50) in ppm are shown in Table 10. The data of Lethal dose clearly shows that compound 6d exhibit highest toxic action with LC50 = 0.22 ppm. at 0.02–0.08 ppm. The activity at this minimal amount may be due to the presence of
extra conjugated olefinic C = C bond. Compound 6d seemed to be promising and after some modifications will be considered in future study. The biochemical effect of the compound 6d is also necessary to understand the effect to plants and soil. The further study may be useful to know the impact with the environment.
| Comp. | Dose in ppm | % mortality | LC50 (95% level) ± S.E. | Regression equation Y = a + bx | Heterogeneity X2=(n-1) | Variance | Fiducial limit |
|---|---|---|---|---|---|---|---|
| 6a | Control 0.02 0.04 0.06 0.08 | 0 20 30 50 30 | 0.41 ± 0.11 | 4.61 | 18.940 | 0.014 | Upper limit: -1.3865 Lower limit: -1.8177 |
| 6b | Control 0.02 0.04 0.06 0.08 | 0 40 40 50 60 | 0.51 ± 0.14 | 4.98 | 15.376 | 0.021 | Upper limit: -1.4246 Lower limit: -1.9734 |
| 6c | Control 1 2 3 4 | 0 20 30 40 60 | 0.7458 ± 0.36 | 4.94 | 4.071 | 2.9508 | Upper limit: -1.4414 Lower limit: -3.696 |
| 6d | Control 0.02 0.04 0.06 0.08 | 0 50 50 60 60 | 0.22 ± 0.23 | 5.317 | 10.27 | 0.057 | Upper limit: -1.2067 Lower limit:-2.1083 |
| 6e | Control 0.02 0.04 0.06 0.08 | 0 30 40 50 60 | 0.76 ± 0.13 | 4.8324 | 0.1042 | 0.0156 | Upper limit: -1.6375 Lower limit: -2.1275 |
| 6f | Control 0.02 0.04 0.06 0.08 | 0 20 30 50 70 | 0.74 ± 0.11 | 4.6902 + 4.1937 | 0.3725 | 0.0118 | upper limit=-1.6563 Lower limit: -2.0823 |
| 6a: (E)-ethyl 2-(4,5-dihydro-1H-imidazol-2-yl)-3-phenylacrylate; 6b: (E)-ethyl 2-(4,5-dihydro-1H-imidazol-2-yl)-3-(4-methoxyphenyl)acrylate; 6c: ethyl 2-(4,5-dihydro-1H-imidazol-2-yl)-3-(2-hydroxyphenyl)acrylate; 6d: (2E,4E)-ethyl 2-(4,5-dihydro-1H-imidazol-2-yl)-5-phenylpenta-2,4-dienoate; 6e: (E)-ethyl 2-(4,5-dihydro-1H-imidazol-2-yl)-3-(4-nitrophenyl)acrylate; 6f: (E)-ethyl 3-(4-chlorophenyl)-2-(4,5-dihydro-1H-imidazol-2-yl)acrylate | |||||||
The exploration of biological activities through pass analysis is shown in Table 11. The compounds have been considered biologically seem to potentials whenever its Pa values are higher than the Pi values. In comparison, Pa < 0.8 suggests high drug activities, 0.5 > Pa < 0.8 shows moderate therapeutic potentials and Pa < 0.5 shows poor pharmaceutical activity
As per PASS predictions all the compounds (6a-6e) showed pharmaceutical activity.
| Compound | Pa | Pi | Biological Activities |
|---|---|---|---|
| (E)-ethyl 2-(4,5-dihydro-1H-imidazol-2-yl)-3-phenylacrylate (6a) | 0,749 | 0,005 | Insulin promoter |
| 0,735 | 0,001 | Alpha 1L adrenoreceptor agonist | |
| 0,730 | 0,036 | Antieczematic | |
| E)-ethyl 2-(4,5-dihydro-1H-imidazol-2-yl)-3(4-methoxyphenyl)acrylate (6b) | 0,709 | 0,043 | Antieczematic |
| 0,732 | 0,040 | Gluconate 2-dehydrogenase (acceptor) inhibitor | |
| ethyl 2-(4,5-dihydro-1H-imidazol-2-yl)-3-(2-hydroxyphenyl)acrylate (6c) | 0,700 | 0,022 | Fibrinolytic |
| 0,665 | 0,004 | Rhinitis treatment | |
| 0,651 | 0,002 | Alpha 1L adrenoreceptor agonist | |
| (2E,4E)-ethyl 2-(4,5-dihydro-1H-imidazol-2-yl)-5-phenylpenta-2,4-dienoate (6d) | 0,719 | 0,039 | Antieczematic |
| (E)-ethyl 2-(4,5-dihydro-1H-imidazol-2-yl)-3-(4-nitrophenyl)acrylate (6e) | 0,719 | 0,039 | Antieczematic |
| (E)-ethyl 3-(4-chlorophenyl)-2-(4,5-dihydro-1H-imidazol-2-yl)acrylate (6f) | 0,793 | 0,004 | Insulin promoter |
| 0,781 | 0,041 | Phobic disorders treatment | |
| 0,749 | 0,014 | 5-O-(4-coumaroyl)-D-quinate 3'-monooxygenase inhibitor | |
| 0,729 | 0,001 | Alpha 1L adrenoreceptor agonist |
In conclusion we report the facile and easy synthesis of Imidazole scaffolds through extension of our previous work. The compounds were characterized and have been confirmed on the basis of I.R.,1H NMR and mass spectrometry. We have analyzed the structural parameters by using the DFT method with a basis set 6-311 + + G(d, p). Biological activities studied from PASS online software. The difference in HOMO and LUMO energy supports the interaction of charge transfer within the molecule. The chemical reactivity and thermodynamic properties along with MEP, and FMO analysis have been investigated theoretically. The charge density on different type of atoms has been explored in the present research work using computed Mulliken atomic charges. The MEP plot shows that the negative, positive potential sites are around the atoms. Antimicrobial active screening of different compound sere studied. We found that our reported compounds showed antimicrobial activity against P.vulgaris only. The toxicity screening was done against Etiella zinkenella and we found that compound 6d exhibit highest toxic action with LC50 = 0.22 ppm. at very low concentration ranging from 0.02 to 0.08 ppm. Our identified compounds were subjected to biological properties calculated through PASS we observer and all the test compounds showed excellent probability to be active (Pa)
A mixture of nitrile (10 mmole), thioacetamide (1 mmole) in ethylenediamine (7 cm3) was refluxed with stirring for 3–3.5 h. After completion of reaction diisopropyl ether and acetone or ethanol was added to the reaction mass. The sticky solid obtained was further purified with alcohol. Recrystallisation of water soluble imadazole was carried out by adding diisopropyl ether the solid obtained was purified using alcohol. All the compounds synthesized gave satisfactory elemental analyses and spectral data consistent with the assigned structures.
1) (E)-ethyl 2-(4, 5-dihydro-1H-imidazol-2-yl)-3-phenylacrylate (6a): Colour: Yellow.. IR: 3325.28 (-NH), 2900.94 (-CH) 1647.21(-C = O), 1558.48(C = C olefinic) cm− 1. 1H NMR (500 MHz, DMSO-d6): 8.176 ∂ (S, 1H,- NH), 7.278–7.237 ∂ (m, -ArH), 5.875 ∂ (s, 1H, -CH), 4.352–4.394 ∂ (q, 2H, -CH2), 1.394–1.379 ∂ (t, 3H, -CH3), 3.265–3.598 ∂ (d, H, -CH2).
LC/MS (m/z) Anal. Calcd. for C14H16O2N2 is 244.12; found 244
2) E)-ethyl 2-(4, 5-dihydro-1H-imidazol-2-yl)-3(4-methoxyphenyl) acrylate (6b): Colour: Dark Yellow. IR: 3342. 64 (-NH), 2981.95(-CH), 1653.00 (-C = O), 1508.33 (-C = C olefinic), 1029.99 (-OCH2), 1018.41 (-OCH3) cm− 1. 1H NMR (500 MHz, DMSO-d6): 3.692 ∂ (S, 3H,- OCH3), 7.167–7.185 ∂ (s, -ArH), 8.025–8.043 ∂ (s, -ArH), 5.544 ∂ (d, 1H, -CH), 2.501–2.5441 ∂ (d, 2H, -CH2), 8.177 ∂ (d, 1H, NH), 4.348–4.391 ∂ (q, 2H, -CH2), 1.392–1.406 ∂ (t, 3H, -CH3). LC/MS (m/z) Anal. Calcd. for C15H18O3N2 is 274.13; found 274.
3) ethyl 2-(4, 5-dihydro-1H-imidazol-2-yl)-3-(2-hydroxyphenyl) acrylate (6c): Colour: Black. IR: 3600 (-OH), 3136.25 (NH), 2920.23 (-CH), 1645.28 (-C = O), 1539.28 (-C = C olefinic) cm− 1. LC/MS (m/z) Anal. Calcd. for C15H18O3N2 is 260.12; found 261.
4) (2E,4E)-ethyl 2-(4,5-dihydro-1H-imidazol-2-yl)-5-phenylpenta-2,4-dienoate (6d): Colour: Orange. IR: 3230.77 (-NH), 2943.37 (-CH), 1653.00 (-C = O), 1525.69 (-C = C olefinic) cm-1, 1H NMR (500 MHz, DMSO-d6): 8.463 ∂ (S, 1H,- NH), 8.295 ∂ (m, 5H,-ArH),
7.160 ∂ (S, 1H,-CH), 5.915 ∂ (s, 1H, -CH), 6.744 ∂ (s, 1H, -CH), 3.199–3.305 ∂ (d, 2H, CH2), 4.352–4.394 ∂ (q, 2H, -CH2), 1.116–1.493 ∂ (t, 3H, -CH3). LC/MS (m/z) Anal. Calcd. for
C16H18O2N2 is 270.14; found 275
5) (E)-ethyl 2-(4, 5-dihydro-1H-imidazol-2-yl)-3-(4-nitrophenyl) acrylate (6e): Colour: Reddish. IR: 3221.12 (-NH), 2926.01 (-CH), 1649.14 (-C = O), 1502.55 (-NO2) cm− 1. 1H NMR (500 MHz, DMSO-d6): 8.747 ∂ (S, 1H, - NH), 2.362–2.504 ∂ (m, 2H, -CH2), 7.887–7.941 ∂ (d, -ArH), 7.607–7.625 ∂ (d, -ArH), 4.886 ∂ (s, -CH), 4.360–4.604∂ (q, 2H, -CH2), 1.783–1.805 ∂ (t, 3H, -CH3). LC/MS (m/z) Anal. Calcd. for C14H15O4N3 is 289.11; found 289.
6) (E)-ethyl 3-(4-chlorophenyl)-2-(4, 5-dihydro-1H-imidazol-2-yl) acrylate (6f): Colour: Reddish.IR: 3230.77 (-NH), 2943.37 (-CH), 1620.00 (-C = O), 698.23 (-Cl) cm− 1. 1H NMR (500 MHz, DMSO-d6): 8.722 ∂ (s, 1H, -NH), 2.628–2.643 ∂ (m, 2H, -CH2), 7.895–7.899 ∂ (d, 1H, -ArH), 7.582–7.585 ∂ (d, 1H, -ArH), 5.993 ∂ (S, 1H, -CH), 4.318–4.965∂ (q, 2H, -CH2), 1.432–1.439 ∂ (t, 3H, -CH3). LC/MS (m/z) Anal. Calcd. for C14H15O2N2Cl is 278.08; found 278.
Conflict of Interest
The authors declare no conflict of interest.
Funding Declaration:
No Funding
Author Contribution
The following authors has contributed for the manuscriptAnkita M. Rayate Synthesis of Imidazole, Computational Studies and PASS AnalysisManoj R. Gaware Characterization Dnyaneshwar D. Lokhande InfrastructureAmol H. Kategaonkar GuidanceArun M. Bhagare GuidanceBharat N. Shelke GuidanceAvinash S. Kale Anti Microbial ActivitySapana S. Bhamare Antilarvicidal Activity
Acknowledgement
The author thanks Principal, Research Center, Department of Chemistry, G. M. D. Arts, B. W. Commerce and Science College, Sinnar for providing research laboratory and infrastructure facilities and Research Central Facility, Savitribai Phule Pune University, Pune for providing NMR and Mass spectral analysis. Authors also would like to gratefully thank for Gaussian-09 package.
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Scheme I is available in the Supplementary Files section.
No competing interests reported.
- supplementarydataimadazole1.docx
- scheme1.png
Scheme-I: Reaction between benzaldehyde, ethyl cyanoacetate in presence of thiourea and ammonium chloride at 100-105oC followed by reflux with ethylenediamine in presence of thioacetamide for 3-3.5 hrs. under solvent free condition
