SYNTHESIS AND MOLECULAR DOCKING STUDY OF BIOACTIVE QUINOLINO- BENZIMIDAZOLE DERIVATIVES
HTML Full TextSYNTHESIS AND MOLECULAR DOCKING STUDY OF BIOACTIVE QUINOLINO- BENZIMIDAZOLE DERIVATIVES
N. J. Deshmukh 1, J. T. Deshmukh * 2 and M. C. Mandewale 2
Department of Chemistry 1, Vivekanand College, Kolhapur- 416003, Maharashtra, India.
Department of Chemistry 2, Government of Maharashtra’s Ismail Yusuf College of Arts, Science and Commerce, Jogeshwari (East) - 400060, Mumbai, India.
ABSTRACT: A series of some quinolino-benzimidazole/thiazole derivatives (3a-3h) have been synthesized from2-hydroxyquinoline-3-formaldehyde derivatives (1a-1d) and 1, 2-phenylenediamines/2-aminothiophenols (2a-2c). The synthesized compounds were characterized by FTIR, 1H-NMR and Mass Spectrometry. All the compounds were screened in-vitro for their antibacterial activity against Mycobacterium tuberculosis (H37 RV strain) ATCC No-27294. Among the compounds tested, compounds 3e showed potent antitubercular activity against M. tuberculosis at MIC 6.25 µg/mL. We extended our study to explore the inhibition mechanism by conducting molecular docking analysis by using Schrödinger.
Keywords: |
Quinoline, Benzimidazole, MIC, Heterocyclic, Tuberculosis
INTRODUCTION: Heterocyclic chemistry is one of the largest classical divisions of organic chemistry. Moreover, they are of immense importance not only both biologically and industrially but to the functioning of any developed human society as well. Their participation in a wide range of areas cannot be underestimated. The majority of pharmaceutical products that mimic natural products with biological activity are heterocycles. Most of the significant advances against disease have been made by designing and testing new structures, which are often heteroaromatic derivatives. Benzimidazole is a heterocyclic aromatic organic compound. This bicyclic compound consists of the fusion of benzene and imidazole.
The most prominent benzimidazole compound in nature is N-ribosyl-dimethylbenzimidazole, which serves as an axial ligand for cobalt in vitamin B12 1. Benzimidazole nucleus is an important heterocyclic ring because of its synthetic utility and broad range of pharmacological activities. Some benzimidazole derivatives with different pharmacological effects, including antifungal 2, anti-helminthic 3, anti-HIV 4, antihistaminic 5, 6, 7, antiulcer 8, 9, cardiotonic 10, antihypertensive 11, 12 and neuroleptic 13 are in clinical use.
Extensive biochemical and pharmacological studies have confirmed that these molecules are effective against various strains of microorganisms. Based on recent literature and in continuation of our research 14, 15, 16, 17, 18, 19, 20, 21 for more potent antibacterial agents, we synthesized and screened quinolinobenzimidazole derivatives (3a-3h). The compounds (3a-3h) were prepared using reported methodology 22 by using o-phenylene diamines and various substituted quinolone aldehydes in presence of catalytic NH4Cl in ethanol.
EXPERIMENTAL:
Materials and Methods: All required chemicals and solvents were purchased from Sigma-Aldrich (Munich, Germany) and Merck Co. (Darmstadt, Germany) and used without further purification. The NMR spectra were recorded on a Bruker Avance 300 apparatus in DMSO-d6. The chemical shifts are measured on the δ (ppm) scale using TMS (Tetramethylsilane) as the internal standard reference. Infrared (IR) spectra measured on an FTIR-7600 Lambda Scientific Pty. Ltd. using KBr disk for the range 4000-400 cm-1. Mass spectra obtained on BRUKER ESQUIRE HCT spectrometer.
General Procedure of Preparation: Compound 2a-2c (1 mmol) was dissolved in 4 ml ethanol in 20 ml round flask. Then, with constant stirring, 1 mmol of 1a-1e was slowly added followed by NH4Cl (30 mol %). The resulting reaction mixture was stirred for 2 h at 80 °C. The reaction progress was checked with TLC. After completion of the reaction, it was poured in ice-cold water. The precipitates were then collected by filtration, washed with distilled water and purified by recrystallization from ethanol to give the pure product.
FIG. 1: SCHEME OF PREPARATION OF COMPOUNDS 3a-3h
Synthesis of 3-(1H-benzimidazol-2-yl)quinolin-2-ol [3a]: Yield 86%, 1HNMR (300 MHz, DMSO-d6) δ:6.31-6.58 (m, 2H),7.05-7.45 (m, 3H), 7.58-7.73 (m, 2H), 7.81–7.96 (m, 1H), 9.11 (m, 1H), 11.89 (s, 1H, -NH), 12.18 (s, 1H, -OH); Mass Spectra: [M+1] 262.53, IR (KBr, ν, cm-1): 3426 (-OH), 1612, 1406, 1038, 721. Anal. Calc. For C16H11N3O: C, 73.55; H, 4.24; N, 16.08. Found. C, 73.80; H, 4.03; N, 16.47.
Synthesis of 3-(1,3-benzothiazol-2-yl)quinolin-2-ol [3b]: Yield 83%, 1H NMR (300 MHz, DMSO-d6) δ 6.24-6.25(m, 1H), 6.39-6.44(m, 1H), 6.56-6.61(m, 1H), 6.71-6.76(m, 1H), 6.87-7.19(m, 1H), 7.31-7.34(m, 1H), 7.46-7.51(m, 1H), 7.67-7.69(m, 1H), 7.83(s, 1H), 12.02(s, 1H); Mass Spectra: [M+1] 281.35; IR (KBr, ν, cm-1 ): 3415, 1604, 1328, 1034, 760. Anal. Calc. For C16H10N2OS: C, 69.05; H, 3.62; N, 10.07. Found. C, 68.85; H, 3.76; N, 10.13.
TABLE 1: STRUCTURES OF THE COMPOUNDS 3a-3h
Entry | Product |
3a | |
3b | |
3c | |
3d | |
3e | |
3f | |
3g | |
3h |
Synthesis of 3-(1H-benzimidazol-2-yl)-6-fluoro-quinolin-2-ol [3c]: Yield 89%, 1H-NMR (300 MHz, DMSO-d6) δ 7.22 (m,2H), 7.47-7.53 (m, 2H), 7.63-7.72 (m, 2H), 7.83-7.86 (m, 1H), 9.12 (s, 1H), 12.54 (s, 1H), 12.67 (s, 1H). Mass Spectra: [M+1] 280.85; IR (KBr, ν, cm-1): 3450, 1612, 1341, 738; Anal. Calc. For C16H10FN3O: C, 68.81; H, 3.61; N, 15.05. Found. C, 68.93; H, 3.48; N, 14.92.
Synthesis of 6-fluoro-3-(6-methyl-1H-benz-imidazol-2-yl) quinolin-2-ol [3d]: Yield 90%, 1H NMR (300 MHz, DMSO-d6) δ 2.42 (s, 3H), 7.03-7.05 (m, 1H), 7.33 (m, 1H), 7.47-7.57 (m,3H), 7.82-7.85 (m, 1H), 9.08 (s, 1H), 11.98 (s, 1H), 12.53 (s,1H); Mass Spectra: [M+1] 294.42; IR (KBr, ν, cm-1): 3428, 1611, 1331, 736. Anal. Calc. For C17H12FN3O: C, 69.62; H, 4.12; N, 14.33. Found. C, 69.97; H, 4.08; N, 14.20.
Synthesis of 3-(1,3-benzothiazol-2-yl)-6-fluoro-quinolin-2-ol[3e]: Yield 86%, 1HNMR (300 MHz, DMSO-d6) δ 6.98-7.13 (m, 2H), 7.44 (m, 1H), 7.46-7.63 (m, 1H), 7.91-7.94 (m, 1H), 8.06-8.17 (m, 2H), 9.20 (s, 1H), 12.61 (s, 1H); Mass Spectra: [M+1] 297.87; IR (KBr, ν, cm-1): 3398, 1602, 1347, 742. Anal. Calc. For C16H9FN2OS: C, 64.85; H, 3.06; N, 9.45. Found. C, 65.11; H, 3.21; N, 9.40.
Synthesis of 3-(1H-benzo[d]imidazol-2-yl)-6-methoxyquinolin-2-ol [3f]: Yield 78%, 1HNMR (300 MHz, DMSO-d6) δ3.74 (s, 1H, -OCH3), 7.12-7.20 (m, 2H), 7.37-7.40 (m, 1H), 7.52 (m, 1H), 7.69-7.77 (m, 3H), 9.08 (m, 1H), 11.77 (s, H, -NH), 12.38 (S, 1H, -OH); Mass Spectra: [M+1] 292.57; IR (KBr, ν, cm-1): 3428, 1614, 1368, 764. Anal. Calc. For C17H13N3O2: C, 70.09; H, 4.50; N, 14.42. Found. C, 70.27; H, 4.38; N, 14.29.
Synthesis of 3-(1H-benzo[d]imidazol-2-yl)-6-methylquinolin-2-ol [3g]: Yield 76%, 1HNMR (300 MHz, DMSO-d6) δ 2.37 (s, 3H), 7.20-7.50 (m, 3H), 7.70 (m, 4H), 9.01 (s, 1H), 11.78 (s,1H), 12.38(s, 1H); Mass Spectra: [M+1] 276.57; IR (KBr, ν, cm-1): 3422, 1608, 1340, 1026, 762; Anal. Calc. For C17H13N3O: C, 74.17; H, 4.76; N, 15.26. Found. C, 74.52; H, 4.81; N, 15.33.
Synthesis of 3-(1H-benzo[d]imidazol-2-yl)-7-methylquinolin-2-ol [3h]: Yield 79%, 1HNMR (300 MHz, DMSO-d6) δ 2.36 (s, 3H), 7.06-7.22 (m, 2H), 7.50 (m, 1H), 7.70 (m,4H), 9.01 (s, 1H), 11.78 (s,1H), 12.38(s, 1H); Mass Spectra: [M+1] 276.41; IR (KBr, ν, cm-1): 3430, 1609, 1360, 1024, 762; Anal. Calc. For C17H13N3O: C, 74.17; H, 4.76; N, 15.26. Found. C, 73.97; H, 4.29; N, 15.40.
RESULTS AND DISCUSSION:
Chemistry: The target compounds Quinolino-benzimidazole / thiazole derivatives (3a-3h) successfully synthesized from 1a-1d and 2a-2c. For structure identification of these compounds 3a-3h we have utilized advanced techniques like NMR, MASS, FTIR and Elemental analysis.
The FTIR spectrum of compound 3d showed strong absorption peak at 3428 and 1611 corresponding to -OH group of quinoline ring and -C=N- group of benzimidazole group respectively. In addition to expected aromatic signals 1H-NMR spectra of compound 3d show four singlets at 2.42 (-CH3, benzimidazole), 9.08 (C-H, quinoline ring), 11.98 (-N-H, imidazole ring) and 12.53 ppm (-OH, quinoline ring). Moreover, the Mass spectrum of 3d revealed a molecular ion peak at m/z 294.42 (M+H) corresponding to the molecular formula [C17H12FN3O]. In a similar manner, compounds 3a–3h were prepared and characterized.
Molecular Docking Studies: The molecule 3e was found to be best docked among the compound series having docking score of -9.128 as compared to native cocrystallized one (-10.208) for the Enoyl-Acyl Carrier Protein Reductase protein (PDB ID: 2X22). It also had a good binding energy of -72.299. The compound 3e was also found to better docked than those for std. drugs like Bedaquiline and Ciprofloxacin (-6.389 and -5.932 Kcal/mol respectively).
FIG. 2: SUPERIMPOSITION OF BEST DOCKED LIGAND SKY BLUE WITH THE NATIVE ONE FOR PROTEIN 2×22
FIG. 3: BINDING POCKET OF HIGHDOCK MOLECULE (FOR PS PROTEIN PDB ID: 3ivx)
FIG. 4: A] 2D INTERACTIONS OF BEST DOCK COMPOUND 3e WITH TARGET PROTEINS 2×22 B] 2D INTERACTIONS OF BEST DOCK COMPOUND 3a WITH TARGET PROTEINS 3ivx C] 2D INTERACTIONS OF CIPROFLOXACIN WITH TARGET PROTEINS 3ivxd] 2D INTERACTIONS OF BEST DOCK CIPROFLOXACIN WITH TARGET PROTEINS 2×22
TABLE 2: ADME PREDICTIONS FOR COMPOUNDS (3a-3h) by QikProp
Entry | MW | #stars | dipole | volume | QPlogPo/w | QPPCaco | #metab | % HumanOral
Absorption |
Rule
of Five |
PSA |
3a | 261.282 | 1 | 8.367 | 842.283 | 3.05 | 1038.369 | 0 | 100 | 0 | 64.593 |
3b | 278.328 | 0 | 4.918 | 863.08 | 3.043 | 1606.077 | 1 | 100 | 0 | 51.468 |
3c | 279.273 | 1 | 5.772 | 858.436 | 3.286 | 1038.537 | 0 | 100 | 0 | 64.589 |
3d | 293.3 | 0 | 5.683 | 918.314 | 3.596 | 1038.486 | 1 | 100 | 0 | 64.594 |
3e | 296.318 | 0 | 2.283 | 879.232 | 3.286 | 1606.283 | 1 | 100 | 0 | 51.466 |
3f | 291.309 | 0 | 8.608 | 917.202 | 3.152 | 1037.426 | 1 | 100 | 0 | 72.882 |
3g | 275.309 | 0 | 8.859 | 902.246 | 3.36 | 1038.082 | 1 | 100 | 0 | 64.596 |
3h | 275.309 | 0 | 8.764 | 902.319 | 3.361 | 1037.814 | 1 | 100 | 0 | 64.595 |
TABLE 3: MOLECULAR DOCKING STUDY FOR COMPOUND (3a-3h) ALONG WITH PrimeMMGBSA dG BIND ENERGY VALUES
Comp.
ID |
PDB ID:2x22 (RMSD=0.089) | PDB ID:3ivx (RMSD=0.083) | ||||
Docking score
(Kcal/mol) |
Residues
involved |
MMGBSA dG Bind
energy |
Docking score
(Kcal/mol) |
Residues
involved |
MMGBSA dG Bind
energy |
|
Native ligand | -10.208
|
TYR158(H-BOND) | -98.343
|
-9.746
|
SER196, SER197, HIE44, VAL187, HIE47, MET40(H-BOND), HIE44
(PI-PI STACKING), LYS160 (SALT BRIDGE) |
-52.067
|
3a | -8.337
|
ILE194
(H-BOND), TYR158 (PI-PI STACKING) |
-56.002
|
-8.557
(BEST DOCK) |
GLY164 (H-BOND), ASP161(H-BOND), PRO38(H-BOND) | -43.836
|
3b | -8.722
|
ILE194
(H-BOND), TYR158 (PI-PI STACKING) |
-71.085
|
-5.961
|
LYS160(PI-CATION), SER197, HIE44(H-BOND), HIE44
(PI-PI STACKING) |
-59.733
|
3c | -8.568
|
ILE194
(H-BOND), TYR158 (PI-PI STACKING) |
-56.929
|
-6.252
|
HIE44(PI-PI STACKING), HIE47, MET40 (H-BOND) | -48.655
|
3d
|
-8.904
|
ILE194(H-BOND), TYR158
(PI-PI STACKING) |
-56.35
|
-3.689
(LEAST DOCK) |
HIE47, ASP161(H-BOND), HIE44
(PI-PI STACKING) |
-55.168
|
3e | -9.128
(BEST DOCK) |
ILE194(H-BOND), TYR158
(PI-PI STACKING) |
-72.299
|
-6.326 | SER197, HIE44(H-BOND), HIE44(PI-PI STACKING), LYS160
(PI-CATION) |
-60.368
|
3f | -8.372
|
LYS165 (H-BOND), ILE194 (H-BOND), TYR158 (PI-PI STACKING) | -60.927
|
-6.733
|
MET195,HIE47,VAL187(H-BOND),HIE44
(PI-PI STACKING) |
-59.272
|
3g | -8.538
|
ILE194(H-BOND), TYR158
(PI-PI STACKING) |
-55.616
|
-7.108
|
GLY164(H-BOND) | -46.936
|
3h | -8.15
(LEAST DOCK) |
ILE194(H-BOND), TYR158
(PI-PI STACKING) |
-58.758
|
-7.036
|
HIE47(H-BOND) | -52.757
|
Bedaquiline | -6.389
|
TYR158 (H-BOND). | -79.099
|
-6.623
|
GLN164, ASP161(H-BOND); ASP(SALT BRIDGE); TYR82, PHE73 (PI-PI STACKING) | -53.623
|
Ciprofloxacin | -5.932
|
PRO156 (H-BOND), ILE194 (H-BOND) | -58.72
|
-3.879
|
SER196, HIE44(H-BOND) | -52.535
|
In the case of pantothenate synthetase Protein (PDB ID: 3IVX), molecule 3a was found to be the best dock having docking score of -8.557 as compared to native one (-9.746). The molecule 3a was also found to have good docking score than those of std. drugs like Bedaquiline and Ciprofloxacin (-6.623 and -3.879 Kcal/mol respectively). There was no violation of Lipinski’s rule for all the compound prepared Table 2. The percent Human oral absorption values, as well as the caco cell permeability values, were found to be good.
Anti-tuberculosis Study: The anti-tubercular activity of the compounds 3a-3h evaluated against Mycobacterium tuberculosis (H37 RV strain) ATCC No.-27294. The method applied is similar to that reported by Lourenco et al. 23
TABLE 4: ANTITUBERCULAR ACTIVITY RESULTS
Test
Sample |
Sample concentration in
µg/mL (MIC) |
3a | 25.00 |
3b | 12.50 |
3c | 25.00 |
3d | 12.50 |
3e | 06.25 |
3f | 12.50 |
3g | 50.00 |
3h | 25.00 |
Ciprofloxacin | 3.12 |
Pyrazinamide | 3.12 |
Streptomycin | 6.25 |
CONCLUSION: The target compounds (3a-3h) successfully synthesized and characterized. This synthetic strategy allows for the incorporation of the imine, quinoline, and benzimidazole in a single scaffold. The anti-tubercular activity evaluated using blue Alamar method to identify the more effective compound. The compounds under study show moderate to good anti-tubercular potency. Compound 3e was found most active against M. tuberculosis with 6.25 µg/mL. These results are in good agreement with molecular docking results.
ACKNOWLEDGEMENT: The authors thank Principal and Head Department of Chemistry, Government of Maharashtra, Ismail Yusuf Arts, Science, and Commerce College for providing research facilities. The authors also thank Management and Principal of C. S.’s Patkar-Varde College, Goregaon (W), Mumbai for their constant encouragement and support. The authors also acknowledge the help of Dr. Kishore Bhat of Governmental Dental College, Belgaum, for facilitating anti-TB assays and providing the procedure for the same.
CONFLICTS OF INTEREST: No conflict of interest.
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How to cite this article:
Deshmukh NJ, Deshmukh JT and Mandewale MC: Synthesis and molecular docking study of bioactive quinolino-benzimidazole derivatives. Int J Pharm Sci & Res 2020; 11(1): 445-50. doi: 10.13040/IJPSR.0975-8232.11(1).445-50.
All © 2013 are reserved by International Journal of Pharmaceutical Sciences and Research. This Journal licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License.
Article Information
54
445-450
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English
IJPSR
N. J. Deshmukh, J. T. Deshmukh * and M. C. Mandewale
Department of Chemistry, Government of Maharashtra’s Ismail Yusuf College of Arts, Science and Commerce, Jogeshwari (East), Mumbai, India.
iycmustapha@gmail.com
05 April 2019
22 July 2019
13 August 2019
10.13040/IJPSR.0975-8232.11(1).445-50
01 January 2020