SYNTHESIS AND MOLECULAR DOCKING STUDY OF BIOACTIVE QUINOLINO- BENZIMIDAZOLE DERIVATIVES

SYNTHESIS 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.

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

TABLE 3: MOLECULAR DOCKING STUDY FOR COMPOUND (3a-3h) ALONG WITH PrimeMMGBSA dG BIND ENERGY VALUES

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

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.

REFERENCES:

1. Manna K and Aggarwal Y: Microwave-assisted synthesis of new indophenazine 1, 3, 5-trisubstituted pyrazoline derivatives of benzofuran and their antimicrobial activity. Bioorg Med Chem Lett 2009, 19: 2688-92.
2. Berg D, Buchel KH, Plempel M and Zywietz A: Action mechanisms of cell‐division‐arresting benzimidazoles and of sterol biosynthesis‐inhibiting imidazoles, 1, 2, 4‐Triazoles, and Pyrimidines 1986; 29: 221-29.
3. Saimot AG, Cremieux AC, Hay JM, Meulemans A, Giovanangeli MD, Delaitre B and Coulaud FP: Lancet 1983; 17: 652-56.
4. Chimirri A, Grasso S, Monforte AM, Monforte P, Zappala M and Farmaco I: 1991; 46: 925-33.
5. Niemegeers JE, Awouters F and Janssen AJ: Agents and Actions 1986; 18: 141-44.
6. Iemura R, Hori M and Ohtaka H: Chem Pharm Bull 1989; 37: 962-66.
7. Benavides J, Schoemaker H, Dana C, Claustre Y, Delahaye M, Prouteau M, Manoury P, Allen JV, Scatton B, Langer SZ, Arbilla S and Arzneim F: 1995; 45: 551-58.
8. Ishihara K, Ichikawa T, Komuro Y, Ohara S, Hotta K and Arzneim F: Drug Res 1994; 44: 827-30.
9. Graham DY, Mccullough A, Sklar M, Sontag JS, Roufail WM, Stone R, Bishop RH, Gitlin, Cagliola AJ, Berman RS and Humphries T: Digestive Diseases and Sciences 1990; 35: 66-72.
10. Piazzesi G, Morano L and Ruegg JC: Arzneim Forsch Drug Res 1987; 37: 1141-43.
11. Wiedemann, Peil H, Justus H, Adamus S, Brantl V and Lohmann H: Arzneim Forsch Drug Res 1985; 35: 64-69.
12. Kubo K, Kohara Y, Imamiya E, Sugiura Y, Inada Y, Furukawa and Nishikawa K: Naka J Med Chem 1993; 36: 2182-95.
13. Janssen AJ, Allewijn FTN and Arzneim F: Drug Res 1968; 18: 279-82.
14. Mandewale M, Kokate S, Thorat B, Sawant S and Yamgar R: Zinc complexes of hydrazone derivatives bearing 3,4-dihydroquinolin-2(1H)-one nucleus as new anti-tubercular agents. Arabian Journal of Chemistry 2016; 30: 1-11 doi: 10.1016/j.arabjc.2016.07.016
15. Mandewale M, Thorat B, Nivid Y, Jadhav R, Nagarsekar A and Yamgar R: Synthesis, structural studies and antituberculosis evaluation of new hydrazone derivatives of quinoline and their Zn (II) complexes. Journal of Saudi Chemical Society. Journal of Saudi Chemical Society 22(2): 218-28.
16. Mandewale M, Thorat B, Shelke D and Yamgar R: Synthesis and biological evaluation of new hydrazone derivatives of quinoline and their Cu (II) and Zn (II) complexes against Mycobacterium tuberculosis. Bioinorganic Chemistry and Applications 2015. doi: http://dx.doi.org/10.1155/2015/153015.
17. Mandewale M, Thorat B and Yamgar R: Synthesis and anti-mycobacterium study of some fluorine-containing Schiff bases of quinoline and their metal complexes. Der Pharma Chemica 2015; 7: 207-215.
18. Yamgar R, Nivid Y, Nalawade S, Mandewale M, Atram R and Sawant S: Novel zinc (II) complexes of heterocyclic ligands as antimicrobial agents: synthesis, characterization, and antimicrobial studies. Bioinorganic Chem and Appl 2014; 1-10. doi: http://dx.doi.org/10.1155/ 2014/276598
19. Nazirkar B, Mandewale M and Yamgar R: Synthesis, characterization and antibacterial activity of Cu (II) and Zn (II) complexes of 5-aminobenzofuran-2-carboxylate Schiff base ligands, Journal of Taibah University for Science 2019; 13(1): 440-49.
20. Mali SN, Sawant S, Chaudhari HK and Mandewale MC: In-silico appraisal, Synthesis, Antibacterial screening and DNA cleavage for 1, 2, 5-thiadiazole derivative, Current Computer-Aided Drug Design 2019. doi: 10.2174/ 1573409915666190206142756
21. Mandewale MC, Patil UC, Shedge SV, Dappadwad UR and Yamgar RS: A review on Quinoline hydrazone derivatives as a new class of potent antitubercular and anticancer agents. BSU Journal of Basic and Applied Sciences 2017; 6: 354-61.
22. Kathirvelan D, Yuvaraj P, Babu K, Nagarajan AS and Reddy SR: A green synthesis of benzimidazoles, Indian Journal of Chemistry 2013; 52B: 1152-56.
23. Lourenco MS, DeSouza MN, Pinheiro AC, Ferreira ML, Goncalves RB, Nogneira TM and Peralta MA: Evaluation of the anti-tubercular activity of nicotinic and isoniazid analogues. ARKIVOC 2007; 15: 181-191.
    

    ---

    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.

    ---