SYNTHESIS AND ANTIMICROBIAL ACTIVITY OF SOME QUINOLINE DERIVATIVES

SYNTHESIS AND ANTIMICROBIAL ACTIVITY OF SOME QUINOLINE DERIVATIVES

Indu Singh ^*1 and Arun Kumar ²

Department of Chemistry ¹, Janta Vedic College ,Baraut - 250611, Baghpat, India

Department of Community ², Medicine, L.L.R.M. Medical College, Meerut - 250004, U.P, India

ABSTRACT: Cyclocondensation of 5-6 and 7-8 with chloroacetyl chloride in presence of triethylamine give 9-10 and 11-12 respectively. All the synthesized  compounds 1-12 have been screened for their antibacterial as well as antifungal activities and compared with reference drugs streptomycin and fusidic acid respectively. These synthesized compounds were screened for their antibacterial activity against S. aureus and B. subtillis and antifungal activity against A. niger and C. albicans. The melting points were determined in open glass capillaries tubes. Purity of the compounds was checked by thin layer chromatography (TLC) on silica gel G plates and spots were located by using iodine chamber. All the newly synthesized compounds were confirmed by elemental (C, H, N) and spectral IR, ¹HNMR analysis. In this series compound 10 showed better antibacterial activity than reference drug streptomycin and compounds 10 and 12 were found to be more potent antifungal agents than reference drug fusidic acid

Quinoline, Azetidinone,

Antibacterial activity,

Antifungal activity

INTRODUCTION: Quinoline derivatives represent one of the most active classes of compounds possessing a wide spectrum of biological activity. They are widely used in pharmaceuticals and agrochemicals. Several reports have been published on the biological activity of quinoline derivatives including their antimicrobial ^{1, 2}, antibacterial ³, anti-inflammatory ⁴, anticancer ⁵ and anticonvulsant ⁶ activities. Similarly, various azetidinones have attracted considerable attention as they are also endowed with a wide range of pharmaceutical activities including anticonvulsant⁷, antimicrobial ⁸, anti-inflammatory ^{9, 10} and antibacterial ^{11, 12} activities.

Looking to the medicinal importance of quinolines and azetidinones, we report here the synthesis of new class of heterocyclic molecules in which all of these moieties are present and try to develop potential bioactive molecules.

METERIAL AND METHODS:

All reagents and solvents were of analytical grade and used directly. Reactions were routinely performed in oven-dried borosil glassware. The melting points of compounds were determined in open capillaries with the help of thermonic melting point apparatus and were uncorrected. The homogeneity of all newly synthesized compounds was routinely checked by thin layer chromatography (TLC) on silica gel G plates and spots were located by using iodine chamber. Elemental analysis (C, H, N) of all the synthesized compounds were determined by Perkin-Elmer 2400 elemental analyzer, and results were found within the ± 0.4% of theoretical values. The IR spectra were recorded on a Beckman Acculab-10 spectrometer (ν_max in cm^-1) and the ¹H NMR spectra were recorded by Brucker DPX-300 MHz using CDCl₃ as solvent.

 Pharmacological studies:

All the newly synthesized metal complexes were tested for their antimicrobial activity. The effects of unknown metal complexes were compared with the standard drug streptomycin for bacteria and fusidic acid for fungi. Antibacterial activity was performed against S. aureus, B. subtillis and antifungal activity against A. niger and C. albicans. The antibacterial activity was assayed by cup plate method ¹³ and antifungal activity was assayed by standard agar disc diffusion method ¹⁴.

RESULTS AND DISCUSSION:

The antibacterial activity of compounds 1-12 and the standard drug streptomycin, was carried out against S. aureus and B. substillis. Results showed the varying degree of antibacterial activity of all the compounds tested (table-1). From the result it is clear that compound 10 showed excellent antibacterial activity, better than the standard drug and good inhibition zones against all the bacterial strains. Compounds 9,11 and 12 showed good antibacterial activity against all the tested organism. The other compounds of this series showed a moderate activity as compared to standard drug. Compounds 1-12 along with the reference drug fusidic acid were also tested for antifungal activity against A. niger and C. albicans (Table 1). The results of the antifungal screening revealed that all the tested compound 1-12 showed moderate to good antifungal properties. Out of these compounds tested, compounds 10 and 12 were found to be more potent antifungal agents against all the fungal strains than the reference drug.

TABLE 1:  ANTIBACTERIAL AND ANTIFUNGAL ACTIVITY OF COMPOUNDS 1-12

Preparation of Benzylic azides/2-methyl benzylic azide:

To a solution of benzyl alcohol (1.0 equiv) in Dichloromethane (2.6 ml) was added PBr₃ (0.34 equiv) at room temperature. The reaction mixture was stirred for 1 h and then the solvent was removed under reduce pressure. The crude product was dissolved in DMSO (2.6 ml) and NaN₃ (2.5 equiv) was added at 0⁰C. The mixture was stirred 16 h and diluted with water and extracted with EtOAc. The product was dried with Na₂SO₄ and concentrated under reduced pressure to obtain the crude material which was purified on silica gel to yield the benzylic azides.

Preparation of Ethyl quinoline-3-carboxylate (1)

To a solution of substituted benzylic azide (1.0 mol) in toluene (20 ml) were added TfOH (1.0 mol) at room temperature respectively. The reaction mixtures were stirred until the evolution of N₂ gas bubbles subsided. The reaction mixtures were stirred for 3h and then added with sat. NaHCO₃ to dilute the reaction. The reaction mixtures were extracted with EtOAc (40 ml) and then DDQ was added and stirred for 5 min. The solvent was removed under reduced pressure to obtain the crude material which as purified on silica gel using hexane to yield compounds 1-2.

Yield (67), m.p:156 ⁰C; IR (KBr) _max in cm^-1 1296 (C-N), 1575 (-N=CH), 1724 (-C=O), 1784 (COOEt), 3017 (C-H aromatic); ¹H-NMR (DMSO-d₆ δ ppm): 3.25 (s, 5H, OC₂H₅), 7.72-8.30 (m, 6H, ArH); Anal. Calcd. for C₁₂H₁₁NO₂ :  C, 71.63; H, 5.51; N, 6.96: Found: C, 71.66; H, 5.54; N, 6.94%.

 Ethyl 8-methylquinoline-3-carboxylate (2):

Yield (61), m.p: 173⁰C; IR (KBr) _max in cm^-1 1299 (C-N), 1573 (-N=CH), 1720 (-C=O), 1787 (COOEt), 3015 (C-H aromatic); ¹H-NMR (DMSO-d₆ δ ppm): 2.23 (s, 3H, CH₃), 3.27  (s, 5H, OC₂H₅), 7.70-8.31 (m, 5H, ArH); Anal. Calcd. for C₁₃H₁₃NO₂ :  C, 72.54; H, 6.09; N, 6.51: Found: C, 72.56; H, 6.12; N, 6.54%.

Preparation of Quinoline-3-carbohydrazide (3):

A mixture of compounds1-2 (1.0 mol) and hydrazine hydrate (2.0 mol) in absolute ethanol (80 ml) was refluxed for 20 h respectively. The reaction mixtures were cooled and poured on crushed ice and separated solids were filtered, washed with cold water, dried and recystalliized from ethyl acetate to yield compound 3-4. Yield (56), m.p: 168⁰C; IR (KBr) _max in cm^-1 1295 (C-N), 1577 (-N=CH), 1726 (-C=O), 3013 (C-H aromatic),  3324 (-C-NH); ¹H-NMR (DMSO-d₆ δ ppm):  4.65 (hump, 2H, NH₂ exchangeable), 7.46 (br, 1H, NH exchangeable), 7.71-8.30 (m, 6H, ArH); Anal. Calcd. for C₁₀H₉N₃O :  C, 64.16; H, 4.85; N, 22.45: Found: C, 64.18; H, 4.84; N, 22.44%.

SCHEME: 1

Methylquinoline-3-carbohydrazide (4):

Yield (52), m.p: 185⁰C; IR (KBr) _max in cm^-1 1297 (C-N), 1579 (-N=CH), 1723 (-C=O), 3010 (C-H aromatic), 3326 (-C-NH); ¹H-NMR (DMSO-d₆ δ ppm): 2.21 (s, 3H, CH₃), 4.65 (hump, 2H, NH₂ exchangeable), 7.40 (br, 1H, NH exchangeable), 7.72-8.31 (m, 5H, ArH); Anal. Calcd. for C₁₁H₁₁N₃O :  C, 65.66; H, 5.51; N, 20.88: Found: C, 65.69; H, 5.54; N, 20.85%.

Preparation of N’-(pyridine-2-ylmethylene) quinoline-3-carbohydrazide (5):

A solution of compounds 3-4 (1.0 mol) in methanol (50 ml) were refluxed with picolinaldehyde (1.0 mol) in the presence of glacial acetic acid (4 ml) for 11h respectively. The reaction mixtures were concentrated, cooled and then poured into ice water. The separated solids were filtered and recrystallized from ethanol to yield compounds 5-6.

Yield (47), m.p: 192⁰C; IR (KBr) _max in cm^-1 1295 (C-N), 1512 (N-N), 1573 (-N=CH), 1726 (-C=O), 3013 (C-H aromatic), 3322 (-C-NH); ¹H-NMR (DMSO-d₆ δ ppm):  7.44 (d, 1H, NH), 7.71-8.33 (m, 10H, ArH), 8.63 (s, 1H, -N=CH); Anal. Calcd. for C₁₆H₁₂N₄O :  C, 69.55; H, 4.38; N, 20.28: Found: C, 69.56; H, 4.39; N, 20.24%.

 8-Methyl - N’- (pyridine - 2 - ylmethylene) quinoline -3-carbohydrazide (6):

Yield (44), m.p: 195⁰C; IR (KBr) _max in cm^-1 1294 (C-N), 1507 (N-N), 1577 (-N=CH),  1728 (-C=O), 3016 (C-H aromatic), 3324 (-C-NH); ¹H-NMR (DMSO-d₆ δ ppm): 2.25 (s, 3H, CH₃), 7.43 (d, 1H, NH), 7.73-8.30 (m, 9H, ArH), 8.61 (s, 1H, -N=CH); Anal. Calcd. for C₁₇H₁₄N₄O :  C, 70.33; H, 4.86; N, 19.30: Found: C, 70.36; H, 4.84; N, 19.34%.

 N’-(Pyridine - 2 - ylmethylene) quinoline-3-carbohydrazide (7):

A mixture of compound 3-4 (1.0 mol) and different substituted benzyldehyde (1.0 mol) in 50 ml of methanol along with glacial acetic acid (2-3 drops) was refluxed for 12 h. The reaction mixtures were cooled. The solids were obtained then filtered, washed with water, dried and recrystallized from appropriate solvents to furnish compounds 7-8.

Yield (), m.p: 214⁰C; IR (KBr) _max in cm^-1 1292 (C-N), 1505 (N-N), 1574 (-N=CH), 1723 (-C=O), 3012 (C-H aromatic), 3325 (-C-NH), 3450 (OH); ¹H-NMR (DMSO-d₆ δ ppm): 7.41 (d, 1H, NH), 7.70-8.29 (m, 10H, ArH), 8.66 (s, 1H, -N=CH), 12.20 (s, 1H, OH); Anal. Calcd. for C₁₆H₁₂N₄O :  C, 69.55; H, 4.38; N, 20.28: Found: C, 69.57; H, 4.34; N, 20.26%.

 8-Methyl-N’-(pyridine-2 -ylmethylene) quinoline -3-carbohydrazide (8):

Yield (45), m.p: 221⁰C; IR (KBr) _max in cm^-1 1297 (C-N), 1509 (N-N), 1577 (-N=CH),  1726 (-C=O), 3014 (C-H aromatic), 3326 (-C-NH), 3455 (OH); ¹H-NMR (DMSO-d₆ δ ppm): 2.23 (s, 3H, CH₃), 7.46 (d, 1H, NH), 7.73-8.31 (m, 9H, ArH), 8.64 (s, 1H, -N=CH), 12.25 (s, 1H, OH);   Anal. Calcd. For C₁₇H₁₄N₄O:  C, 70.33; H, 4.86; N, 19.30: Found: C, 70.36; H, 4.84; N, 19.34%.

 Preparation of N-(3-Chloro-2-oxo-4-(pyridine-2-yl)azetidin-1-yl)quinoline-3-carboxamide (9):

Take the solution of chloroacetyl chloride (1.0 mol) in dry dioxane (50 ml), was added drop wise during 2h to a well stirred solution of compounds 5-6 (1.0 mol) and compounds 7-8  (1.0 mol) respectively. The reaction mixtures were stirred continuously 4h, cooled and poured it into water. A solids were obtained, filtered and washed with water and recystallized from acetone to yield compounds 9-10 and compounds 11-12.

Yield (43), m.p: 231⁰C; IR (KBr) _max in cm^-1 661 (C-Cl), 1299 (C-N), 1513 (N-N), 1571 (-N=CH),  1729 (-C=O), 3012 (C-H aromatic), 3324 (-C-NH), 3458 (OH); ¹H-NMR (DMSO-d₆ δ ppm):   7.43 (d, 1H, NH), 7.70-8.31 (m, 10H, ArH), 8.65 (s, 1H, -N-CH-pyridine), 8.84 (s, 1H, N-CH of azetidinone); Anal. Calcd. for C₁₈H₁₃ClN₄O₂ :  C, 61.28; H, 3.71; N, 15.88: Found: C, 61.26; H, 3.74; N, 15.87%.

 N-(3-Chloro-2-oxo-4-(pyridine-2-yl) azetidin - 1-yl)-8-methylquinoline-3-carboxamide (10):

Yield (39), m.p: 237⁰C; IR (KBr) _max in cm^-1 665 (C-Cl), 1292 (C-N), 1509 (N-N), 1577 (-N=CH),  1722 (-C=O), 3014 (C-H aromatic), 3320 (-C-NH), 3452 (OH); ¹H-NMR (DMSO-d₆ δ ppm): 2.21 (s, 3H, CH₃), 7.40 (d, 1H, NH ), 7.72-8.30 (m, 9H, ArH), 8.60 (s, 1H, -N-CH-pyridine), 8.80 (s, 1H, N-CH of azetidinone); Anal. Calcd. for C₁₉H₁₅ClN₄O₂ :  C, 62.21; H, 4.12; N, 15.27: Found: C, 62.24; H, 4.14; N, 15.24%.

 N-(3-Chloro-2-(2-hydroxyphenyl)-4-oxoazetidin-1-yl)-8-methylquinoline-3-carboxamide (11):

Yield (40), m.p: 245⁰C; IR (KBr) _max in cm^-1 660 (C-Cl), 1297 (C-N), 1507 (N-N), 1575 (-N=CH),  1729 (-C=O), 3013 (C-H aromatic), 3326 (-C-NH), 3455 (OH), 3324 (-C-NH); ¹H-NMR (DMSO-d₆ δ ppm): 7.42 (d, 1H, NH ), 7.70-8.32 (m, 10H, ArH), 8.61 (s, 1H, -N-CH-pyridine), 8.82 (s, 1H, N-CH of azetidinone), 12.21 (s, 1H, OH); Anal. Calcd. for C₁₉H₁₄ClN₃O₃ :  C, 62.05; H, 3.84; N, 11.43: Found: C, 62.04; H, 3.82; N, 11.44%.

 N-(3-Chloro-2-(2-hydroxyphenyl)-4-oxoazetidin-1-yl)-8-methylquinoline-3-carboxamide (12):

Yield (38), m.p: 265⁰C; IR (KBr) _max in cm^-1 667 (C-Cl), 1298 (C-N), 1505 (N-N), 1573 (-N=CH),  1721 (-C=O), 3018 (C-H aromatic), 3329 (-C-NH), 3453 (OH); ¹H-NMR (DMSO-d₆ δ ppm): 2.23 (s, 3H, CH₃), 7.46 (d, 1H, NH ), 7.71-8.30 (m, 9H, ArH), 8.63 (s, 1H, -N-CH-pyridine), 8.83 (s, 1H, N-CH of azetidinone), 12.21 (s, 1H, OH); Anal. Calcd. for C₂₀H₁₆ClN₃O₃ :  C, 62.91; H, 4.22; N, 11.01: Found: C, 62.94; H, 4.24; N, 11.04%.

 CONCLUSION: Compounds 1-8 exhibited mild to moderate antibacterial and antifungal activities. Cyclization of compounds 5-8 into their corresponding azetidinone congeners 9-12 markedly enhanced the antibacterial as well as antifungal activities.

 ACKNOWLEDGEMENT: We are thankful to SAIF Punjab University, Chandigarh India for spectral and analytical analysis of newly synthesized compounds. We are also thankful to Department of Microbiology LLRM Medical College Meerut UP for their antimicrobial activity.

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    How to cite this article:

    Singh I and Kumar A: Synthesis and Antimicrobial Activity of Some Quinoline Derivatives. Int J Pharm Sci Res 2016; 7(6): 2563-67.doi: 10.13040/IJPSR.0975-8232.7(7).2563-67.

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