INTRODUCTION:

Nomenclature and Numbering system:

Quinolines are class of organic compound of the heteroaromatic series characterized by a double-ring structure composed of benzene and pyridine ring fused at two adjacent carbon atoms. The benzene ring contains six carbon atoms, while the pyridine ring contains five carbon atoms and one nitrogen atom¹. Quinoline also known 1-azanapthaline, 1-benzazine or benzo [b] pyridine is a heterocyclic organic compound, with formula C₉H₇N and it is a colourless liquid with strong odour. Quinoline skeleton posses pharmacological properties such as antimalerial, cytotoxic activity, antitumor activity, antidotal and antibacterial, antimicrobial and antifungal activities, and also used as antifoaming and flavouring agent^2-5.

2. Various Method of Quinoline synthesis⁶:

1] Skraup Synthesis:

Quinoline is produced when aniline, conc sulfuric acid, glycerol and mild oxidizing agent are heated together, the reaction proceeds via dehydration of glycerol acrolein. It is the best reaction for synthesis of quinoline.

2] Doebner-Miller Ring Synthesis:

The interaction of enone group (carbonyl group) to aniline takes place producing quinoline derivative. Improvement of this reaction includes the use of 2 phase organic or aqueous acid system.

3] Friedlander Synyhesis:

The reaction proceeds through aldol type condensation O-amino aryl aldehyde are reacted with a ketone carrying an alpha methylene group.

4] Combes Synthesis:

Condensation of 1, 3 dicarbonyl compound with the arylamine gives the high yield of amino enone, which can be cyclized with conc acid.In order to access 4-unsubstituent quinoline, a 1, 3 keto aldehyde, guarantees the regioselactivity.

5] Camps Quinoline Sythesis:

Camps quinoline synthesis is (also known as camps cyclization) chemical reaction whereby o-acyl Aminoacetophenone is transform into two different hydroxyl quinolines (A and B) by using hydroxide ion.the relative proportions of the hydroxyquinolines (A and B) produced are dependent upon the reaction conditions and structure of the starting material. Although the reaction product is commonly depicted as a quinoline (the enol form), it is believed that the keto form predominates in both the solid state and in solution, making the compound a quinolone.

6] Niementowski Quinoline Synthesis:

The Niementowski quinoline synthesis is the chemical reaction of anthranilic acid and ketones or aldehyde to form alpha hydroquinoline derivatives.

7] Gould-Jacobs Reaction:

The Gould-Jacobs reaction is an organic synthesis for the preparation of quinolines in this reaction aniline or an aniline derivatives first react with malonic acid derivative ethyl ethoxymethylenemalonate with substituted of the ethoxy group by nitrogen. A benzannulation takes place by application of heat to a quinoline. The ester group is hydrolyzed by sodium hydroxide to the carboxylic acid and decarboxylation again by application of heat to 4-hydroxyquinoline.

3. REACTIONS OF QUINOLINE⁷:

1] Electrophilic Reaction-

Regiochemistry.

Under strong acidic condition reaction occurs via ammonium salt.

Attacks occurs at the benzo-rather than hetero-ring.

Reactions are faster these of pyridine but slower than those of naphthalene.

a] Nitration Reaction-

In case of quinolines equal amount of the 5-and 8-isomer are produced.

b] Sulfonation-

Halogenation is also possible but product distribution is highly dependent on condition. It is possible to introduce halogen into the hetero-ring under the correct condition. Friedel-craft alkylation/acylation is not usually possible.

2] Nucleophilic Reaction-

Regiochemistry,

Attack occur at hetero-rather than benzo-ring. They are enerally more reactive than pyridines to nucleophilic attack.

Carbon Nucleophilic-

Oxidation is required to regenerate aromaticity.

Amination-

Displacement of halogen-

4. OBJECTIVES:

1. To design, synthesis and evaluation of new quinoline derivatives by proposed route of synthesis.

2. To characterize structure of synthesized quinoline derivatives by physiochemical and spectroscopical analysis.

3. To screen the synthesized derivatives for possible biological activity.

5. MATERIAL AND METHOD:

5.1.1 Chemicals:

The chemicals used in present work AR grade and LR grade, purchased from Research laboratory and sigma alrich. Fine chemicals and research lab chemicals and used as received. The list of chemicals used were 5-chloro-2-nitrobenzaldehyhe, 3-methoxy-2 nitrobenzaldehyde, acetophenone, acetyl furan, cylohexanone, n-methylpyrilidone, Iso butyl methyl ketone, conc-HCl, n-hexane, ethylacetate silica gel, light paraffin oil, ethanol.The water used was double distilled deionised water.

5.1.2 Identification and characterization of synthesized product:

The synthesized compounds were scaled for yield and purified by recrystallisation with suitable solvent system. The purified compounds were assigned for physical constant determination and further subjected for spectral analysis like thin layer chromatography, Infrared spectroscopy, Nuclear magnetic resonance spectroscopy and Gas chromatography and Mass spectroscopy.

1. Melting point determination:

The melting point of the synthesized compounds were determined using Veego VMP-I melting point apparatus and recorded in degree celsius.

2. Thin layer chromatography:

Thin layer chromatography was performed on percolated silica gel plates with suitable solvent system. The Rf values were recorded accordingly.

3. Infrared spectroscopy:

The Infrared spectra for the synthesized compounds were recorded using JASCO-FTIR 410 spectrophotometer using potassium bromide pellet technique.

4. Nuclear magnetic resonance spectroscopy: 1HNMR and 13 CNMR spectra of the synthesized compounds were taken using tetramethyl silane as an internal standard. 1HNMR spectra were recorded with DMSO and CDCl3 as a solvent.

5. Gas chromatography and Mass spectroscopy:

Gas chromatography and mass spectra of synthesized compounds were recorded using methanol as a solvent.

5.2 Scheme for synthesis:

5.3 Proposed Mechanism For Scheme:

The mechanism based on the Friedlaender Reaction.The Friedlaender synthesis of quinoline is a classic method in that involves two steps, where in first step reduction of onitro aryl aldehyde is first achieved by using the suitable reducing agent and its converted into the o-amino aryl aldehyde followed by the condensation of enolizable carbonyl compound in presence of a Bronsted or Lewis catalyst. The relative instability of the intermediate (o-amino aldehyde). With its strong tendency to undergo selfcondensation made such reaction.

5.4 Reaction:

5.5 List of compound synthesized:

Compound

Chemical Name

Structure

6-chloro-2-benzoquinoline

6-chloro-2-furan,3-methylquinoline

7-methoxy-2-furan-3-methylquinoline

6-chloro-2-methyl-3-ethylquinoline

6-chloro-2-pyrrole(1-methyl)quinoline

5.6. Procedure for Synthesis:

Conventional Synthesis-

In a single neck round bottom flask take a substituted o-nitro aryl aldehyde (2 mmol) and an enolizable ketone (2 mmol) were uniformly mixed with SnCl2.2H2O (6 mmol), the mixture was stirred vigorously. Then the resulting mixture was reflux for 5 hrs. The reaction mixture was cooled at room temperature and rendered basic with the 10% NaHCO3, and then extracted with ethylacetate. The precipitate which obtained after filter purified by recrystalistion from ethanol. Which is further purified by the coloumn chromatography over silica gel by using the suitable mobile phase like the n-hexane: ethyl acetate 9:1 respectively.

5.8 SPECTRAL DATA OF SYNTHESIZED COMPOUNDS:

1]6-Chloro-2-benzoquinoline:

IR (KBr, cm-1): 791 (C-Cl), 1568.81 (Aromatic C=C), 1669 (C=N).

1H-NMR (delta ppm): 7.9 (Aromatic ring), 8.2 (Pyridine).

13C-NMR (delta ppm): 79 (C-Cl), 135 (Aromatic ring), 130 (C in Aromatic ring), 30 (C-C) 57 (C-N), 112 (C=C).

2]6-Chloro-3-methyl-2-furanquinoline:

IR (KBr, cm-1): 1140 (C-O-C), 539 (C-Cl), 1523.49 (C=C), 1703 (C=N).

1H-NMR (delta ppm):7.8 (Aromatic ring), 1.213 (CH3), 8.5 (Pyridine), 7.4 (furan).

13C-NMR (delta ppm): 127 (C in Aromatic ring), 79 (C-Cl), 56 (C-O), 32 (C-N), 15 (C-CH3), 132 (Aromatic ring).

3] 7-methoxy-3-methyl-2-furanquinoline:

IR (KBr, cm-1): 1655 (C=N), 1305 (OCH3), 1079.94 (C-O-C), 1396 (C=C), 1610 (CC Stretch).

1H-NMR (delta ppm): 3.812 (O-CH3), 7.21 (Aromatic ring), 7.4 (furan), 1.4 (CH3), 8.2 (Pyridine).

13C-NMR (delta ppm): 140 (Aromatic ring), 146 (C in Aromatic ring), 79 (C-O), 31 (C-N), 15 (C-CH3)

4] 6-Chloro-2-methyl-3-ethylquinoline:

IR (KBr, cm-1): 1346.07 (C=C), 551.54 (C-Cl), 1645 (C=N)

1H-NMR (delta ppm): 7.76 (Aromatic ring), 1.21 (CH2), 1.21 (CH3), 2.410 (C2H5), 7.3 (Pyridine)

13C-NMR (delta ppm): 79 (C-Cl), 31 (C-CN), 13 (C2H5), 129 (Aromatic ring), 146 (C in Aromatic ring), 115 (C=C).

5] 6-Chloro-2-pyrrole (1-methyl) quinoline:

IR (KBr, cm-1): 564 (C-Cl), 1114.69 (C-C), 3390 (N-CH3), 1474 (C=C), 1660 (C=N)

1H-NMR (delta ppm): 7.592 (Aromatic ring), 8.1 (Pyridine), 1.4 (CH3), 6.7 (Pyrrole).

13C-NMR (delta ppm): 79 (C-Cl), 25 (C-C), 32 (C-N), 129 (Aromatic ring), 132 (C in Aromatic ring), 115 (C=C).

6. BIOLOGICAL EVALUATION:

Antimicrobial Sensitivity Test:

Antimicrobial sensitivity test has been carried out using disc-diffusion method performed in Nutrient agar medium for bacteria and Sabouraud’s agar medium for fungi.

Preparation of culture media:

5.6 gm of Nutrient agar medium was dissolved in 200 ml of distilled water, boiled and sterilized in autoclave at 15 lbs pressure (121⁰C) for 15 min. After sterilization the medium was divided in three parts and 20 ml each Bacterial suspension were added to three different parts of medium (pour plate method for inoculation). These mixtures were then poured in sterile petri-plates in aseptic conditions. Approximately 20-25 ml of media was poured on each plate. the media was allowed to get solidified and then prepared bores with the help of cork bores (0.85cm) without further delay known concentration of synthesized derivatives was applied at the aliquot spacing to the surface of culture plates, it was then transfered quickely to the incubator for 24 hrs at 37 ⁰C.

OBSERVATIONS:

(a) Petri plate showing Zone of inhibition in (mm) of extract against Basillus subtilis.

(b) Petri plate showing Zone of inhibition in (mm) of extract against Pseudomonas aeruginosa.

7. RESULT AND DISCUSSION:

The main objective of the study was to design and synthesized substitute Quinoline derivatives. The substituted Quinoline derivatives were synthesized in fairly good yield. A total five derivatives were synthesized (SS1-SS5).The yield obtained from the synthesized compound ranging from 54%-67%.

Thin layer chromatography was used to acess the complection of the reactions and purity of the final product giving a single spot on the TLC Plate (Silica Gel G), with various solvent system.

The structural elucidation of synthesized compounds were done by interpretation of IR, 1HNMR, 13 CNMR, Mass. All the compounds gives the satishfactory IR, NMR data.

IR Spectroscopy:

Data exhibited peaks at wave number 550-800 shows C-Cl group, 1450-1600 shows C=C in Aromatic group, 1600-1700 shows C=N group, 1600-1700 shows C-C stretch group, 900-1300 shows C-O-C group.

13CNMR Spectroscopy

Data exhibited peaks at 125-150 shows Aromatic ring, 10-80 shows C-Cl group, 40-80 peaks shows C-O group, 0-50 peaks shows C-N group.

1HNMR Spectroscopy:

Value 7-8 shows presence of Aromatic ring, 0-1.5 shows CH3, 7.4-8.5 shows Pyridine, 3-5 shows methoxy group.

The synthesized compounds were screened for the Anti-bacterial and Anti-fungal activity.

7.1 Anti-bacterial Activity:

The synthesized compounds were screened for the Anti-bacterial activity against two gram positive bacteria.

1] Bacilius Subtilis-6633

2] Staphylococcus aureus-2943

Compounds were screened for antibacterial activity against one gram negative bacteria

1] Pseudomonas aerogenosa-19429

And activity compared to the standard drug- Ampicilin.

Method used: Cup plate method.

7.2 Anti-fungal Activity:

The Synthesized Compounds were screened for Anti-fungal activity against the following strains

1. Candida albicans: 3628

2. Aspergillus niger: 1003

3. Candida utilis: 3055

And the activity was compared with standard drug-Fluconazole.

Method used: Cup plate method.

8. CONCLUSION:

The synthetic scheme reported in this study design is novel example in heterocyclic synthesis. The synthesis of different Quinoline derivatives was carried out by using substituted nitrobenzaldehyde as starting material. This was further reacted with different enolizable ketone group in presence of stannous chloride, to yield various Quinoline derivatives (SS1-SS5).with yields ranging from 54% to 67%.

The IR, NMR and Mass for all synthesized compounds corresponds to anticipated structures.

All the confirmed compounds were screened for Antibacterial and Antifungal activity. Results suggested that-

For Bacillus subtilis-

Amongst all synthesized derivatives compounds SS3, SS4, SS5 shows demonstrated satisfactory activity when compared to standard drug Ampicilin against Bacillus subtilis. These compounds possess substitution of heterocyclic ring which migh be responsible for maximum activity.

For Staphylococcus aureus-

Amongst all synthesized derivatives compounds SS2, SS3, SS5 shows demonstrated satisfactory activity when compared to standard drug Ampicilin against Staphylococcus aureus these compound possess substituted of heterocyclic ring which might be responsible for maximum activity.

For Pseudomonas aerogenosa-

Amongst all synthesized compounds SS1, SS2, SS3, SS5 Shows demonstsrated higher activity but lesser than the Ampicilin against Pseudomonas aerogenosa these compounds possess substituted of heterocyclic ring which might be responsible for maximum activity.

All the confirmed compounds were screened for Antifungal activity. Result suggested that-

For Candida albicans-

Amongst all synthesized derivatives, compounds SS1, SS2, SS3, SS5 Shows demonstrated satishfactory activity but lesser than the Fluconazole against Candida albicans because of heterocyclic and fused heterocyclic substituent were exhibited and might be responsible for maximum activity.

9. REFERENCE:

1. Pramod N, Jayakumar Swamy BHM, Vijay Kamat,Neelam Raj et al, Sep 2011, Synthesis Characterization and Wound Healing Activity of 1-[8-Methyl-Foro (2, 3b) Quinoline-2yl] Ethanone Derivatives, International Journal of Chemical and Pharmaceutical Science,Vol.2 [3], 9-10.

2. P.P.Jumade, S.J.Chourasia, U.V.Kharabe, D.Mude et al, 2009, Synthesis of newer Mannich bases of Quioline Derivatives for Antibacterial Activity, International Journal of Chemical Science, Vol.7 (3), 1519-1520.

3. Divyesh C. Mungra, Manish P. Patel, Ranjan G.Patel et. al, 2009,An efficient one-pot synthesis and in vitro Antibacterial Activity of new pyridine derivatives bearing the tetrazoloquinoline nucleus, General Paper, 64-74.

4. Ram Shankar Upadhayaya, Jaya Kishor Vandavasi, et al, 2010, Novel Quinoline and Napthalene derivatives as Potent Antimicrobial Agent, European Journal of Medicinal Chemistry, Vol. (45), 1854-18.

5. Srinubabu Maddela, Makula Ajitha, et al, May 2014, Designed and Synthesis of Novel Quinoline 3-Carbohydrazone Derivatives for their Antimicrobial and Antioxidant activity, International Journal of Pharmacy and Pharmaceutical Science, Vol. (6), 254258.

6. N. Kannappan, B.S.R.Reddy, S.Sen et.al, 2009, Synthesis and Chemical Characterization of Quinoline Imine Derivatives, Journal of Applied Chemical Research, Vol. (9), 59-61.

7. Clark J.S., 2012, Heterocyclic Chemistry, 54-59.

Received on 03.03.2018 Modified on 01.04.2018

Res. J. Pharma. Dosage Forms and Tech.2018; 10(3):163-168.

DOI: 10.5958/0975-4377.2018.00025.3

Compound No.	Molecular Formula	Molecular Weight	M.P. Range (⁰C )	Mobile Phase	Rf Value
1	C₁₅H₁₀NCl	239.45	125	n-Hexane:ethylacetate (9:1)	0.64
2	C₁₄H₁₀NOCl	243.45	230	n-Hexane:ethyl acetate (9:1)	0.82
3	C₁₅H₁₃ NO	223	240	n-Hexane:ethyl acetate (9:1)	0.56
4	C₁₁H₁₂ NCl	193.45	215	Petether:ethyl acetate (5:5)	0.82
5	C₁₄H₁₁ NCl	228.45	259	n-Hexane:ethyl acetate (9:1)	0.62