Antibacterial Evaluation of Novel 2-Aryl-Quinoline -3- Carbaldehyde Derivatives

 

Hemant Badwaik¹*, S. Venkataraman², Deepa Thakur¹, Minu Vinod¹, J.Raamamurthy² and Kiran Deshmukh².

¹Rungta College of Pharmaceutical Sciences and Research, Bhilai (C.G)

²K.M. College of Pharmacy, Madurai (T.N)

*Corresponding Author E-mail: hemantbadwaik@rediffmail.com

ABSTRACT:

Acetanilide was cyclized via Vilsmeier–Haack reagent to give 2- chloro -3- formyl quinoline. The aldehydic group was protected to prevent the preferential attack of nitrogen nucleophiles. The protection of aldehydic group in the present system was achieved with ethylene glycol to afford dioxolan derivative. Dioxolan derivative treated with nitro substituted phenyl hydrazine in alcoholic solution followed by deprotection of aldehydic group afforded the 2-(2-(2-nitrophenyl) hydrazinyl) quinoline-3-carbaldehyde and 2-(2-(2, 4-dinitrophenyl) hydrazinyl) quinoline-3-carbaldehyde. The synthesized derivatives were screened for antimicrobial activity.

 

 

 

INTRODUCTION:

Antibiotics are one of our most important weapons in fighting bacterial infections and have greatly benefited the health-related quality of human life since their introduction. However, over the past few decades these health benefits are under threat as many commonly used antibiotics have become less and less effective against certain illnesses not only because many of them produce toxic reactions but also due to emergence of drug resistant bacteria. It is essential to investigate newer drugs with lesser resistance. Systematic studies among various pharmacological compounds have revealed that any drug may have the possibility of possessing diverse functions and thus may have useful activity in completely different spheres of medicine^{1, 2}.

 

Quinoline and their derivatives are receiving increasing importance due to not only anti-malarial but also anti-bacterial, anti-viral, anti-fugal, anti-asthmatic, antihypertensive, analgesic & anti-inflammatory, cytotoxic, anti-platelet, antiprion, H⁺/K⁺ ATPase inhibitor, leukotrien biosynthesis inhibitor activity^3-7. Due to such a wide range of applicability in medicinal field, there is increasing interest in the development of efficient methodologies for the synthesis of quinoline derivatives.

 

Vilsmeier-Haack reagent aided synthesis of 2-chloro-3 formyl quinolines, occupy a prominent position as they are key intermediates for further various functional group interconversions. The aldehydic group was protected to prevent the preferential attack of nitrogen nucleophiles. The protection of aldehydic group in the present system was achieved with ethylene glycol to afford dioxolan derivative. Dioxolan derivative treated with nitro substituted phenyl hydrazine in alcoholic solution followed by deprotection of aldehydic group afforded the nitro substituted aryl-2-quinoline. The synthesized derivatives were screened for antimicrobial activity.

 

ANTIBACTERIAL ACTIVITY:

Antibacterial activities of the compounds were assessed by in vitro growth inhibitory activity against Escherichia coli (ATCC 25922) and Staphylococcus aureus (ATCC 25923) by using the disc diffusion method^8,9. The compounds to be tested were dissolved in DMF to final concentrations 50 μg per ml soaked in filter paper (Whatman No 4) discs of 6 mm diameter and 1 mm thickness. The discs were placed on the already bacterial seeded plates and incubated at 35 ± 2 °C for 24 h. Amikacin disc (30 μg per disc) was used as standard antibacterial drug. The inhibition zones were measured after subtracting inhibition due to solvent used.

 

EXPERIMENTAL:

The melting points of the synthesized compounds were determined by open capillary tube method and results were uncorrected. The purity of compounds were checked by TLC using silica gel G  as an adsorbent, chloroform and ethyl acetate (7:3) were used as mobile phase. The spot was visualized by Iodine vapour. The structures of the synthesized compounds were characterized by IR and H-NMR spectral analysis in which it complies with the normal values. IR spectra’s in KBR were recorded on a Perkin-Elmer 337 spectrophotometer and ¹H-NMR spectra’s were recorded on a Bruker DRX 200 MHz spectrophotometer using TMS as an internal standard.

 

2- Chloro -3- formyl quinoline [2].

To a solution of acetanilide (5 mmoles in dry DMF (15 mmoles) at 0-5°C POCL₃ (60mmoles) was added drop wise with stirring and mixture was then stirred at 80-90°C for time ranging between 4-16 hr. The mixture was poured onto crushed ice, stirred for 5 minutes and the resulting solid filtered, washed well with water and dried. The compound was recrystallized from ethyl acetate. Yield 80%; mp 143-145˚c; IR (KBr, cm^-1): 1688.06 (CO); 1H NMR (CDCl₃): 10.5 (s, 1H, CHO), 7.3 -8 (m, 4H, aromatic), 8.3 (s, 1H, hetro aromatic).

 

2-Chloro-3-(1, 3-dioxolan-2-yl) quinoline [3].

A solution of 2- chloro -3- formyl quinoline (2 mmoles) in toluene (20ml) containing ethylene glycol (6 mmoles) and few crystals of P-toluenesulfonic acid was heated under reflux for 4-5 hr in the presence of molecular sieve using a Dean-Stark trap. The cooled solution was treated with saturated aqueous sodium carbonate (10ml), dried (Na₂SO₄) and evaporated under vacuum to give 2-chloro-3- (1,3 – dioxolan-2-yl) quinolines as pale yellow solid, pure enough for further use. The crude products were recrystallised from ethyl acetate-pet. ether-toluene mixture. Yield 90%; mp 45 - 47˚c; IR (KBr, cm^-1): 1358.06 & 1110 (cyclic ether); 1H NMR (CDCl₃): 4.05 (m, 4H, (CH₂)₂), 6.1 (s, 1H, CH), 7.3 -8 (m, 4H, aromatic), 8.3 (s, 1H, hetro aromatic).

 

2-Phenyl-hydrazino-3-(1,3-dioxolan-2-yl) quinoline derivatives [4].

To an ethanolic solution of (Dioxolan quinoline Derivatives) (1mmole) were added substituted phenyl hydrazine (1mmole) and refluxed under pressure. The mixture was poured onto crushed ice, stirred for 5 min and the resulting solid filtered, washed well with water and dried. The crude products were recrystallised from ethanol.

 

[4a] Yield 87%; mp 70-73˚C; IR (KBr, cm^-1):3250 (Ar-NH), 1505.03 & 1306.81(Ar-NO₂ ); 1H NMR (CDCl₃): 4.0 [m, 4H, (CH₂)₂], 5.8 (s, 1H, CH), 6.1 (d, 2H, NH-NH), 6.7 -7.8 (m, 8H, aromatic), 8.1 (s, 1H, hetro aromatic).

 

[4b] Yield 90%; mp 75-77˚C; IR (KBr, cm^-1):3244.3 (Ar-NH), 1495.75 & 1326.44 (Ar-NO₂ ); 1H NMR (CDCl₃): 4.0 [m, 4H, (CH₂)₂], 5.8 (s, 1H, CH), 6.1 (d, 2H, NH-NH), 6.7 - 8.0 (m, 7H, aromatic), 8.1 (s, 1H, hetro aromatic).

 

2-Phenyl-hydrazino-3-formyl quinoline derivatives [5].

To a solution of 2-phenyl-hydrazino-3-(1,3-dioxolan-2-yl) quinolines (1 mmoles) in acetone ( 5ml),was added TsOH (0.5 mmole) and the mixture stirred at room temperature for 30 min. On completion of reaction acetone was removed under pressure and ice was added to quench the catalyst. The combined organic layers were washed with water and dried over sodium sulphate. The solvent was removed under pressure to obtain the solid product, which was recrystallised from ethanol.

 

[5a] Yield 85%; mp 150-152˚C; IR (KBr, cm^-1): 1687.66 (CO), 1505.03 & 1306.81(Ar-NO₂ ), 3250 (Ar-NH); 1H NMR (CDCl₃): 4.0 [m, 4H, (CH₂)₂], 5.8 (s, 1H, CH), 6.1 (d, 2H, NH-NH), 6.7 -7.8 (m, 8H, aromatic), 8.1 (s, 1H, hetro aromatic),10.6 (s, 1H, CHO).

 

[5b] Yield 92%; mp 168-170˚C; IR (KBr, cm^-1): 1687.66 (CO), 1495.75 & 1326.44 (Ar-NO₂ ), 3250 (Ar-NH); 1H NMR (CDCl₃): 4.0 [m, 4H, (CH₂)₂], 5.8 (s, 1H, CH), 6.1 (d, 2H, NH-NH), 6.7 -8.0 (m, 7H, aromatic), 8.2 (s, 1H, hetro aromatic),10.6(s, 1H, CHO).

 

SCHEME

 

Table: Antibacterial activity

S.N	Compounds		Zone of Inhibition  against
	Structure	Code	E.coli	S.aureus
1		2	50%	32.3%
2		5a	70.0%	61.17%
3		5b	74.24%	66.33%
4	Amikacin (Standard)	s	100%	100%
5	DMSO (Control)	c	0.00%	0.00%

 

RESULT AND DISCUSSION:

Acetanilide was cyclized via Vilsmeier–Haack reagent to give 2- chloro -3- formyl quinoline. The aldehydic group was protected to prevent the preferential attack of nitrogen nucleophiles. The protection of aldehydic group in the present system was achieved with ethylene glycol to afford dioxolan derivative. Dioxolan derivative treated with nitro substituted phenyl hydrazine in alcoholic solution followed by deprotection of aldehydic group afforded the nitro substituted aryl-2-quinoline. The structures of the synthesized compounds were characterized by IR and ¹H-NMR spectral analysis in which it complies with the normal values. Compound 2 show weak antibacterial activity against S. aureus & E. coli, compound 5a and 5b possess moderate activity against S. aureus and good antibacterial activity against E. coli. The result revels that substitution of aryl hydrazine group at 2 position of 2- chloro -3- formyl quinoline enhances the antibacterial characteristics of the compounds.

 

REFERENCES:

1.       Abadi A, Hegazy G, El-zaher A. Bioorganic & Medicinal Chemistry. 2005, 13, 5759-5765.

2.       Henichart J, Perzyna A, Kulpsch F, Pommery N, et.al. Bioorganic & Medicinal Chemistry letters. 2004, 14, 2363-2365.

3.       Korth C, Klingenstein R, Melnyk P, Leliveld R, et.al. J.Med.Chem.2006, 49.

4.       Yum E, Yang O, Kyu Kang S, Cheon H, Kim S, et.al. Bull. Korean Chem. Soc. 2004, 25, 7, 1091-1094.

5.       Deshmukh M, Shelar M, Patils, et.al. Indian Journal of Heterocyclic Chemistry. 1997, 6, 181-184.

6.       Viahov R, Parushev S, Valhov J. Pure & Appl. Chem, 1990, 7, 1303-1306.

7.       Cheon H, Lim H, Lee D, European Journal of Pharmacology. 2001, 411, 181-186.

8.       Nandhakumar R.; Vishwanathan H.; Suresh T.; Mohan P.S. Fitoterapia 2002, 73, 734.

9.       Karvembu, R.; Natarajan, K. Polyhedron 2002, 21, 219.

 

 

Received on 21.02.2011        Modified on 23.03.2011

Accepted on 12.04.2011        © AJRC All right reserved