Synthesis and Biological Evaluation of Some Novel Quinoline Derivatives

Sarade A.N., Kalyane N.V. and Shivkumar B.

Department of pharmaceutical chemistry, B. L.D.E.A’S college of Pharmacy, Bijapur, Karnataka, 586103. India

*Corresponding Author E-mail: an.sarade@gmail.com

ABSTRACT:

Antiviral, anti-inflammatory. Most potent is antimicrobial activity so we thought to synthesize some novel quinoline moiety incorporating with different aromatic and heterocyclic aldehydes moiety. The conventional methodology was adopted to synthesize the titled compound from starting material resorcinol and ethyl acetoacetate which is heated for 20min with conc. Sulfuric acid to give 7-hydroxy-4-methyl coumarine. The 4-(7-hydroxy-4-methyl-2-oxoquinolin-1(2H)yl)benzene sulfonamide which is prepared by condensation of 7-hydroxy-4-methyl coumarine and sulphanilamide with glacial acetic acid for 6 hrs. and poured in to cold water, precipitate form. 4-(7-hydroxy-4-methyl-2-oxoquinolin-1(2H)yl)benzene sulfonamide is further reacted with different substituted aromatic and heterocyclic aldehydes in presence of acetic acid as catalyst in ethanol by refluxing for 8 hr to yield the different derivatives of quinoline. The synthesized compounds were characterized by TLC, Melting point and spectral data. Melting points were determining by using precision melting point apparatus in open capillaries and are uncorrected. The purity of the compounds was checked by TLC, IR, 1H-NMR, Mass spectrum. The synthesized all quinoline derivatives were screened for anti bacterial activity.

KEYWORDS: Quinoline, 7-Hydroxy-4-methyl coumarine, Sulphanilamide, Antimicrobial activity.

INTRODUCTION:

The incidence of microbial infections has been increasing worldwide over the past two decades because of widespread emergence of bacterial resistance to the currently available beta-lactam antibiotics, quinolones, macro lids etc¹. A matter of concern in the treatment of microbial infection is the limited number of efficacious antimicrobial agents, which clearly highlights the urgent need of novel antimicrobial agents.

A large variety of synthetic compounds having therapeutic use in some other ailments possess antibacterial activity. The medicinal properties of quinoline drugs include antibacterial², anticonvulsant³, antimalarial⁴, Anti-tuberculosis⁵, Cytotoxic⁶. On the basis of this premise, few 4-(7hydroxy-4-methyl-2-oxoquinolin-1(2H)yl)benzene sulfonamide analogue synthesized and tested for antimalarial antibacterial activity screening. The present study was aimed at evaluation of antibacterial activity of 4-(7hydroxy-4-methyl-2-oxoquinolin-1(2H)yl)benzene sulfonamide analogues with substituted heterocyclic ring at the side chain using different aromatic aldehydes. 4-(7hydroxy-4-methyl-2-oxoquinolin-1(2H)yl)benzene sulfonamide as lead compound in the development of a new series of antibacterial agents.

EXPERIMENTAL:

1) Preparation Of 7-Hydroxy-4-Methyl Coumarin^7,8:-(Fig-1)

The main method for the synthesis of coumarins is the Pechmann reaction of substituted phenols with methyl or ethyl acetoacetate in the presence of protonic acid (conc. H₂SO₄), Lewis acids (AlCl₃, ZnCl₂, ZnCl₂/Al₂O₃, ZrCl₄ etc.), dehydrating agents (P₂O₅) or montmorillonite clay. The mechanism of this condensation involves three reactions: hydroxyalkylation, transesterification, and dehydration, which occur concomitantly condensing the two reactants to form the coumarin heterocycle.

2) Preparation Of 4-(7-Hydroxy-4-Methyl-2-Oxoquinolin-1(2h)- Yl)Benzene sulfonamide :-^9,10 (Fig-2)

An equimolar (0.06) mix. Of first step (7-hydroxy-4-methyl coumarin) and sulfanilamide was refluxed for 6hrs with glacial acetic acid and the progress of reaction was maintained by TLC. After completion of reaction contents were poured in to crushed ice to form solid mass which was collected and recrystalized from ethanol or chloroform.

3) General Procedure For The Preparation Of Schiff Bases Compound- (Qd 1-6)^11,12(Fig-3):- A equimolar solution of 4-(7-hydroxy-4-methyl-2-oxoquinolin-1(2H)yl)benzene sulfonamide 3.27gm (0.01mole) is dissolved in 10ml of ethanol and to this solution substituted aldehydes in equimolar qty (0.01mole) (Table no. 1) is added with 4-6 drops of glacial acetic acid was added, this reaction mixture is kept under reflux for 10 hours. After cooling to room temperature this solution was added to ice cold water. Compound gets separated as solid, filtered, dried and recrystalized with ethanol. Melting point is noted in ⁰C, the yield is mentioned in. %. And all the other compounds are prepared by using the same procedure as above.

Fig-1

Fig-2

Fig-3

Fig. 4:- IR spectra of 4-(7-hydroxy-4-methyl-2-oxoquinolin-1(2H)- yl)benezenesulfonamide :-

Spectral data for

4-(7-Hydroxy-4-Methyl-2-Oxoquinolin-1(2h)- Yl)Benzene sulfonamide (fig-4)

Light yellow solid, 75.51% yield; Rf : 0.55(chloroform : methanol=3:1);IR spectrum (KBr), 3500 (O-H str); 3370 (N-H str); 3108 (C-H str);1666 (C=O str.);1275, 1180 (C-N str.); 666 (C-S str);

Qd-1 (fig-5,6,7)

IR spectrum (KBr), 3500 (O-H str); 3108 (C-H str); 1673 (C=O str.); 1518 (C=N str.); 1070 (C-N str.); 666 (C-S str);

1H NMR (DMSO), d (ppm): 2.32 (s, 3H,CH₃), 5.99 (s, 1H, OH); 6.32(s, 1H, N=CH); 6.63-8.08 (m, 12H, Ar-H); 9.95(s, 1H, CH, quinoline),

MS (API), m/z (%): 418(100).

Fig 5:-IR Spectra of Qd-1:-

Fig 6:-MASS Spectra of Qd-1:-

Fig 7:-¹HNMR Spectra of Qd-1:-

Qd-2 (fig-8,9,10)

IR spectrum (KBr), 3500 (O-H str); 3108 (C-H str); 1672 (C=O str.); 1516 (C=N str.); 1180 (C-N str.); 680 (C-S str);

1H NMR (DMSO), d (ppm): 2.31 (s, 3H,CH₃); 2.48 (s, 3H,OCH₃, 5.97 (s, 1H, OH); 6.62(s, 1H, N=CH); 6.73-8.03 (m, 11H, Ar-H); 9.79(s, 1H, CH, quinoline),

MS (API), m/z (%): 448(100)

Fig 8:-IR Spectra of compound Qd-2:-

Fig 9:-MASS Spectra of Qd-2:-

Fig 10:-¹HNMR Spectra of Qd-2:-

Qd-3 (fig-11)

IR spectrum (KBr), 3500 (O-H str); 3100 (C-H str); 1670 (C=O str.); 1517 (C=N str.); 11800 (C-N str.); 680 (C-S str);

Fig 11:-IR Spectra of Qd-3:-

Qd-4 (fig-12)

IR spectrum (KBr), 3500 (O-H str); 3100 (C-H str); 1672 (C=O str.); 1517 (C=N str.); 1160 (C-N str.); 680 (C-S str);

Fig 12:-IR Spectra of Qd-4:-

Qd-5 (fig-13)

IR spectrum (KBr), 3500 (O-H str); 3108 (C-H str); 1672 (C=O str.); 1516 (C=N str.); 1158 (C-N str.); 686 (C-S str);

Fig 13:-IR Spectra of Qd-5:-

TABLE-1:- Physicochemical parameters of quinoline derivatives

S. NO	Compound code	R	Molecular Formula	Molecular Weight	Melting point (⁰C)
1	Qd-1		C₂₃H₁₈N₂O₄S	418.12	258-260⁰C
2	Qd-2		C₂₄H₂₀N₂O₅S	448.27	130-134⁰C
3	Qd-3		C₂₄H₂₀N₂O₅S	448.25	189-193⁰C
4	Qd-4		C₂₃H₁₈N₂O₅S	434.24	270-272⁰C
5	Qd-5		C₂₅H₂₁N₂O₄S	445.12	272-275⁰C
6	Qd-6		C₂₄H₂₀N₂O₄S	432.27	255-258⁰C

Qd-6 (fig-14)

IR spectrum (KBr), 3500 (O-H str); 3100 (C-H str); 1672 (C=O str.); 1517 (C=N str.); 1159 (C-N str.); 690 (C-S str);

Fig 14:-IR Spectra of Qd-6:-

ANTIMICROBIAL ACTIVITY:-

Antibacterial activity:

Antibacterial activities of synthesized compounds were examined in vitro by known agar diffusion cup method. All the compounds were tested for activity against gram-positive bacteria like Bacillus cereus ATCC 10987, Staphylococcus aureus ATCC 6538 and Bacillus subtilis ATCC 6633 and gram-negative bacteria Escherichia coli ATCC 10536. The culture medium was nutrient agar. All the compounds were dissolved in DMF (500ppm concentration) and DMF used as control. Ciprofloxacin was employed as the standard drug. The results are summarized in Table 2.

Table no. 2: -Anti-bacterial activity data of synthesized quinoline derivatives.

Sr. No	Compound	Zone of inhibition diameter (mm)
		*E.coli*	*S.Aureus*
1	Qd-1	10	07
2	Qd-2	24	22
3	Qd-3	22	23
4	Qd-4	19	18
5	Qd-5	14	15
6	Qd-6	20	21
7	Qd-7	21	19
8	Qd-8	22	23
9	Qd-9	24	23
10	Qd-10	24	22
11	Qd-11	12	10
12	S	34	31
13	C	-	-

Zone of inhibition of synthesized compounds [Qd1-Qd11].(Against Bacteria.)

Note: - 0-15 mm poor activity, 15-25 mm moderate activity, 25 above good.

Standard(S) = Ciprofloxacin Control (C) = DMF

Methods used for screening:-

In screening, the test compounds were first dissolved in sterile Dimethylformamide (DMF) which has shown the inhibition of E. coli, so later sterile 1,4–Dioxane was used to dissolve the test compounds which was filter sterilized by using membrane filter of 0.2u, as its boiling point is below 121^oC and thermo-instable. Compounds were tested for its antibacterial activity at 50-100 ug/ml concentration. Ciprofloxacin was used as standard which was dissolved in sterile water.1, 4-Dioxane, water were also tested as control.

RESULTS AND DISCUSSION:

All the reactions were monitored by TLC, structure and purity of the anticipated compounds were characterize by physical constant and FTIR spectral studies initially followed by NMR and Mass spectroscopy.

The antimicrobial screening results presented on above table reveals that compounds Qd-2, Qd-3, exhibited poor activity at 50 μg/ml, but at 100 μg/ml they have shown moderate activity against S.aureus and E.coli. And Qd-2, Qd-3 shown the very good activity against S.aureus at 100 μg/ml when compared with the standard drug Ciprofloxacin.

CONCLUSION:

From the results of antibacterial activity it is clearly concluded that the synthesized compounds are promisingly significant, good antimicrobial agents. As per the results of screening it is clearly indicated that the compounds of the scheme have shown good antibacterial and antifungal activity equipotent with the standard drugs. This is because of the presence of groups like -OCH₃ at the different positions of phenyl nucleus and heterocyclic system attached to quinoline nucleus.

ACKNOWLEDGEMENTS:

The authors are thankful to Dr. N.V. Kalyane Principal of B.L.D.E.A’s College of Pharmacy, Bijapur for providing research facilities and microbial strains. We also extend our thanks to Shivaji University, Kolhapur and Karnataka University, Dharwad for Providing spectral data of synthesized compounds.

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Received on 19.02.2011 Modified on 03.03.2010

Research J. Pharm. and Tech. 4(5): May 2011; Page 827-831