INTRODUCTION:

The 2-azetidinone (β-lactam) ring system is the common structural feature of a number of broad spectrum β-lactam antibiotics, which have been widely used as chemotherapeutic agents to treat bacterial infections and microbial diseases^1-2. The biological activity of the β -lactam skeleton is generally believed to be associated with the chemical reactivity of their β -lactam ring and on the substituent’s especially at nitrogen of the 2-azetidinone ring. The wide range of pharmacological profile shown by 2-azetidinone includes antimicrobial, antifungal, antitubercular, cholesterol absorption inhibitor, tryptase and chymase inhibitor, thrombin inhibitor, human leukocyte elastase inhibitor, human cytomegalovirus inhibitor, cysteine protease cathepsin K inhibitor, antidiabetic, anti-inflammatory and analgesic activity, anticancer, and vasopressin VIa antagonist activities^3-6.

Thiazolidinone is an important scaffold known to be associated with several biological activities, 1,3-Thiazolidin-4-ones are heterocycles that have an atom of sulfur at position 1, an atom of nitrogen at position 3 and a carbonyl group at position 4. Substituents in the 2-3-, and 5-position may be varied, numerous methods for the synthesis of thiazolidinones and also their diverse reactions offer enormous scope in the field of medicinal chemistr^7-9.The wide range of pharmacological profile shown by 4-Thiazolidinone includes antiretroviral, antimicrobial, antimalarial, antidiarrhoeal, anti-yellow fever virus, antiarrhythmic, anticonvulsant and anti-inflammatory activities^10-13.

Schiff bases have also been shown to exhibit a broad range of biological activities, including antifungal, antibacterial, antimalarial, antiproliferative, anti-inflammatory, antiviral, and antipyretic properties. Imine or azomethine groups are present in various natural, natural-derived, and non-natural compounds. The imine group present in such compounds has been shown to be critical to their biological activities^14-17.

MATERIALS AND METHODS:

All the reagents used for synthesis were analytical grade commercial products and used without further purification. The melting points of the synthesized compounds were determined using an electric melting point apparatus by open capillary method (expressed in degree Celsius) and are uncorrected. The progress of reactions and purity of synthesized compounds were checked on silica gel-G TLC plates using various solvent combinations of different polarity. The spots were detected with iodine vapors as visualizing agent. The FT-IR spectra of the synthesized compounds were recorded on a FT-IR perkin Elmer Spectrum RX-I spectrometer using KBr disc in the range of 4000-400 cm^-1. The proton NMR (¹H NMR) spectra were recorded in Bruker AC-F 400 FT-NMR spectrometer at a frequency of 400 MHz. Spectra were obtained in deuterated acetone (acetone-d6) using TMS (δ 0.00 ppm) as an internal standard at room temperature. Chemical shift (δ) values are expressed in ppm relative to internal standard.

Synthetic Scheme:

Fig.1: Synthetic Scheme for Schiff bases of aryl amines based 2-Azetidinones and 4-Thiazolidinones

General method for Synthesis of novel aryl amines based 2-azetidinones and 4-thiazolidinones:

Procedure for synthesis of Acetanilide (Step I): Anilines [0.01mol] were dissolved in 15 ml of glacial acetic acid and treated with 10 ml of acetic anhydride. This reaction mixture was poured into ice to obtain respective acetanilide as solid products (2a-f).

Procedure for synthesis of 2-Chloro-3-formylquinoline (Step II):

Charged 500ml 3N RBF with 0.12mol of DMF at 0°C, 0.35 mol of POCl₃ for a period of an hour at 0°C. It was allowed to stir at 0°C for an hour. 0.05mol of acetanilides was added portion wise for a period of 30 min at 0°C; the reaction mixture refluxed at 85 °C for 16 hours and was monitored by TLC. After completion of reaction, the reaction mixture was quenched with 300 gm of ice and stirred at 0°C for 30 min. It was then extracted with ethyl acetate and this layer was evaporated to obtain solid substances. The compounds were obtained as solids (3a-c).

Procedure for synthesis of 4-(1H-benzoimidazol-2-yl) aniline (Step III):

Phenylenediamine (0.01mol), and Para amino benzoic acid (0.01mol) were taken into 500ml RBF, to this 10ml of poly phosphoric acid was added and heated on sand bath at 200ºC for 2 h.

Procedure for synthesis of Schiff’s base (Step IV):

In a 100 ml 3N RBF, 0.01mol 2, 6-dichloro-3-formylquinoline derivatives and 0.01mol of 2-(4-aminophenyl) benzimidazole were dissolved in ethanol and catalytic amount of sulphuric acid was added into it. It was then allowed to reflux for 4 hours and was monitored by TLC. After completion of reaction the reaction mixture was poured into ice, solid mass separated out was filtered, washed several times with water, dried, and recrystallized with ethanol to obtain desired products. The compounds were obtained as solids (4a-c), (5a-c), (6a-c).

Procedure for synthesis of 2-Azetidinone derivatives (Step V):

A mixture of Schiff’s bases [0.001mol] and triethyl amine [0.002mol] was dissolved in 1-4-dioxane. To this well stirred mixture, a cooled solution of chloroacetyl chloride [0.002mol] was added. Then this reaction mixture was refluxed with stirring for about 12 hours and was monitored by TLC. After the completion of reaction the triethyl amine hydrochloride salt formed was filtered off and the reaction mixture was poured into crushed ice. The precipitate obtain was filtered washed several times with water, dried, and recrystallized from ethanol to get desired compound (10a-c).

Procedure for synthesis of 4-Thiazolidinone derivatives (Step VI):

A mixture of Schiff base [0.001mol] and catalytic amount of zinc chloride in DMF was taken in dean stark apparatus and to it. Thioglyclic acid [0.002mol] in DMF was added to this. Then this reaction mixture was refluxed with stirring for about 12 hours and was monitored by TLC. After the completion of reaction, the reaction mixture was poured into crushed ice and was extracted with ethyl acetate. This ethyl acetate layer was distilled off to obtain the desired products; the obtained compounds were dried, and recrystallized from ethanol to get desired compounds (7a-c), (8a-c), (9a-c).

Antibacterial activity:

The antibacterial activity of the synthesized compounds was evaluated systematically against Bacillus subtilis, protease, Escherichia coli and Staphylococcus aeruginosa, which are the representative types of gram positive and gram-negative organisms respectively. The inhibition zones (in mm) of synthesized compounds were determined by cup-plate method¹⁸. The sterilized medium (autoclaved at 121°C for 20min) was inoculated using 18 hr slant cultures of the test organisms and transferred into sterile petri dishes and allowed to the media to solidify. Cups of 8mm diameters were made on solidified media. Solutions of the synthesized compounds at a concentration of 50μg/ml and 100μg/ml were prepared in DMSO. 50μl of each solution was placed in cups by means of sterile pipette. In each plate, one cup was used for standard and other two for test solutions. The plates thus prepared were left for 90 min in a refrigerator for diffusion. The plates were incubated at 37°C for 24 hrs and examined for inhibition zones. The experiment was performed in duplicate and the average diameter of the zones of inhibition was recorded Ciprofloxacin (50μg/ml) was used as standard.

Antifungal activity:

The anti-fungal activity of all compounds was determined on potato dextrose agar medium against Aspergillus niger and Candida albicans. Clotrimazole 50 μg/ml was used as a standard and DMSO was used as control. The sterile molten potato dextrose medium was cooled to 45^oC and inoculated with test organisms and the contents mixed thoroughly and poured into the sterile petri dishes under aseptic conditions. All the inoculated petri dishes were incubated at 28^oC for 4 days and the extent diameter of inhibition was measured as the zone of inhibition in millimeters of diameter. Solutions of the synthesized compounds at a concentration of 50μg/ml and 100μg/ml were prepared in DMF. Clotrimazole was used as standard anti-fungal for comparison and solution were prepared by using sterile water, so that the concentrations of the solution were 100μg/ml.

RESULTS AND DISCUSSON:

The results revealed that novel aryl amines based 2-azetidinones and 4-thiazolidinones derivatives were synthesized in satisfactory yields and pharmacologically evaluated for their in vitro antimicrobial activity.

Table No. 1: Physical data of synthesized compounds of Acetanilides (2a-e):

Compound	R1	R2	R3	Yield (%)	Melting Point (⁰C)	R
2a	H	H	Cl	90	180-182	0.90
2b	H	H	H	88	154-156	0.88
2c	H	CH₃	H	92	212-214	0.86
2d	H	H	CH₃	85	150-152	0.92
2e	H	H	OCH₃	86	157-159	0.87

Table No. 2: Physical data of synthesized compounds of 2-Chloro-3-formylquinoline (3a-e):

Compound	R1	R2	Yield (%)	Melting Point (⁰C)	R
3a	Cl	H	65	162-164	0.92
3b	H	H	60	156-158	0.90
3c	H	CH₃	64	166-168	0.88
3d	CH₃	H	62	152-154	0.94
3e	OCH₃	H	58	160-162	0.86

Table No. 3: Physical data of synthesized compounds of 4-(1H-benzoimidazol-2-yl) aniline (4a-b):

Compound	R	Yield (%)	Melting Point (⁰C)	R
4a	H	85	162-164	0.85
4b	Cl	88	165-167	0.88

Table No. 4: Physical and Spectral data of synthesized compounds of Schiff’s base (13a-h):

Compound Code	R₁	R₂	R	Nature	Melting point (⁰C)	% Yield	Rf values	₁H NMR (300 MHz, CDCl3)	FTIR (KBr) cm-1
13a	H	H	H	Brick red Solid	320	74	0.85	δ 9.20 (1H, s), 7.74-7.80 (2H, s), 7.53-8.05(4H, dd, J = 2.35, 9.2Hz), 8.05(1H, s), 2.80 (3H, s).	758 (C-Cl), 1680(C=O), 1658(C=N)
13b	OCH₃	H	H	Pink Solid	340	76	0.80	δ 9.24 (1H, s), 7.51-7.66(2H, s), 7.33-8.05(4H, dd, J = 2.35, 9.2Hz), 7.92(1H, s), 2.50 (3H, s).	755 (C-F), 1689(C=O), 1668(C=N)
13c	OCH₃	H	Cl	Brown Solid	375	75	0.83	δ 9.24 (1H, s), 7.51-7.66(2H, s), 7.33-8.05(4H, dd, J = 2.35, 9.2Hz), 7.92(1H, s), 2.50 (3H, s), 2.34 (3H, s).	752 (C-H), 1691(C=O), 1659(C=N)
13d	H	CH₃	H	Yellow Solid	355	81	0.85	δ 9.27 (1H, s), 7.78-8.06(2H, s), 7.33-8.05(4H, dd, J = 2.35, 9.2Hz), 7.60-7.98(2H, s), 7.92(1H, s), 2.50 (3H, s), 2.39 (3H, s).	768 (C-CH₃), 1651 (C=N), 1680(C=O)
13e	H	CH₃	Cl	Brick red Solid	380	70	0.82	δ 9.20 (1H, s), 7.17-7.31(2H, s), 7.33-8.05(4H, dd, J = 2.35, 9.2Hz), 7.79(1H, s), 2.50 (3H, s), 3.83 (3H, s).	750 (C-H), 1669 (C=N), 1670(C=O)
13f	H	H	Cl	Brown Solid	300	70	0.80	δ 9.26 (1H, s), 7.50-7.68(2H, s), 7.33-8.05(4H, dd, J = 2.35, 9.2Hz), 7.70(1H, s), 2.50 (3H, s), 3.83 (3H, s).	750 (C-OCH₃), 1695 (C=O), 1659(C=N)
13g	Cl	H	H	Violet Solid	290	72	0.86	δ 9.20 (1H, s), 7.55-7.68(2H, s), 7.53-8.05(4H, dd, J = 2.35, 9.2Hz), 7.80(1H, s), 2.60 (3H, s), 3.93 (3H, s).	750 (C-H), 1660 (C=N), 1680(C=O)
13h	Cl	H	Cl	Light Pink solid	310	74	0.84	δ 9.22 (1H, s), 7.60-7.88(2H, s), 7.53-8.00(4H, dd, J = 2.35, 9.2Hz), 7.90(1H, s), 2.70 (3H, s), 3.63 (3H, s).	750 (C-H), 1670 (C=N), 1690(C=O)

Physical and spectral data of synthesized compounds of 2-Azetidinones (14a-d):

Compound 14a: R₁=H, R₂=H, Red solid, MP: 352⁰C, Yield: 74, Rf: 0.85.

₁H NMR (300 MHz, CDCl3): δ 9.27 (1H, s), 7.64-7.82(2H, s), 7.33-8.05(4H, dd, J = 2.35, 9.2Hz), 8.11(1H, s), 2.50 (3H, s).

FTIR (KBr) cm-1: 759 (C-Cl), 1680(C=O), 1658(C=N)

Compound 14b: R₁=OCH₃, R₂=H, Brown solid, MP: 380⁰C, Yield: 76, Rf: 0.80.

₁H NMR (300 MHz, CDCl3): δ 9.24 (1H, s), 7.51-7.66(2H, s), 7.33-8.05(4H, dd, J = 2.35, 9.2Hz), 7.92(1H, s), 2.50 (3H, s).

FTIR (KBr) cm-1: 755 (C-F), 1689(C=O), 1668(C=N)

Compound 14c: R₁=CH₃, R₂=Cl, Brown solid, MP: 355⁰C, Yield: 75, Rf: 0.83.

₁H NMR (300 MHz, CDCl3): δ 9.24 (1H, s), 7.51-7.66(2H, s), 7.33-8.05(4H, dd, J = 2.35, 9.2Hz), 7.92(1H, s), 2.50 (3H, s), 2.34 (3H, s).

FTIR (KBr) cm-1: 752 (C-H), 1691(C=O), 1659(C=N).

Compound 14d: R₁=CH₃, R₂=H, Yellow solid, MP: 325⁰C, Yield: 81, Rf: 0.85.

₁H NMR (300 MHz, CDCl3): δ 9.27 (1H, s), 7.78-8.06(2H, s), 7.33-8.05(4H, dd, J = 2.35, 9.2Hz), 7.60-7.98(2H, s), 7.92(1H, s), 2.50 (3H, s), 2.39 (3H, s).

FTIR (KBr) cm-1: 768 (C-CH₃), 1651 (C=N), 1680(C=O).

Physical and spectral data of synthesized compounds of 4 –Thiazolidinone (15a-g):

Compound 15a: R₁=H, R₂=H, Red solid, MP: 350⁰C, Yield: 76, Rf: 0.88.

₁H NMR (300 MHz, CDCl3): δ 9.27 (1H, s), 7.64-7.82(2H, s), 7.33-8.05(4H, dd, J = 2.35, 9.2Hz), 8.11(1H, s), 2.50 (3H, s).

FTIR (KBr) cm-1: 759 (C-Cl), 1680(C=O), 1658(C=N)

Compound 15b: R₁=OCH₃, R₂=H, Brown solid, MP: 380⁰C, Yield: 76, Rf: 0.80.

₁H NMR (300 MHz, CDCl3): δ 9.24 (1H, s), 7.51-7.66(2H, s), 7.33-8.05(4H, dd, J = 2.35, 9.2Hz), 7.92(1H, s), 2.50 (3H, s).

FTIR (KBr) cm-1: 755 (C-H), 1689(C=O), 1668(C=N).

Compound 15c: R₁=CH₃, R₂=Cl, Brown solid, MP: 355⁰C, Yield: 75, Rf: 0.83.

₁H NMR (300 MHz, CDCl3): δ 9.24 (1H, s), 7.51-7.66(2H, s), 7.33-8.05(4H, dd, J = 2.35, 9.2Hz), 7.92(1H, s), 2.50 (3H, s), 2.34 (3H, s).

FTIR (KBr) cm-1: 752 (C-CH₃), 1691(C=O), 1659(C=N).

Compound 15d: R₁=Cl, R₂=H, Yellow solid, MP: 325⁰C, Yield: 81, Rf: 0.85.

₁H NMR (300 MHz, CDCl3): δ 9.27 (1H, s), 7.78-8.06(2H, s), 7.33-8.05(4H, dd, J = 2.35, 9.2Hz), 7.60-7.98(2H, s), 7.92(1H, s), 2.50 (3H, s), 2.39 (3H, s).

FTIR (KBr) cm-1: 768 (C-H), 1651 (C=N), 1680(C=O).

Compound 15e: R₁=H, R₂=Cl, Light Pink solid, MP: 332⁰C, Yield: 84, Rf: 0.85.

₁H NMR (300 MHz, CDCl3): δ 9.29 (1H, s), 7.51-7.66(2H, s), 7.33-8.05(4H, dd, J = 2.35, 9.2Hz), 7.92(1H, s), 2.50 (3H, s), 2.34 (3H, s).

FTIR (KBr) cm-1: 752 (C-Cl), 1691(C=O), 1659(C=N).

Compound 15f: R₁=CH₃, R₂=H, Violet solid, MP: 360⁰C, Yield: 78, Rf: 0.80.

₁H NMR (300 MHz, CDCl3): δ 9.34 (1H, s), 7.61-7.68(2H, s), 7.53-8.05(4H, dd, J = 2.35, 9.2Hz), 7.92(1H, s), 2.50 (3H, s).

FTIR (KBr) cm-1: 755 (C-F), 1689(C=O), 1668(C=N).

Compound 15g: R₁=Cl, R₂=Cl, Brown solid, MP: 342⁰C, Yield: 80, Rf: 0.85.

₁H NMR (300 MHz, CDCl3): δ 9.30 (1H, s), 7.78-8.06(2H, s), 7.63-8.05(4H, dd, J = 2.35, 9.2Hz), 7.80-7.98(2H, s), 7.92(1H, s), 2.50 (3H, s), 2.40 (3H, s).

FTIR (KBr) cm-1: 768 (C-H), 1651 (C=N), 1680(C=O).

Biological Evaluation of Synthesized Compounds:

Antimicrobial Activity: The synthesized compounds were screened for their in-vitro antibacterial activity by cup plate method with gram positive and gram negative organism i.e. Bacillus subtilis, Bacillus pumilus, Escherichia coli and Pseudomonas aeruginosa and antifungal activity with Aspergillus niger and Candida albicans. Ciprofloxacin and Clotrimazole were used in assay as a standard control drug. DMSO was used as diluents which is ineffective to the growth of microbes. The antimicrobial activities were tested at 50mg/l, and 100mg/l concentration.

Table No. 5: Antibacterial and antifungal activities of synthesized compounds

Sample Code	Inhibition zone diameter in mm*
	*B. Subtilis*		*B. Pumilus*		*E. Coli*		*P. Aeruginosa*		*A. Niger*		*C. Albicans*
	100 µg/ml	50 µg/ml	100 µg/ml	50 µg/ml	100 µg/ml	50 µg/ml	100 µg/ml	50 µg/ml	100 µg/ml	50 µg/ml	100 µg/ml	50 µg/ml
14a	12	11	10	09	16	12	18	10	15	12	16	14
14b	13	10	14	11	18	13	20	12	19	11	18	10
14c	13	8	12	13	18	8	19	14	12	10	15	12
14d	15	13	16	14	19	14	17	15	23	20	20	18
15a	10	8	6	7	10	9	12	10	9	9	11	10
15b	14	10	6	9	19	11	13	12	8	7	7	9
15c	12	11	10	9	15	12	13	11	7	6	7	6
15d	18	14	15	14	16	13	19	15	19	18	16	15
15e	10	8	6	4	8	6	13	14	21	20	18	15
15f	7	5	11	10	14	9	12	8	6	5	3	4
15g	17	15	14	13	19	17	18	16	5	4	7	9
Ciprofloxacin	20	19	22	18	19	18	20	21	-	-	-	-
Clotrimazole	-	-	-	-	-	-	-	-	25	23	20	18
DMSO	-	-	-	-	-	-	-	-	-	-	-	-

*Each value is an average of three independent determinations ± standard deviation

Note: ‘-‘denotes no activity, 4-6mm poor activity, 7-9mm moderate activity, 10 mm and above 10mm good activity.

CONCLUSION:

The Schiff’s bases of aryl amines based their azetidinone; thaizolidinone derivatives have been synthesized to screen the potential antimicrobial agent. The synthesis of various substituted Schiff’s bases of aryl amines based their azetidinone, thaizolidinone derivatives have been prepared using reported synthetic procedures, and the melting point, ¹H-NMR, and IR spectrophotometric studies were used in characterized the compounds. The synthesized compounds were tested for their potential biological activity as antimicrobial agent. The antimicrobial results presented in the Table 7 revealed that the Schiff’s bases of aryl amines based azitidinone and thiazolodinones analogues showed good activity towards gram positive and gram negative bacteria as compared to ciprofloxacin.

ACKNOWLEDGEMENT:

Authors thankfully acknowledge the Management and Principal of Aditya Pharmacy College for their kind cooperation in providing the facilities required for the completion of the research work.

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Received on 18.06.2019 Modified on 21.07.2019

Research J. Pharm. and Tech. 2020; 13(1):168-172.

DOI: 10.5958/0974-360X.2020.00034.7