Original Article

, Volume: 15( 2)

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Synthesis and Characterization of Some Schiff Base Derivatives Containing Sydnone as Antimicrobial Agents

*Correspondence:

Patel KC , Department of Chemistry, Veer Narmad South Gujarat University, Surat, Gujarat, India, Tel: +91-8141668910; E-mail: ss68910@gmail.com

Abstract

The series of Schiff base derivatives incorporating with Mannich base of 3-(3-nitrophenyl) sydnone were synthesized by conventional routes and evaluated for their antimicrobial activities against E. coli, P. aerugenosa, S. aureus, S. pyogenus, C. albicans, A. niger and A. clavatus. Most of the compounds showed moderate to very good biological activity. The structures of synthesized compounds 6a-j were elucidated by C, H, and N analysis, FT-IR, 1H NMR, 13C NMR and Mass Spectrometry.

Keywords

Schiff base; Mannich base; Sydnone; Antibacterial; Antifungal

Introduction

Medicinal chemistry concerns essentially the understanding and explanation of the mechanisms of the drugs. It explains the design and production of compounds that can be used for the prevention, treatment or cure of human and animal diseases. Medicinal chemistry includes the study of already existing drugs, their biological properties and their structure activity relationships. Mesoionic compounds are five membered heterocyclic conjugated betains. At present the most frequently used ‘mesoionic’ structure is of sydnone proposed by Baker and Ollis [1,2]. The sydnone ring bears a fractional positive charge balanced by a corresponding negative charge located on covalently attached oxygen [3]. Due to the unique structure, sydnone possesses both the conjugated and polar character, which makes it sensitive to both electric and magnetic fields. Many sydnone compounds have been found to exhibit pharmacological and biological activities viz, antibacterial [4], antitumor [5,6], antifungal [7], antimalarial [8], anti-inflammatory [9], analgesic, anthelmintic [10], antioxidant [11]. They also show significant response of coronary dilation test, collagen induced platelet aggregation inhibition, local an aesthetic, ant writhing, anticonvulsant, muscle relaxation and moderate cardio tropic activity. A hydrogen atom at the 4th position of the sydnone ring allows substitution with a wide variety of electrophiles, such as bromination, nitration, acylation, and sulfonation. It seems to be possible to substitute the 4th position by electron-releasing groups such as the methylene group by Mannich reaction [12-14].

The compounds containing carbon and nitrogen, which joined together with double bond, include mainly the products of reaction between aldehyde or ketonic components and primary aliphatic or aromatic amines, ammonia, hydrazine, N-phenyl hydrazine, hydroxylamine hydrochloride, semicarbazide, thiosemicarbazide and their substituted derivatives [15]. These compounds are known as Schiff bases to honours Schiff, who first discovered such compounds [16,17]. They are well known intermediates for the preparation of azetidinone, thiazolidinone, formazone, acrylacetamide and many other derivatives. Schiff base have been found to possess pharmacological activities viz, antibacterial [18], antifungal, anti-HIV [19], antiviral [20], anticancer [21], anticonvulsant [22], tuberculostatic [23], anti-inflammatory [24] and antioxidant [25] and DNA interaction [26].

Materials and Methods

Experimental

All the chemicals used were of analytical grade and the solvents were distilled before use. All the melting points reported are uncorrected and were recorded using an electro-thermal melting point apparatus. The structure of synthesized compounds was confirmed by elemental analysis (C, H, N) which was performed on Thermo Scientific FLASH 2000 at G.N.F.C. (Gujarat Narmada Valley Fertilizer Company Ltd., Bharuch). Infrared spectra were recorded with FT-IR Spectrophotometer Perkin Elmer in the frequency range 4,000 cm^-1 to 400 cm^-1 with samples embedded in KBr disks. Proton nuclear magnetic resonance (1H NMR) spectra of the compound were recorded with a Bruker Advance II 400 Hz NMR and carbon (¹³C) NMR spectra of the compounds were recorded with a Bruker Avance II 400 NMR spectrometer using DMSO-d₆ as a solvent and tetramethylsilane (TMS) as an internal reference at sophisticated analytical instrument facilities (SAIF), Chandigarh. Thin-layer chromatography analysis were performed using aluminium backed Silica-gel plates (Merck 60 F524) and examined under short wave ultraviolet (UV) light.

Procedure for the Synthesis of the Compounds (6a-j)

Synthesis of (3-nitrophenyl) glycine (2)

This step, a condensation, involved neutralizing an aqueous solution of chloroacetic acid (0.94 g, 0.01 mol) with an equimolar equivalent of 10% NaOH and adding this solution to an aqueous solution of 3-nitro aniline (1.38 g, 0.01 mol) over a period of 4 h. This reaction mixture was heated for 10 h and the clear liquor was then filtered while hot to remove any decomposition product and refrigerated overnight. The resulting crystals were again filtered to obtain compound 2. Yield 87%, m.p. 145-147ºC. IR: (KBr) v (cm^-1): 3465 (OH str. of acid), 1773 (>C=O of acid), 1601, 1507 (C=C of aromatic), 1514 (asym.), 1323 (sym.) (-NO₂); ¹H NMR (DMSO-d₆): δ (ppm): 4.07 (s, 2H,-CH₂-), 6.34 (s, 1H,-NH-), 7.25 (d, 1H, Ar-H), 7.37 (t, 1H, Ar-H), 7.59 (d, 1H, Ar-H), 7.66 (s, 1H, Ar-H), 13.12 (s, 1H,-COOH); ¹³C NMR (DMSO-d₆: δ (ppm): 45.91 (-CH₂-), 106.45 (Ar-C), 112.29 (Ar-C), 119.57 (Ar-C), 130.38 (Ar-C), 148.54 (Ar-C of C-N), 148.72 (Ar-C of C-N), 171.98 (>C=O of acid).

Synthesis of N-(3-nitrophenyl)-N-nitrosoglycine (3)

To an ice-cooled solution of 2 (1.96 g, 0.01 mol) in 40 ml of water, a solution of sodium nitrite (0.69 g, 0.01 mol) in 5 ml of water was added drop by drop with stirring. After stirring for another 2 h and leaving the solution to stand overnight, the reaction mixture was filtered through a Buckner funnel, and the nitroso compound was precipitated by adding concentrated hydrochloric acid to the filtrate. Yellowish needles were obtained as product, yield 87 %, m.p. 154°C to 157°C. IR: (KBr) v (cm^-1): 3461 (O-H of acid), 1774 (>C=O of acid), 1616, 1513 (C=C of aromatic), 1597 (N=O str.), 1524 (asym.), 1335 (sym.) (-NO₂); ¹H NMR (DMSO-d₆): δ (ppm): 4.05 (s, 2H,-CH₂-), 6.85 (d, 1H, Ar-H), 7.39 (t, 1H, Ar-H), 7.55 (d, 1H, Ar-H), 7.62 (s, 1H, Ar-H), 13.08 (s, 1H, COOH); ¹³C NMR (DMSO-d6₆): δ (ppm): 62.25 (-CH₂-), 113.11 (Ar-C), 122.49 (Ar-C), 129.52 (Ar-C), 130.42 (Ar-C), 143.33 (Ar-C of-C-N-), 148.75 (Ar-C of C-N), 173.08 (>C=O of acid).
Synthesis

Synthesis of 3-(3-nitrophenyl) sydnone (4)

A mixture of 3 (2.835 g, 0.0126 mol) and acetic anhydride (15 ml) was stirred at room temperature for 12 h in the dark. The solution was poured slowly into cold water which was very well stirred. The pH of the content was adjusted to 7.0 with 10% Sodium bicarbonate solution. The crude sydnone obtained was washed well with water, dried and recrystallized from 95% ethanol afforded a yield of 92% of light yellow needles, m.p. 147°C-149°C. IR: (KBr) v (cm^-1): 3108 (C-H of sydnone), 1752 (>C=O of sydnone), 1622, 1517 (C=C of aromatic), 1518 (asym.), 1327 (sym.) (˗NO₂); ¹H NMR (DMSO-d₆): δ (ppm): 4.05 (s, 1H,-CH-of sydnone), 7.59 (t, 1H, Ar-H), 8.19 (d, 1H, Ar-H), 8.25 (s, 1H, Ar-H); ¹³C NMR (DMSO-d₆): δ (ppm): 114.71 (Ar-C), 123.43 (C4 of sydnone), 126.69 (Ar-C), 132.31 (Ar-C), 136.55 (Ar-C), 139.44 (Ar-C of C-N), 147.93 (Ar-C of C-N), 169.18 (C5 of sydnone).

Synthesis of 4-(((4-aminophenyl) amino) methyl)-3-(3-nitrophenyl) sydnone (5)

The mixture of compound 3-(3-nitrophenyl) sydnone (2.07 g, 0.01 mol), paraformaldehyde (0.25 g, 0.00833 mol) and p-phenylenediamine (1.296 g, 0.012 mol) were added to 10 ml of acetic acid and 10 ml ethanol and whole mixture was heated at 70°C for 3 h. After cooling ethanol was distilled off, 20 ml of water was added and neutralized with aqueous sodium bicarbonate to afford the crude product. Recrystallization from 95% ethanol yielded 96% of title compound as crystalline solid. M.P. 207-209°C. IR: (KBr) v (cm^-1): 3269 (-NH-), 2932, 2860, (-CH₂-of Mannich base), 1749 (>C=O of sydnone), 1628, 1508 (C=C of aromatic), 1525 (asym.), 1332 (sym.) (-NO₂); ¹H NMR (DMSO-d₆): δ (ppm): 4.29 (s, 2H,-CH₂-of Mannich base), 4.59 (s, 2H,-NH₂), 6.08 (d, 2H, Ar-H), 6.54 (d, 2H, Ar-H), 6.76 (s, 1H,-NH-), 7.59 (t, 1H, Ar-H), 8.22 (d, 2H, Ar-H), 8.27 (s, 1H, Ar-H); ¹³C NMR (DMSO-d₆): δ (ppm): 49.03 (-CH₂-of Mannich base), 114.72 (Ar-C), 117.11 (Ar-C), 118.53 (Ar-C), 126.71 (Ar-C), 132.33 (Ar-C), 136.48 (Ar-C),136.83 (Ar-C of C-N), 139.41 (Ar-C), 142.4 (C4 of sydnone), 147.91 (Ar-C of C-N), 168.75 (C5 of sydnone).

Synthesis of compounds 6a-j

The Schiff base derivatives were prepared by the equimolar reaction between compound 5 and various substituted aldehydes. Each reactant was dissolved in a minimum amount of methanol, then mixed together and followed by addition of catalytic amount of glacial acetic acid. The solution was refluxed for 8 hrs. then cooled to room temperature and poured into ice cold water. The solid product was filtered, dried and recrystallized from ethanol

All the Schiff base derivatives were synthesized by the same procedure. The antimicrobial activity is given in Table 1.

Table 1: Antimicrobial activity of Compounds 6_a-j.

Characterization

(6a) IR: (KBr) v (cm^-1): 3434 (Ar-OH), 3272 (-NH-), 2928, 2857, (-CH2-of Mannich base), 1752 (>C=O of sydnone), 1651 (-C=N-of Schiff base),1632, 1506 (C=C of aromatic), 1521 (asym.), 1339 (sym.) (-NO₂) 1239, 1049 (C-O-C of-OCH₃); ¹H NMR (DMSO-d₆): δ (ppm): 3.85 (s, 3H,-OCH3), 4.28 (s, 2H,-CH₂-of Mannich base), 6.45 (d, 2H, Ar-H), 6.88 (d, 1H, Ar-H), 7.32 (d, 1H, Ar-H), 7.36 (s, 1H,-NH-), 7.38 (s, 1H, Ar-H), 7.39 (d, 2H, Ar-H), 7.61 (t, 1H, Ar-H), 8.22 (d, 2H, Ar-H), 8.26 (s, 1H, Ar-H), 8.52 (s, 1H,-CH= of Schiff base), 9.57 (s, 1H,-OH); ¹³C NMR (DMSO-d₆): δ (ppm): 49.14 (-CH₂-NH-), 56.11 (C of-OCH₃), 112.15 (Ar-C), 114.74 (Ar-C), 114.82 (Ar-C), 117.05 (Ar-C), 122.92 (Ar-C), 123.18 (Ar-C), 126.74 (Ar-C), 130.89 (Ar-C), 132.23 (Ar-C), 136.51 (Ar-C), 139.44 (Ar-C of-C-N), 140.41 (Ar-C of-C-N), 142.41 (C4-sydnone), 147.84 (Ar-C of-C-N), 147.93 (Ar-C of-C-N), 149.33 (Ar-C of-C-O), 151.10 (Ar-C of-C-O), 160.07 (C of-CH=N-), 168.78 (C5-sydnone); MS m/z (rel. int. %): 462.4 (M+1)⁺.

(6b) IR: (KBr) v (cm^-1): 3425 (Ar-OH), 3266 (-NH-), 2919, 2865, (-CH2-of Mannich base), 1747 (>C=O of sydnone), 1632 (-C=N-of Schiff base), 1621, 1509 (C=C of aromatic), 1525 (asym.), 1345 (sym.) (-NO₂) 1252, 1060 (C-O-C of-OCH₃); ¹H NMR (DMSO-d₆): δ (ppm): 3.89 (s, 3H,-OCH₃), 4.29 (s, 2H,-CH₂-of Mannich base), 6.44 (d, 2H, Ar-H), 6.89 (t, 1H, Ar-H), 7.04 (d, 1H, Ar-H), 7.34 (d, 1H, Ar-H), 7.36 (s, 1H,-NH-), 7.38 (d, 2H, Ar-H), 7.58 (t, 1H, Ar-H), 8.24 (d, 2H, Ar-H), 8.28 (s, 1H, Ar-H), 8.86 (s, 1H,-CH= of Schiff base), 13.79 (s, 1H,-OH); ¹³C NMR (DMSO-d₆): δ (ppm): 49.10 (-CH₂-NH-), 56.11 (C of-OCH₃), 114.72 (Ar-C), 114.83 (Ar-C), 115.04 (Ar-C), 116.62 (Ar-C), 119.51 (Ar-C), 123.12 (Ar-C), 124.44 (Ar-C), 126.76 (Ar-C), 132.33 (Ar-C), 136.55 (Ar-C), 139.42 (Ar-C), 140.39 (Ar-C of-C-N-), 142.38 (C4-sydnone), 147.79 (Ar-C of-C-N-), 149.03 (Ar-C of-C-O-), 150.09 (Ar-C of-C-O-), 160.05 (C of-CH=N-), 168.77 (C5-sydnone); MS m/z (rel. int. %): 462.4 (M+1)⁺.

(6c) IR: (KBr) v (cm^-1): 3425 (Ar-OH), 3266 (-NH-), 2919, 2865, (-CH2-of Mannich base), 1749 (>C=O of sydnone), 1634 (-C=N-of Schiff base), 1621, 1509 (C=C of aromatic), 1525 (asym.), 1345 (sym.) (-NO₂); ¹H NMR (DMSO-d₆): δ (ppm): 4.31 (s, 2H,-CH₂-of Mannich base), 6.47 (d, 2H, Ar-H), 6.91 (d, 1H, Ar-H), 7.17 (t, 1H, Ar-H), 7.33 (t, 1H, Ar-H), 7.35 (s, 1H,-NH-), 7.39 (d, 2H, Ar-H), 7.59 (t, 1H, Ar-H), 7.62 (d, 1H, Ar-H), 8.24 (d, 2H, Ar-H), 8.29 (s, 1H, Ar-H), 8.41 (s, 1H,-CH= of Schiff base), 11.14 (s, 1H,-OH); ¹³C NMR (DMSO-d₆): δ (ppm): 48.08 (-CH₂-NH-), 114.71 (Ar-C), 114.78 (Ar-C), 117.81 (Ar-C), 120.56 (Ar-C), 121.40 (Ar-C), 123.11 (Ar-C), 126.67 (Ar-C), 132.12 (Ar-C), 132.33 (Ar-C), 132.41 (Ar-C), 136.54 (Ar-C), 139.41 (Ar-C), 140.45 (Ar-C of-C-N-), 142.46 (C4-sydnone), 147.78 (Ar-C of-C-N-), 160.02 (C of-CH=N-), 161.14 (Ar-C of-C-O-), 168.72 (C5-sydnone); MS m/z (rel. int. %): 432.3 (M+1)⁺.

(6d) IR: (KBr) v (cm^-1): 3244 (-NH-), 2926, 2842, (-CH₂-of Mannich base), 1759 (>C=O of sydnone), 1649 (-C=N-of Schiff base), 1632, 1515 (C=C of aromatic), 1531 (asym.), 1352 (sym.) (-NO₂); ¹H NMR (DMSO-d₆): δ (ppm): 4.33 (s, 2H,-CH₂-of Mannich base), 6.43 (d, 2H, Ar-H), 7.34 (s, 1H,-NH-), 7.40 (d, 2H, Ar-H), 7.58 (t, 1H, Ar-H), 8.17 (d, 2H, Ar-H), 8.23 (d, 2H, Ar-H), 8.28 (s, 1H, Ar-H), 8.35 (d, 2H, Ar-H), 8.87 (s, 1H,-CH= of Schiff base); ¹³C NMR (DMSO-d₆): δ (ppm): 49.03 (-CH₂-NH-), 114.71 (Ar-C), 114.81 (Ar-C), 117.80 (Ar-C), 123.18 (Ar-C), 124.09 (Ar-C), 126.67 (Ar-C), 127.79 (Ar-C), 132.33 (Ar-C), 136.56 (Ar-C), 139.44 (Ar-C), 140.41 (Ar-C of-C-N-), 142.39 (C4-sydnone), 142.49 (Ar-C), 147.77 (Ar-C of-C-N-), 147.8.8 (Ar-C of-C-N-), 150.22 (Ar-C of-C-N-), 160.01 (C of-CH=N-), 168.67 (C5-sydnone); MS m/z (rel. int. %): 461.2 (M+1)⁺.

(6e) IR: (KBr) v (cm^-1): 3252 (-NH-), 2916, 2856, (-CH₂-of Mannich base), 1755 (>C=O of sydnone), 1649 (-C=N-of Schiff base), 1632, 1515 (C=C of aromatic), 1531 (asym.), 1352 (sym.) (-NO₂) 1231, 1029 (C-O-C of methoxy); ¹H NMR (DMSO-d₆): δ (ppm): 3.83 (s, 3H,-OCH₃), 3.85 (s, 3H,-OCH₃); 4.33 (s, 2H,-CH₂-of Mannich base), 6.43 (d, 2H, Ar-H), 7.05 (d, 2H, Ar-H), 7.34 (s, 1H,-NH-), 7.38 (d, 2H, Ar-H), 7.42 (d, 1H, Ar-H), 7.55 (s, 1H, Ar-H), 7.63 (t, 1H, Ar-H), 8.24 (d, 2H, Ar-H), 8.26 (s, 2H, Ar-H), 8.54 (s, 1H,-CH= of Schiff base); ¹³C NMR (DMSO-d₆): δ (ppm): 49.1 (-CH₂-NH-), 56.09 (C of-OCH₃), 109.18 (Ar-C), 111.77 (Ar-C), 114.66 (Ar-C), 114.80 (Ar-C), 123.11 (Ar-C), 125.19 (Ar-C), 126.71 (Ar-C), 130.61 (Ar-C), 132.33 (Ar-C), 136.48 (Ar-C), 139.45 (Ar-C), 140.37 (Ar-C of-C-N-), 142.41 (C4-sydnone), 147.78 (Ar-C of-C-N-), 147.87 (Ar-C of-C-N-), 149.89 (Ar-C of-C-O-), 152.14 (Ar-C of-C-O-), 160.02 (C of-CH=N-), 168.71 (C5-sydnone); MS m/z (rel. int. %): 476.4 (M+1)⁺.

Result and Discussion

Chemistry

The multi-component condensation of a primary amine or secondary amine and enolizable carbonyl compound with the aim to synthesized amino methylated products are referred to as the Mannich Reaction. The synthesis of Schiff base derivatives (6_a-j) Mannich base of sydnone is shown in Scheme. 1. We focused on the synthesis of Mannich base by reacting 3-(3-nitrophenyl) sydnone with p-phenylene diamine. Synthesis of 3-(3-nitrophenyl) sydnone [4] comprises of three steps procedure viz, condensation with chloroacetic acid, nitrosation and cyclodehydration. Compound [4] reacted with paraformaldehyde and p-phenylene diamine to give amino methylated compound [5]. This on further condensed with substituted aldehydes in presence of gla. HAc-to give desired Schiff base 6_a-j.

Elemental Analysis and Spectral data were used to confirm the structures of synthesized compounds. Compound (4) showed two characteristics IR absorption band at 3.108 cm^-1 and 1.752 cm^-1 due to C-H and >C=O streaching of the sydnone. ¹H-NMR (DMSO d₆) spectra of compound (4) showed sharp singlet peak at δ 7.42 ppm, characteristics band for active proton at 4th position of sydnone. The absence of this sharp peak in compound (5) confirms the formation of Mannich base. IR spectra of compound (5) showed two characteristics band at 3.269 cm^-1 and 2.860 cm^-1 due to-CH₂and-NH-of Mannich base. ¹HNMR (DMSO-d₆) spectra of compound (5) showed singlet at δ 4.59 ppm due to-NH₂, which was disappeared in compounds 6a-j due to the formation of Schiff base derivatives. The-C=N-streaching of Schiff base in compounds 6_a-j found between 1.665 cm^-1 to 1.595 cm^-1. Some additional peaks appear due to substitution in aromatic ring. ¹³C-NMR spectra showed characteristics signal for the carbonyl carbon around δ 168.7 ppm, methylene carbon around δ 49 ppm.

Antimicrobial activity

Control of microbial population is necessary to prevent transmission of disease, infection, decomposition, contamination and spoilage caused by them. This was one of the purposes of our present work. The synthesized compounds were screened for their in vitro antibacterial activity against Gram positive and Gram negative bacterial strains, compounds were also screened for their in vitro antifungal activity. Gram positive bacteria viz., Staphylococcus aureus, Streptococcus pyogenes, gram negative bacteria viz., Escherichia coli and Pseudomonas aeruginosa were used in this assay. Gentamycin, Ampicillin, Chloramphenicol, Ciprofloxacin and Norfloxacin were used as standard antimicrobial compounds. The antifungal activity was screened in vitro against pathogenic yeast, Candida albicans, and moulds like Aspergillus niger and Aspergillus clavatus. Antifungal compounds, Nystatin and Griseofulvin, were used as standard. The investigation was carried out by Minimum Inhibitory Concentration (MIC) by Broth Dilution Method.

Compounds 6_f (R=4-OCH₃) is most active against Gram Positive bacteria S. aureus, Compounds 6_h (R=2-Cl) is highly active against Gram negative bacterial strain viz., E. coli. Compound 6_j showed excellent antifungal activity against pathogenic yeast C. albicans. All other compounds were showed moderate to good activity and some are inactive against all strains.

Acknowledgement

The authors would like to express their gratitude to the Department of Chemistry, Veer Narmad South Gujarat University, Surat for providing basic research facilities. The authors wish to thank to UGC-BSR-SAP for financial assistance.

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