SYNTHESIS AND ANTIBACTERIAL SCREENING OF SCHIFF BASES DERIVED FROM 3-(5-BROMOTHIOPHEN-2-YL)-1-(4-CHLOROPHENYL)-1H-PYRAZOLE-4-CARBALDEHYDE

SYNTHESIS AND ANTIBACTERIAL SCREENING OF SCHIFF BASES DERIVED FROM 3-(5-BROMOTHIOPHEN-2-YL)-1-(4-CHLOROPHENYL)-1H-PYRAZOLE-4-CARBALDEHYDE

S. V. Manohare ^{* 1} and S. S. Thakare ²

Department of Chemistry ¹, Adarsha Science, J. B. Arts and Birla Commerce Mahavidyalaya, Dhamangaon Rly - 444709, Maharashtra, India.

Rajarshee Shahu Science College ², Chandur Rly - 444904, Maharashtra, India.

ABSTRACT: A series of new Schiff bases were synthesized by condensation of 3-(5-bromothiophen-2-yl)-1-(4-chlorophenyl)-1H-pyrazole-4-carbaldehyde with different aromatic aldehydes. The 3-(5-bromothiophen-2-yl)-1-(4-chlorophenyl)-1H-pyrazole-4-carbaldehyde was prepared from 1-(1-(5-bromothiophen-2-yl)ethylidene)-2-(4-chlorophenyl)hydrazine by the Vilsmeier Haack reaction. The 1-(1-(5-bromothiophen-2-yl)ethylidene)-2-(4-chlorophenyl) hydrazine was prepared by the condensation reaction of 2-acetyl-5-bromothiophene with 4-chlorophynylhydrazine hydrochloride. The structures of newly synthesized compounds were elucidated by NMR, IR, and Mass spectral - data. Prepared Schiff bases were evaluated for antibacterial activity against four organisms: Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa and Klebsiella pneumoniae using streptomycin as a standard drug. Agar well-diffusion method was followed to determine the antimicrobial activity. All prepared Schiff bases showed poor to good activity against test organisms. Based on the zone of inhibition results, it is observed that the newly prepared Schiff bases showed better activity against Klebsiella pneumoniae than Escherichia coli, Staphylococcus aureus, and Pseudomonas aeruginosa. Schiff base 4c showed good activity against Pseudomonas aeruginosa, Schiff base 4l showed good activity against Staphylococcus aureus and all the Schiff bases 4a-4l except 4c showed good activities against Klebsiella pneumoniae.

Hydrazone, Pyrazole Schiff bases, Antimicrobial activity

INTRODUCTION: Heterocyclic compounds have great importance in medicinal chemistry. Pyrazole is an important class of heterocyclic compounds widely used in various areas of chemistry and related sciences.

Pyrazole derivatives have attracted much attention of chemists on account of their wide applications in medicinal chemistry.

These compounds show antimicrobial ^1-3 anti-inflammatory ^{4, 5} antitubercular ⁶, antimalarial ⁷, insecticidal ⁸, antifungal ^{9, 10} and anticancer ^11-13 activities. Schiff bases an important scaffold have attracted the interest of chemists due to wide applications in synthetic chemistry and biological point of views. They are also serving as backbone for the synthesis of various heterocyclic compounds.

They are important compounds due to their wide range of pharmacological activities such as antimicrobial ^14-20, anticancer ^21-22, antifungal ^{23, 24}, anti-inflammatory ^{25, 26} and DNA- cleavage ²⁷ activities. In the present article, we present the synthesis, characterization and antimicrobial evaluation of Schiff bases prepared from 3-(5-bromothiophen- 2- yl)- 1- (4- chlorophenyl)- 1H-pyrazole-4-carbaldehyde.

MATERIALS AND METHODS: All the chemicals were procured from Sigma Aldrich and SDFINE chemicals and used without further purification. Melting points were determined in open capillary tube and are uncorrected. The progress of the reactions as well as purity of the compounds was monitored by thin layer chromatography with F–252 silica gel precoated aluminum sheets using petroleum ether-ethyl acetate (9:1) as a developing solvent and spots were visualized with near UV and Iodine. The IR spectra were recorded on Shimadzu spectrophotometer using KBr pellets and expressed in cm^-1. The NMR spectra were recorded on BRUKER ADVANCE (400 FT-NMR) spectrophotometer in DMSO using tetramethylsilane as an internal standard, and chemical shift values are expressed in δ ppm. The MASS spectra were recorded on Waters UPLC-TQC MASS spectrometer.

Procedure for Preparation of (hydrazone) 1-(1-(5-bromothiophen-2-yl) ethylidene)- 2-(4-chloro-phenyl) hydrazine 2: 2-acetyl-5-bromothiophene (0.01 mol), p-chlorophenylhydrazone hydro-chloride (0.01 mol) and 2-3 drops of glacial acetic dissolved in 20 ml ethanol. The reaction mixture was stirred on a magnetic stirrer at room temperature for three hours. After the completion of reaction yellow precipitate was obtained, which was filtered, washed and purified by recrystallization with ethanol. Yellow solid, melting point -148 ºC, yield- 70%.

Procedure for Preparation of (Pyrazole) 3-(5-bromothiophen- 2- yl)- 1- (4-chlorophenyl)- 1H-pyrazole-4-carbaldehyde 3: 0.03 mol of POCl₃ was added dropwise to an ice-cold  solution of 1-(1-(5-bromothiophen-2-yl)ethylidene)- 2-(4-chloro-phenyl) hydrazine (3) (0.01 mol) in 10 ml DMF. The reaction mixture was stirred for half an hour at room temperature first and then at 70 ºC for about five hours on a magnetic stirrer. The resulting mixture was poured onto crushed ice and neutralized with a saturated sodium bicarbonate solution. The pale green precipitate obtained was purified by recrystallization with ethanol.

Yellow solid, melting point-158 ºC,  yield- 80%, IR (KBr cm ^-1); 1674 cm ^-1 ( C═O), 2785 cm ^-1 (CHO), 3182 cm ^-1 (H--Ar), 1531 cm ^-1 (C═N). ¹H-NMR (DMSO-d₆, δ, ppm): 9.9 (s, 1H, CHO), 9.3 (s, 1H, Pyrazole), 7.9 (d, 1H, Ar--H), 7.2 (d, 1H, Ar--H), 7.8 (d, 2H, Ar—H), 7.5(d, 2H, Ar--H). Mass; (M⁺) 365, (M⁺+2) 367.

Procedure for Preparation of Schiff Bases 4a-4l: Equimolar quantities of 3-(5-bromothiophen-2-yl)-1-(4-chlorophenyl)-1H-pyrazole-4-carbaldehyde 3 (0.01 mol) and different aromatic amines (0.01 mol) and 2-3 drops of glacial acetic were dissolved in 20 ml ethanol. The reaction mixture was refluxed for 3 to 4 h in water bath and cooled at room temperature. Yellow precipitate was obtained which was filtered, washed and purified by recrystallization with ethanol. Physical and Spectral data of representative Schiff bases are as given below.

1- (3- (5- bromothiophen- 2- yl)- 1- (4- chloro-phenyl)-1pyrazol-4-yl-Nphenyl methanimine 4a: Yellow solid, yield- 70%, melting point- 118 ºC. IR (KBr, cm^-1); 3104 cm^-1 (H--Ar), 1620 cm^-1 (HC═N), 1589 cm^-1 (C═N), 1500 cm^-1 (C═C). ¹H-NMR (DMSO-d₆, δ, ppm): 9.2 (s, 1H, pyrazole), 8.6 (s, 1H, HC═N), 6.9-8.0 (m, 11H, Ar--H). Mass; (M⁺) 442.

1-(3-(5-bromothiophen-2-yl)-1-(4-chlorophenyl)-1H- pyrazol- 4- yl)- N- (4- chlorophenyl) methanimine 4b: Yellow solid, yield-85%, melting point-136 ºC. IR (KBr, cm^-1); 3140 cm^-1 (H--Ar), 1612 cm^-1 (HC═N), 1535 cm^-1 (C═N), 1500 cm^-1 (C═C). ¹H-NMR (DMSO-d₆, δ, ppm): 9.1 (s, 1H, pyrazole), 8.6 (s, 1H, HC═N), 6.6-8.0 (m, 10H, Ar--H). Mass; (M⁺) 478.

1-(3-(5-bromothiophen-2-yl)-1-(4-chlorophenyl)-1H- pyrazol- 4- yl)- N- (4-bromophenyl) methanimine 4c: Yellow solid, yield-50%, melting point-142 ºC. IR (KBr, cm^-1); 3142 cm^-1 (H--Ar), 1631 cm^-1 (HC═N), 1539 cm^-1 (C═N), 1500 cm^-1 (C═C). ¹H-NMR (DMSO-d₆, δ, ppm): 9.4 (s, 1H, pyrazole), 8.6 (s, 1H, HC═N), 6.5-8.0 (m, 10H, Ar--H). Mass; (M⁺) 478.

1- (3- (5- bromothiophen- 2- yl) -1- (4- chloro-phenyl)- 1H- pyrazol -4- yl) –N -(p- tolyl) methanimine 3d: Yellow solid, yield-55%, melting point -120 ºC. IR (KBr, cm^-1); 3136 cm^-1 (H--Ar), 1624 cm^-1 (HC═N), 1597 cm^-1 (C═N), 1500 cm^-1 (C═C). ¹H-NMR (DMSO-d₆, δ, ppm): 9.1 (s, 1H, pyrazole), 8.6 (s, 1H, HC═N), 2.5 (s, 3H CH₃), 6.4-8.0 (m, 10H, Ar--H). Mass; (M⁺) 456.

1-(3-(5-bromothiophen-2-yl)-1-(4-chlorophenyl)-1H- pyrazol- 4- yl)- N- (4-nitrophenyl) methani-mine 4e: Yellow solid, yield-50%, melting point-128 ºC. IR (KBr, cm^-1); 3128 cm^-1 (H--Ar), 1631 cm^-1 (HC═N), 1597 cm^-1 (C═N), 1527 cm^-1 (C═C). ¹H-NMR (DMSO-d₆, δ, ppm): 9.4 (s, 1H, pyrazole), 8.6 (s, 1H, HC═N), 6.6-8.0 (m, 10H, Ar--H). Mass; (M⁺) 489

1-(3-(5-bromothiophen-2-yl)-1-(4-chlorophenyl)-1H-pyrazol-4-yl)-N-(4-hydroxyphenyl) methani-mine 4f: Yellow solid, yield-60%, melting point-158 ºC. IR (KBr, cm^-1); 3097 cm^-1 (H--Ar), 1620 cm^-1 (HC═N), 1546 cm^-1 (C═N), 1508 cm^-1 (C═C). ¹H-NMR (DMSO-d₆, δ, ppm): 9.1 (s, 1H, pyrazole), 8.6 (s, 1H, HC═N), 6.4-8.0 (m, 10H, Ar--H). Mass; (M⁺) 458

SCHEME 1

 TABLE 1: ANTIMICROBIAL ACTIVITY OF SCHIFF BASES 4a-4l

--No activity detectable under experimental condition

Antibacterial Assay: All the synthesized Schiff bases were screened for antimicrobial activity by using four organisms namely Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa and Klebsiella pneumoniae using streptomycin as a standard drug. Agar well-diffusion method was followed to determine the antimicrobial activity. Bacterial cultures were grown in exponential phase in nutrient broth at 37 ºC for 8 h and adjusted to a final concentration 0.5 McFarland turbidity standard. The nutrient agar plate (thickness 4 to 5 mm) surface is inoculated by spreading a volume of the microbial inoculums over the entire agar surface. A hole with a diameter 6 to 8 mm has punched aseptically with a sterile stainless steel borer. 20 μl of the chemical agent of desired concentration was introduced into the well with the help of micropipette and allowed to diffuse at room temperature for 1 h. The plates were incubated at 37 ºC for 18 h for bacterial pathogens. The diameter of the inhibition zone (mm) was measured with zone reading scale. The antibacterial activity of the synthesized Schiff bases against mention organisms is given in Table 1.

RESULTS AND DISCUSSION:

Chemistry: The Schiff bases have been prepared from 3- (5- bromothiophen- 2- yl)- 1- (4-chloro-phenyl)-1H-pyrazole-4-carbaldehyde (3) according to synthetic route as mention in the scheme. Structures of all the compounds were established by IR, ¹H-NMR spectroscopy and Mass spectrometry data. The compound1-(1-(5-bromo-thiophen- 2- yl) ethylidene)- 2- (4- chlorophenyl) hydrazine (2) obtained from the reaction between 2- acetyl- 5- bromothiophene and p- chlorophenyl hydrazine hydrochloride. Compound (2) then subjected to Vilseimer-Haack raction to formed 3-(5-bromothiophen-2-yl)- 1- (4- chlorophenyl)- 1H-pyrazole-4-carbaldehyde (3). The formation of compound (3) was confirmed by a sharp signal at 1674 cm^-1 for C═O stretching and  two signals at 2885 cm^-1 and 1785 cm^-1  for (H—CO) in the IR spectrum, singlet signal at δ 9.9 ppm for  CHO proton and also singlet signal at 9.3 for pyrazolyl proton in the 1H-NMR spectrum.

In the mass spectrum of compound (3) the molecular ion peak was observed at m/z = 365, which corresponds to molecular weight. Schiff bases 4a-4l were formed, when compound (3) was reacted with different aromatic amines in the presence of glacial acetic acid as a catalyst.

The structure of newly synthesized Schiff bases were confirmed by the presence of strong signal at 1620-1635 cm^-1 in the IR spectrum, the 1H-NMR spectra showed the sharp singlets at δ 9.1-9.4 ppm for pyrazolyl proton and δ 8.6 due to proton of HC═N group of Schiff bases and multiples for aromatic protons are observed in the range of 6.4-8.0 ppm. The m/z values for the characterized Schiff bases obtained are in good agreement with the molecular weights.

Antimicrobial Activity: The results of anti- bacterial screening are shown in Table 1. All prepared Sciff bases showed poor to good activity against test organisms. Based on the zone of inhibition results, it is observed that the newly prepared Schiff bases showed better activity against Klebsiella pneumoniae than Escherichia coli, Staphylococcus aureus, and Pseudomonas aeruginosa. Schiff base 4c showed good activity against Pseudomonas aeruginosa, Schiff base 4l showed good activity against Staphylococcus aureus and all the Schiff bases 4a-4l except 4c showed good activities against Klebsiella pneumonia. Schiff bases 4a-4l showed poor activity against Escherichia coli.

CONCLUSION: A new series of Schiff bases were prepared and the structures of newly synthesized Schiff bases were confirmed by IR spectroscopy, 1H-NMR spectroscopy, and Mass spectrometry. These newly prepared Schiff bases showed poor to good activity against the test organisms.

ACKNOWLEDGEMENT: The authors are thankful to SAIF, IISc. Bangalore for ¹H-NMR analysis, SAIF, CDRI, Lucknow for Mass analysis and Shri Shivaji Science College, Amravati for IR analysis. One of the authors is grateful to UGC, for the award of teacher fellowship under XII plan of UGC (File no. 29-19/14 WRO.)

CONFLICT OF INTEREST: The authors report no conflict of interest.

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    How to cite this article:

    Manohare SV and Thakare SS: Synthesis and antibacterial screening of schiff bases derived from 3-(5-bromothiophen-2-yl)-1-(4-chlorophenyl)-1H-pyrazole-4-carbaldehyde. Int J Pharm Sci & Res 2019; 10(8): 3741-45. doi: 10.13040/IJPSR.0975-8232.10(8).3741-45.

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