*Corresponding Author:
S. K. Sahu
University Department of Pharmaceutical Sciences, Utkal University, Vani Vihar, Bhubaneswar - 751 004, India
E-mail: [email protected]
Date of Submission 9 January 2006
Date of Revision 11 April 2007
Date of Acceptance 12 October 2007
Indian J Pharm Sci 2007, 69 (5): 689-692  

Abstract

A series of Schiff's bases have been prepared by condensation of substituted benzaldehydes with primary arylamines and the corresponding 4-thiazolidinones have been prepared by the reaction of Schiff's bases with thioglycolic acid in benzene. The resulting 4-thiazolidinones on reaction with substituted benzaldehydes in anhydrous sodium acetate by Knoevenagel's condensation have afforded 2-phenyl(substituted)-3-aryl-5-benzilidine(substituted) thiazolidine-4-ones, which on cyclization with phenyl hydrazine in anhydrous sodium acetate have furnished the title compounds. The structures have been established on the basis of spectral data. All the compounds have been screened in vitro for their antibacterial activity. The results of antibacterial activity study revealed promising inhibitory activity for 3,3a,5,6-tetrahydro-2H-pyrazolo[3,4-d] thiazole derivatives with 4-chloro and 4-nitro phenyl substitutions at 5-position against all the tested strains.

Selected substituted thiazoles [1,2] as well as different pyrazole ring containing heterocycles [3,4] possess marked antibacterial activity. The present investigation deals with the development of a series of nitrogen heterocyclic system from easily available starting materials. We report herein the synthesis of 2-phenyl (substituted)-3-aryl-5-benzilidine (substituted) thiazolidine-4-ones (3), their conversion to the title compounds (4) and evaluation of latter for their antibacterial activity.

Melting points were determined in open capillaries and were uncorrected. Purity of the compounds was checked by TLC on silica gel G plates. IR spectra (KBr) were recorded on a Jasco FTIR 410 spectrophotometer (νmax). 1H NMR spectra (CDCl3) were taken on a Bruker DRX 300-MHz spectrometer using TMS as an internal standard (chemical shifts in δ ppm). Elemental analysis (C, H, N) was carried out on a Euro EA (Italy) analyser. Schiff’s bases (I) and the corresponding 4-thiazolidinones (2) were prepared according to literature method [5].

2-Phenyl (substituted)-3-aryl-5-benzilidine (substituted)- thiazolidine-4-ones (3) [6] were synthesized by reß uxing an equimolar mixture (0.001 mol) of compound (2) and substituted benzaldehydes with anhydrous sodium acetate (0.082 g) in glacial acetic acid (20 ml) for 3 h. The reaction mixture was concentrated, cooled and poured into ice cold water. The solid thus separated was filtered, washed with water and crystallized from glacial acetic acid. The physical and elemental analysis data are given in Table 1 and 2, respectively.

Compound Substituents mp(°) Yield
  Ar R RI   (%)
3a1 4-NO2
Phenyl
2-OH 2-OH 151 46.34
b1 4-NO2
Phenyl
4-N(CH3)2 2-OH 88 44.05
c1 4-NO2
Phenyl
4-NO2 2-OH 132 25.97
d1 4-NO2
Phenyl
4-Cl 2-OH 202 20.06
e1 4-NO2-Phenyl 4-OCH3 2-OH 190 36.74
a2 4-Cl Phenyl 2-OH 4-N(CH3)2 108 48
d2 4-Cl Phenyl 4-Cl 4-N(CH3)2 118 48
a3 4-Br Phenyl 2-OH 4-Cl 98 48
c3 4-Br Phenyl 4-NO2 4-Cl 88 37
d3 4-Br Phenyl 4-Cl 4-Cl 130 49
b4 Naphthyl 4-N(CH3)2 4-Cl 206 64
c4 Naphthyl 4-NO2 4-Cl 99 64
d4 Naphthyl 4-Cl 4-Cl 83 49
e4 Naphthyl 4-OCH3 4-Cl 95 81

Table 1: Physical data of 2-phenyl-3-aryl-5- Benzilidine (substituted) thiazolidine-4-ones

Compound Molecular formula C % H % N %
    Calculated Found Calculated Found Calculated Found
3a1 C22H16N2O5S 62.84 62.80 3.83 3.80 6.66 6.64
b1 C24H21N3O4S 64.41 64.37 4.73 4.69 9.39 9.37
c1 C22H15N3O6S 58.79 58.74 3.36 3.32 9.34 9.32
d1 C22H15ClN2O4S 60.20 59.80 3.44 3.40 6.38 6.37
e1 C23H18N2O5S 63.58 63.55 4.17 4.14 6.44 6.42
a2 C24H21Cl N2O2S 65.96 65.92 4.84 4.81 6.41 6.30
d2 C24H20Cl2N2OS 63.28 36.24 4.42 4.38 6.14 6.12
a3 C22H14BrClNO2S 57.84 57.80 3.30 2.9 3.06 3.03
c3 C22H14BrClNO3S 55.88 55.84 3.19 3.16 2.96 2.95
d3 C22H14BrCl2NOS 53.71 53.68 2.87 2.84 2.85 2.83
b4 C28H23ClN2OS 71.39 71.35 4.92 4.88 5.94 5.93
c4 C26H17ClN2O3S 66.02 65.09 3.62 6.58 5.92 5.90
d4 C26H17Cl2NOS 67.52 67.48 3.70 3.30 3.02 3.00
e4 C27H20ClNO2S 70.01 69.97 4.52 4.48 3.14 3.12

Table 2: Elemental analysis of 2-phenyl-3-aryl-5- benzilidine (substituted) thiazolidine-4-ones.

3a1 : IR(KBr, cm-1): 3285(Ar-OH), 3052 (Ar-CH),1739 (C=O),1542 (Ar-NO2). b1: IR (KBr, cm-1): 3294 (Ar-OH), 3045 (Ar-CH), 1736(C=O), 1538 (Ar-NO2), d1: IR (KBr, cm-1): 3292 (Ar-OH), 3038 (Ar-CH), 1733 (C=O), 747 (C-Cl). a2: IR (KBr, cm-1): 3289 (Ar-OH), 3026 (Ar-CH), 1722 (C=O), 754 (C-Cl). d2: IR (KBr, cm-1): 3049 (Ar-CH ), 1746 (C=O),751 (C-Cl). a3: IR (KBr, cm-1): 3295 (Ar-OH), 3031 (Ar-CH), 1742 (C=O), 742 (C-Cl). C3: IR (KBr, cm-1): 3064 (Ar- CH),1752 (C=O), 1546 (Ar-NO2), 759 (C-Cl). b4: IR (KBr, cm-1): 3068 (Ar-CH), 1756 (C=O), 746 (C-Cl). c4: IR (KBr, cm-1): 3059 (Ar-CH), 1731 (C=O), 1560 (Ar-NO2), 745 (C-Cl). d4: IR (KBr, cm-1): 3071 (Ar- CH ),1729 (C=O), 749 (C-Cl). The NMR Spectra of the synthesized compounds (3) of the series revealed peaks around 5.1-5.8 δ (1H, s, C=CH) and 6.5-8.0 δ due to bulk aromatic protons.

2-Phenyl-3,5-diphenyl(substituted)-6-aryl-3,3a,5,6- tetrahydro-2H-pyrazolo-[3,4-d]thiazoles (4) [6] were synthesized by heating under reflux an equimolar (0.001 mol) of compound (3) and phenylhydrazine with anhydrous sodium acetate (0.082 g) in glacial acetic acid (20 ml) for 6 h and cooled to room temperature. The solid thus separated was filtered, washed thoroughly with water and crystallised from glacial acetic acid. The physical and elemental analysis data are given in Tables 3 and 4, respectively.

Compound Substituents mp(°) Yield
  Ar R RI   (%)
4a1 4-NO2Phenyl 2-OH 2-OH 98 99.9
b1 4-NO2Phenyl 4-N (CH3)2 2-OH 138 94.96
c1 4-NO2Phenyl 4-NO2 2-OH 108 95
d1 4-NO2Phenyl 4-Cl 2-OH 140 97.1
e1 4-NO2Phenyl 4-OCH3 2-OH 150 99
a2 4-Cl Phenyl 2-OH 4-N (CH3)2 242 99.75
d2 4-Cl Phenyl 4-Cl 4-N (CH3)2 92 99.7
a3 4-Br Phenyl 2-OH 4-Cl 121 96.8
c3 4-Br Phenyl 4-NO2 4-Cl 105 81.7
d3 4-Br Phenyl 4-Cl 4-Cl 88 90.74
b4 Naphthyl 4-N (CH3)2 4-Cl 87 99.4
c4 Naphthyl 4-NO2 4-Cl 160 98.89
d4 Naphthyl 4-Cl 4-Cl 236 95.5
e4 Naphthyl 4-OCH3 4-Cl 120 97.98

Table 3: Physical data of 2-phenyl-3,5-diphenyl (substituted)-6-aryl-3,3a, 5,6-tetrahydro-2hpyrazolo [3,4-d] thiazoles.

Compound Molecular formula C % H % N %
    Calculated Found Calculated Found Calculated Found
4a1 C28H22N4O4S 65.86 65.82 4.34 4.30 10.97 10.95
b1 C30H27N5O3S 67.02 66.98 5.06 4.96 13.02 13.01
c1 C28H21N5O5S 62.32 62.28 3.92 3.89 12.97 12.96
d1 C28H22ClN4O3S 68.13 68.10 4.28 4.25 11.35 11.33
e1 C29H24N4O4S 66.39 66.35 4.61 4.57 10.67 10.66
a2 C30H27ClN4S 68.35 68.33 5.16 5.14 10.62 10.60
d2 C30H26Cl2N4S 66.03 65.99 4.80 4.50 10.27 10.26
a3 C28H21BrClN3OS 59.73 59.70 3.76 3.74 7.46 7.44
c3 C28H20BrClN4O2S 65.75 65.71 3.01 2.93 3.06 3.05
d3 C28H20BrCl2N3S 57.83 57.80 3.46 3.44 7.22 7.20
b4 C34H29ClN4S 72.76 72.72 5.02 4.17 9.98 9.96
c4 C32H23ClN4O2S 68.25 68.21 4.11 4.08 9.94 9.93
d4 C32H23Cl2N3S 69.55 69.51 4.19 4.15 7.60 7.59
e4 C33H26ClN3OS 72.3 72.00 4.78 4.75 7.66 7.64

Table 4: Elemental analysis of 2-phenyl-3,5-diphenyl (substituted)-6-aryl-3,3a,5,6-tetrahydro-2hpyrazolo[ 3,4-d] thiazoles.

4a1: IR (KBr, cm-1): 3289 (Ar-OH), 3064(Ar-CH), 1539 (Ar-NO2), 1671 (C=N), 1266 (C-N); 1HNMR δ: 3.15 (s,1H,CH), 5.84 (s,1H,CH), 6.58-8.74 (m,17H,Ar- H), 11.14(s,1H,OH). b1: IR (KBr, cm-1): 3290(Ar-OH), 3031(Ar-CH), 1663(C=N), 1539 (Ar-NO2), 1260(C-N); 1HNMR δ: 1.13 (s.6H,2xCH3), 2.95(s,1H,CH),5.64(s, 1H,CH), 6.5-9.24(m,17H,Ar-H). d1: IR (KBr, cm-1): 3284(Ar-OH), 3045 (Ar-CH), 1548 (ArNO2), 1656 (C=N), 1264 (C-N), 748 (C-Cl); 1HNMR δ: 3.04 (s,1H,CH), 5.78 (s,1H,CH), 6.64-8.78 (m,17H,Ar-H), 10.96 (s,1H,OH). a2: IR(KBr, cm-1): 3286 (Ar-OH), 3063 (Ar-CH), 1683 (C=N), 1276 (C-N), 751 (C-Cl); 1HNMR δ: 1.40 (s,1H, 2×CH3), 3.22 (s,1H, CH), 5.75 (s,1H, CH), 5.90-7.97 (m,17H, Ar-CH), 10.99 (s,1H, OH). d2: IR (KBr, cm-1): 3062 (Ar-CH), 1674 (C=N), 1272 (C-N), 756 (C-Cl); 1HNMR δ: 2.02 (s, 6H, 2×CH3), 3.19 (s,1H,CH), 5.79 (s,1H,CH), 6.52-8.68 (m,17H,Ar-H). a3: IR (KBr, cm-1): 3294 (Ar-OH), 3030 (Ar-CH), 1668 (C=N), 1279 (C-N), 755 (C-Cl); 1HNMR δ: 2.17 (s,1H,CH), 5.85 (s,1H,CH), 7.02-9.18 (m,17H,Ar-H), 11.20 (s,1H,OH). c3: IR (KBr, cm-1): 3076 (Ar-CH), 1672 (C=N), 1552 (Ar-NO2), 1274 (C-N); 1HNMR δ: 3.06 (s,1H,CH), 5.72 (s,1H,CH), 5.90-7.97 (m,17H,Ar-H). b4: IR (KBr, cm-1): 3049 (Ar-CH), 1677 (C=N), 1267 (C-N), 744 (C-Cl); 1HNMR δ: 1.98 (s,6H, 2×CH3), 3.22 (s,1H,CH), 5.85 (s,1H,CH), 6.39-8.88 (m,20H,Ar-H). c4: IR (KBr, cm- 1): 3078 (Ar-OH), 1661 (C=N), 1564 (Ar-NO2), 1270 (C-N), 743 (C-Cl); 1H NMR δ: 2.22 (s,1H,CH), 5.08 (s,1H,CH), 5.83-8.88 (m,20H,ArH). d4: IR (KBr, cm-1): 3067 (Ar-CH), 1673 (C=N), 1273 (C-N), 753 (C-Cl); 1HNMR δ: 3.18 (s,1H,CH), 5.82 (s,1H,CH), 6.60-8.81 (m,20H,Ar-H).

No doublet was seen in the NMR spectrum of any of the title compounds, thus indicating that the initial structure got rapid transformation through tautomeric shift of H-atom to the more stable structure as indicated in Scheme 1.

Figure

Scheme 1: Synthetic scheme of title compounds
For 1,2,3,4 a1-e1; Ar = 4-NO2-C6H5, a2-d2; Ar= 4-Cl-C6H5, a3-d3; Ar= 4-Br-C6H5, b4-e4; Ar= Naphthyl. 1,2,3,4 a1-3; R= 2-OH, b1-4; R= 4-N (CH3)2, c1-4; R= 4-NO2, d1- 4; R= 4-Cl, e1-4; R= 4-OCH3. 3,4 a1-e1; R1= 2-OH, a2-d2; R1= 4-N (CH3)2, a3-d3,b4-e4; R1= 4-Cl

Substituted benzaldehydes on condensation with primary arylamines gave Schiff’s bases (1a1-e1, a2-d2, a3-d3, b4-e4), which on reaction with thioglycolic acid in benzene gave the corresponding 4-thiazolidinone (2a1-e1, a2-d2, a3-d3, b4-c4). The latter on reacting with substituted benzaldehydes in anhydrous sodium acetate afforded 2-phenyl(substituted)-3-aryl-5-benzilidine(sub stituted)thiazolidine-4-ones (3a1-e1, a2 , d2, a3 , c3, d3, b4-e4), which in turn reacted with phenylhydrazine in presence of anhydrous sodium acetate to furnish 2-phenyl-3,5-diphenyl(substituted)-6-aryl-3,3a,5,6- tetrahydro-2H-pyrazolo[3,4-d] thiazoles (4a1-e1, a2, d2, a3, c3, d3, b4-e4).

All compounds were screened for their in vitro antibacterial activity by agar cup plate method [7] at 100 μg concentration. Solutions of the test compounds were kept in dimethylsulphoxide. Ampicillin trihydrate (100 μg/ml) was used as a standard drug for comparison and solvent control was kept. The antibacterial activity of various compounds against pathogenic strains in nutrient agar is shown in Table 5. Compounds 4d1, d2, d3, c4, and d4 were found to be the most active against all the microbes. However, all the compounds were comparatively less active than the standard drug.

Compound Inhibition zone diameter (mm)*
S. a A. p E. c K. a
4a1 18 20 17 19
b1 19 18 21 20
c1 17 20 19 18
d1 19 21 21 22
e1 17 18 20 19
a2 19 18 21 20
d2 21 20 23 22
a3 19 20 18 21
c3 20 18 21 19
d3 21 20 22 24
b4 17 19 18 20
c4 19 20 22 21
d4 20 22 21 23
e4 18 17 20 21
Ampicillin trihydrate 31 29 30 31

Table 5: Antibacterial activities of 2-phenyl- 3,5-diphenyl(substituted)-6-aryl-3,3a,5,6- Tetrahydro-2h-pyrazolo [3,4-d] thiazoles

Acknowledgements

The authors wish to thank Dr. G. C. Pradhan, Department of Chemistry, Utkal University, Bhubaneswar for facilities and Prof. C. S. Panda, Department of Chemistry, Berhampur University, Berhampur for his valuable suggestions.

References