S. K. Sahu*, S. K. Mishra, R. K. Mohanta, S. P. Pattanayak and C. S. Panda1

University Department of Pharmaceutical Sciences, Utkal University, Vani Vihar, Bhubaneswar-751 004

1P. G. Department of Chemistry, Behrampur University, Behrampur-760 007, India.

*Corresponding Author:
S. K. Sahu
University Department of Pharmaceutical Sciences, Utkal University, Vani Vihar, Bhubaneswar-751 004
E-mail: tutu_kh@yahoo.com
Date of Submission 21 March 2005
Date of Revision 18 July 2005
Date of Acceptance 05 June 2006
Indian J Pharm Sci, 2006, 68 (3): 377-380  

DOI: 10.4103/0250-474X.26686

Abstract

Condensation of substituted benzaldehydes with primary aryl amines gave a series of Schiff bases(1a 1 -e 1 ,a 2 ,b 2 ,d 2 ,b 3 -e 3 ) which, on reaction with thioglycolic acid, resulted in the formation of the corresponding 4-thiazolidinones(2a 1 -e 1 ,a 2 ,b 2 ,d 2 ,b 3 -e 3 ). These compounds, on condensation with substituted benzaldehydes in anhydrous sodium acetate, furnished 2-phenyl(substituted)-3-aryl-5-benzilidine(substituted)-thiazolidine-4-ones(3a 1 -e 1 ,a 2 ,b 2 ,d 2 , b 3 -e 3 ). The latter, on heating with 2,4-dinitrophenyl hydrazine in anhydrous sodium acetate, gave the title compounds(4a 1 -e 1 ,a 2 ,b 2 ,d 2 ,b 3 -e 3 ). The structures have been established on the basis of elemental analysis and spectral data. The title compounds have been screened in vitro for their possible antibacterial activity

Selected substituted thiazoles [1-3] as well as different heterocyclic systems containing pyrazole ring [4-6] possess potent biological activities. It is also believed that the presence of N-C-S linkage is responsible for the amoebicidal, anticonvulsant, fungicidal [7], and antiviral activities [8]. The present investigation deals with the development of a new series of nitrogen heterocyclic systems from easily available starting materials.

Substituted benzaldehydes on condensation with primary aryl amines gave Schiff bases (1a1-e1,a2,b2,d2,b3-e3) which, on reaction with thioglycolic acid in refluxing benzene, furnished the corresponding 4-thiazolidinones(2a1-e1,a2,b2,d2,b3-e3). The latter, on condensation with substituted benzaldehydes in the presence of anhydrous sodium acetate and glacial acetic acid, afforded the formation of 2-phenyl(substituted)-3-aryl-5-benzilidine (substituted)-thiazolidine-4-ones(3a1-e1,a2,b2,d2,b3-e3) which, in turn, heated with 2,4-dinitrophenyl hydrazine in the presence of anhydrous sodium acetate and glacial acetic acid, furnished the bridgehead nitrogen heterocyclic system, 2-(2,4-dinitrophenyl)-3,5-diphenyl(substituted)-6aryl-3,3a,5,6-tetrahydro-2H-pyrazolo[3,4-d]thiazoles(4a1-e1,a2,b2,d2,b3-e3) (Scheme 1). Newly synthesised compounds were characterised by IR, NMR spectral data and elemental analysis. The title compounds were evaluated for their possible antibacterial activity.

Figure

Scheme 1: Synthetic route.

Melting points were determined in open capillaries and were uncorrected. Purity of the compounds was checked by TLC. IR spectra were recorded on a Jasco FT/IR 410 spectrophotometer in KBr disc. 1H NMR spectra were taken on a Bruker DPX, 300 MHz, spectrometer using TMS as internal reference. C, H, and N analyses were carried out on a Euro EA analyzer (Italy). The bacteria used in the antibacterial activity study were procured from the Department of Bacteriology and Virology, Faculty of Veterinary Science and Animal Husbandry, Orissa University of Agriculture and Technology, Bhubaneswar.

Schiff bases(1a1-e1,a2,b2,d2,b3-e3) and the corresponding 4-thiazolidinones(2a1-e1,a2,b2,d2,b3-e3) were synthesised following the reported method [9].

Synthesis of 2-phenyl (substituted)-3-aryl-5-benzilidine (substituted)-thiazolidine-4-ones(3a1-e1,a2,b2,d2,b3-e3) was achieved by refluxing an equimolar (0.001 mol) mixture of 4-thiazolidinone derivatives (2a1-e1,a2,b2,d2,b3-e3), substituted benzaldehydes, and 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, dried, and recrystallised from glacial acetic acid. The yield and melting points are given in Table 1. (3c1): IR( KBr, vmax in cm-1): 3290(OH), 3045(CHarom.),1736(C=O), 1538(asym.NO2), 1337 (sym.NO2). (3a2): IR(KBr, vmax in cm-1): 3286(OH), 3026(CH-arom.), 1722(C=O), 754(C-Cl). (3b3): IR (KBr, vmax in cm-1): 3063(CH-arom.), 1742(C=O), 743(C-Cl). The NMR spectra of the synthesised compounds (3) of the series revealed peaks around 5.1-5.8 δ (s, 1H, C=CH) and 6.5-8.0 δ due to bulk aromatic protons.

Compd. Substituents mp (°) Yield (%) Molecular formulaa
A r R R1
3a1 4-NO2Ph 2-OH 2-OH 152 47 C22 H16N2 O5 S
3b1 4-NO2Ph 4-N(CH3)2 2-OH 88 45 C24 H21N3 O4 S
3c1 4-NO2Ph 4-NO2 2-OH 132 44 C22 H15N3 O6 S
3d1 4-NO2Ph 4-Cl 2-OH 202 42 C22 H15 N2 O4SCl
3e1 4-NO2Ph 4-OCH3 2-OH 190 46 C23 H18N2 O5 S
3a2 4-Cl Ph 2-OH 4-N(CH3)2 108 48 C24 H21 N2 O2SCl
3b2 4-Cl Ph 4-N(CH3)2 4-N(CH3)2 86 58 C26 H26N3OSCl
3d2 4-Cl Ph 4-Cl 4-N(CH3)2 118 48 C24H20 N2 OSCl2
3b3 Naphthyl 4-N(CH3)2 4-Cl 206 64 C28H23N2OSCl
3c3 Naphthyl 4-NO2 4-Cl 98 65 C26H17N2O3SCl
3d3 Naphthyl 4-Cl 4-Cl 80 49 C26H17NOSCl2
3e3 Naphthyl 4-OCH3 4-Cl 95 69 C27H20NO2SCl

Table 1: Physical Data Of The Synthesised Compounds (3a1-e1,a2,b2,d2,b3-e3)

Synthesis of 2-(2,4-dinitrophenyl)-3,5-diphenyl(substituted)6-aryl-3,3a,5,6-tetrahydro-2H-pyrazolo[3,4-d]thiazoles(4a1e1,a2,b2,d2,b3-e3) was performed by heating an equimolar (0.001 mol) mixture of 2-phenyl(substituted)-3-aryl-5benzilidine(substituted)-thiazolidine-4-ones (3a1-e1,a2,b2,d2, b3-e3), 2,4-dinitrophenyl hydrazine (0.198 g) and anhydrous sodium acetate (0.082 g) in glacial acetic acid (20 ml) under reflux for 6 h, which was then cooled to room temperature. The solid thus separated was filtered, washed thoroughly with water, dried, and recrystallised from glacial acetic acid. The yield and melting points are given in Table 2. (4c1):IR(KBr, vmax in cm-1): 3294(OH), 3031(CH-arom.), 1617(C=N), 1520(asym.NO2), 1346 (sym.NO2); 1H NMR(CDCL3) δ ppm: 3.18(s,1H,CH), 5.82 (s, 1H, CH), 6.60-8.75 (m, 15H, Ar-H), 11.20 (s, 1H, OH). (4a2): IR (KBr, vmax in cm-1): 3285 (OH), 3078 (CH-arom.), 1611 (C=N), 1539(asym.NO2), 1358 (sym.NO2), 751 (C-Cl); 1H NMR (CDCl3) δ ppm: 2.02 (s, 6H, 2×CH3), 3.16 (s, 1H, CH), 5.75 (s, 1H, CH), 5.90 – 7.97(m, 15H, Ar-H), 10.99 (s, 1H, OH). (4b3): IR(KBr, vmax in cm-1): 3059 (CH-arom.), 1614 (C=N), 1518 (asym. NO2), 1337 (sym. NO2), 756 (C-Cl); 1 H NMR (CDCl3) δ ppm: 1.98 (s, 6H, 2×CH3), 3.22 (s, 1H, CH), 5.83 (s, 1H, CH), 6.39- 8.88 (m, 18H, Ar – H).

Compd. Substituents mp (°) Yield (%) Molecular formulab
A r R R1
4a1 4-NO2Ph 2-OH 2-OH 238 52 C28H20N6O8 S
4b1 4-NO2Ph 4-N(CH3)2 2-OH 216 54 C30 H25N7 O7 S
4c1 4-NO2Ph 4-NO2 2-OH 236 68 C28H19N7O9S
4d1 4-NO2Ph 4-Cl 2-OH 222 65 C28H19N6O7SCl
4e1 4-NO2Ph 4-OCH3 2-OH 196 62 C29H22N6O8S
4a2 4-Cl Ph 2-OH 4-N(CH3)2 180 60 C30H24N6 O5SCl
4b2 4-Cl Ph 4-N(CH3)2 4-N(CH3)2 200 42 C32H30N7O4SCl
4d2 4-Cl Ph 4-Cl 4-N(CH3)2 138 68 C30H24N6O4 SCl2
4b3 Naphthyl 4-N(CH3)2 4-Cl 160 64 C34H27N6 O4SCl
4c3 Naphthyl 4-NO2 4-Cl 244 63 C32H21N6 O6SCl
4d3 Naphthyl 4-Cl 4-Cl 199 61 C32H21N5O4 SCl2
4e3 Naphthyl 4-OCH3 4-Cl 220 65 C33H24N5O5SCl

Table 2: Physical data of the synthesised compounds (4a1-e1,a2,b2,d2,b3-e3)

The IR spectra of the title compounds exhibited prominent peaks around 3080-3030 cm-1(CH-arom), 16201600 cm-1(C=N), 1550-1510 cm-1(asym. NO2) and 1360-1330 cm-1(sym. NO2). The NMR spectra of the final compounds (4) of the series revealed peaks around 3.16-3.22 δ (s, 1H, CH), 5.75-5.83 δ (s, 1H, CH) and 5.90-8.88 δ due to bulk aromatic protons. No doublet was seen in the NMR spectrum of any compound of the series, thus indicating that the initial structure got rapid transformation through the tautomeric shift of H-atom to the more stable structure, as indicated in the Scheme 1.

The antibacterial activity of the title compounds was determined by agar cup-plate method [10] against Staphylococcus aureus, Actinomycus pyoginus, Escherichia coli, and Klebsiella aeruginosa. The medium was prepared as per the instructions of the manufacturer of dry Mueller Hinton agar powder (Hi-Media). The test samples were dissolved in dimethyl sulphoxide (DMSO) at a concentration of 100 μg/ml. Ampicillin trihydrate (100 μg/ml) in DMSO was used as reference standard, and the solvent control (only DMSO) was also maintained throughout the experiment. The zones of inhibition are reported in Table 3.

Compd. Zone of inhibition (mm*)
S.a. A.p. E.c. K.a.
4a1 17 15 16 18
4b1 16 19 18 17
4c1 18 16 15 19
4d1 21 18 19 20
4e1 16 15 17 18
4a2 19 20 21 17
4b2 22 21 20 21
4d2 21 22 23 22
4b3 21 20 22 23
4c3 20 22 23 24
4d3 22 23 24 22
4e3 20 18 19 17
Ampicilintrihydrate 29 30 32 31
DMSO 00 00 00 00

Table 3: Antibacterial activity data of the synthesised compounds (4a1-e1,a2,b2,d2,b3-e3)

Synthesised compounds were screened for antibacterial activity by agar cup-plate method, the results of which revealed promising activity for most of the test compounds. Among the compounds, 4b2, 4d2, 4b3, 4c3, and 4d3 were found to be most active against all the microbes tested. Even though the test compounds are less active with reference to the standard drug ampicillin trihydrate, the data reported in this article may be a helpful guide for the medicinal chemists who are working in the area.

Acknowledgements

The authors wish to thank the authorities of Utkal University, Bhubaneswar, for providing laboratory facilities.

References