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Novel Peracetylated N-Lactosyl-1,2,4-Thiadiazolidin-3-one Hydrochlorides: Synthesis and Antimicrobial Studies
Novel Peracetylated N-Lactosyl-1,2,4-Thiadiazolidin-3-one Hydrochlorides: Synthesis and Antimicrobial Studies
Journal of the Korean Chemical Society. 2010. Jun, 54(3): 287-290
Copyright © 2010, The Korean Chemical Society
  • Received : December 01, 2009
  • Accepted : April 06, 2010
  • Published : June 20, 2010
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About the Authors
Anvita S. Dandale
Dept. of Applied Chemistry, Faculty of Tech. & Engg., The M. S. University of Baroda, Vadodara-390001, Gujarat, India
Dattatraya V. Mangte
Shirish P. Deshmukh
spd_anvita@rediffmail.com

Abstract
In the present work we described oxidative cyclisation of peracetylated lactosyl carbamides with N -phenyl- S -chloro isothiocarbamoyl chloride and structural elucidation of novel peracetylated N -Lactosyl-1,2,4-Thiadiazolidin-3-one hydrochlorides. Antimicrobial activities of the title compounds were determined against bacteria S. aureus, E. coli, P. Vulgaris, P. Aeruginosa and fungi A. Niger, Penicillium .
Keywords
INTRODUCTION
Ureides are compounds, which essentially incorporate urea as a substructural component either in open or cyclic form. Some of the important pharmacological 1 activities ascribed to ureides are antiinfectives, antitumor, anticancer and for various metabolic disorders including diabetes and hyperlipidemia. In this view we recently reported the synthesis of peracetylated lactosyl N -carbamides, N -benzothiazolyl carbamides 2 by reaction of hepta acetyl lactosyl isocyanate 3 with aryl amines and benzothiazolyl carbamides respectively. Ureides and their heterocyclic derivatives 4 also possess antibacterial, antifungal and antitumor activity. N -lactosylated compounds and their derivatives are reported to show various applications in medicinal chemistry. 5 - 7
In this work, we described the application of peracetylated lactosyl isocyanate in the synthesis of 1,2,4-thiadiazolidin-3-one containing lactosyl substituent by the cyclisation of 1-hepta- O -acetyl-α-lactosyl-3-aryl carbamides ( 2a-g ) with N-phenyl-S-chloro isothiocarbamoyl chloride ( 1 ).
EXPERIMENTAL
Melting points were recorded on electro thermal melting point apparatus and are uncorrected. Specific rotations [α] D were measured on a Equip-Tronics digital polarimeter model no EQ 800 at 31 ℃ in CHCl 3 . IR spectra were recorded on a Perkin – Elmer spectrum RXI (4000 - 450 cm -1 ) FTIR spectrometer. 1 HNMR spectrum were obtained on a Bruker DRX-300 (300 MHz FT NMR) NMR spectrometer in CDCl 3 solution with TMS as an internal reference. The mass spectra were recorded on a Jeol SX-102 mass spectrometer. 1-hepta- O -acetyl- β -lactosyl-3-aryl carbamides 2 ( 2a-g ) were prepared by nuleophilic addition of hepta- O -acetyl lactosyl isocyanate with amines. N -phenyl- S -chloro isothiocarbamoyl chloride 8 was prepared by chlorination of phenyl isothiocyanate in chloroform.
Physical characterization and analytical data of compounds3a-3g
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Physical characterization and analytical data of compounds 3a-3g
Antibacterial and antifungal activities of compounds3a-3g
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++++ Strongly active (Above 20 mm), +++ moderately active (15 mm to 20 mm), ++ weakly active (8 mm - 14 mm), ---- inactive (below 8 mm).
The antimicrobial activity of synthesized compounds were tested in vitro against bacteria S. aureus, E. coli, P. Vulgaris, P. Aeruginosa and fungi A. niger, Penicillium by cup plate agar diffusion method. The compounds were taken at a concentration of 1 mg/mL and compared with Amikacin and Fluconazole as a positive control for different strains of bacteria and fungi for antibacterial and antifungal activity respectively ( 2 ).
- General procedure for synthesis of compound (3a-g).
2-N-hepta-O-acetyl-β-lactosyl-4-N-aryl-5-phenylimino-1,2,4-Thiadiazolidin-3-one hydrochlorides (3a-g) (Fig. 1): N -phenyl- S -chloro isothiocarbamoyl chloride ( 1 ) (5 mmol) in benzene was added to 1-hepta- O -acetyl- β -lactosyl-3-aryl carbamide ( 2a-g ) (5 mmol) in benzene and refluxed for 3 h. Reaction was monitored by TLC. The solvent was distilled off and the sticky residue obtained was triturated with petroleum ether (60 - 80 o ) to afford a white solid ( 3a-g ). The product was crystalized from ethanol-water.
RESULTS AND DISCUSSION
The synthesis of title compounds ( 3a-g ) . 1 was achieved by the oxidative cyclization of 1-hepta- O -acetyl- β -lactosyl-3-aryl carbamide ( 2a-g ) with N -phenyl- S -chloro isothiocarbamoyl chloride ( 1 ). The synthesized compounds were soluble in common organic solvents and insoluble in water. The structures of the title compounds 3a-g were confirmed by elemental analysis and IR, HNMR, Mass spectra.
The IR spectra 9 - 11 of the compounds showed strong characteristic absorption of lactose unit in the range of 900 -910, 1000 - 1100 cm -1 for stretching vibration of C-H bond. The stretching band for acetyl C=O has appeared in the region 1749-1750 cm -1 . The absorption band for C=N and C-N has appeared in the region 1515 - 1597 cm -1 and 750 - 755 cm -1 respectively.
1 HNMR spectrum 10 - 15 of the products shows characteristic of lactosyl protons at δ 5.6-3.7 ppm and resonance signals for aromatic protons at δ 7.01-7.42 ppm. Acetyl protons are appeared at δ 1.96-2.24 ppm.
. 1
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Mass spectra 16 - 17 exhibited molecular ion peak along with characteristic fragments of lactose unit at m/z , 619, 559, 331, 169 and 109.
- Antimicrobial Activity.
The results of the title compounds for preliminary antibacterial testing are shown in 2 . The results revealed that the majority of the synthesized compounds showed varying degree of inhibition against the tested microorganisms. The phenyl and tolyl derivatives have the best overall antibacterial profile than chloro phenyl derivatives. Compounds 3a, 3f and 3g were found to be more active than standard while 3b and 3d were almost inactive against E. coli . All the tested compounds except 3d exhibited moderate to good activity against S. Aurues . Compound 3d showed comparable activity against P. Aeruginosa to standard while others were less to moderartely active. Compounds 3a and 3e were found more active than standard against P. Vulgaris while others were less to moderate acitve. Again in antifungal activity compounds 3a, 3b, 3d and 3f showed no activity than the other derivatives of the same series. Although the rest of the compounds showed varying degree of inhibition, none were as effective as Fluconazole. In general, the inhibitory activity against the bacteria was higher than that of the fungi.
2-N-hepta-O-acetyl-β-lactosyl-4-N-phenyl-5-phenylimino-1,2,4-Thiadiazolidin-3-one hydrochloride (3a): IR (ν/cm -1 ): 1749 (C=O), 1597 (C=N), 1372 (C-N), 1229 (C-O), 905 and 1050 (lactose), 754 (C-S); 1 HNMR (CDCl 3 ) (δ/ppm): 7.45-7.15 (m, 5H, Ar-H), 5.36-3.77 (m, 14H, lactose unit), 2.18-1.97 (m, 21H, 7COCH 3 ); Mass ( m/z ): (M + ) 960, 887, 883, 869, 619, 331, 211, 169, 109.
2-N-hepta-O-acetyl-β-lactosyl-4-N-o-Cl-phenyl-5-phenylimino-1,2,4-Thiadiazolidin-3-one hydrochloride (3b): IR (ν/cm -1 ): 1752 (C=O), 1590 (C=N), 1373 (C-N), 1230 (C-O), 905 and 1051 (lactose), 755 (C-S); 1 HNMR (CDCl 3 ) (δ/ppm): δ 7.30-7.04 (m, 4H, Ar-H), 5.35-3.77 (m, 14H, lactose unit), 2.21 - 1.96 (m, 21H, 7COCH 3 ); Mass ( m/z ): (M + ) 994, 922, 859, 796, 619, 331, 211, 169, 109.
2-N-hepta-O-acetyl-β-lactosyl-4-N-m-Cl-phenyl-5-phenylimino-1,2,4-Thiadiazolidin-3-one hydrochloride (3c): 1 HNMR (CDCl 3 ) (δ/ppm): δ 7.46-7.14 (m, 4H, Ar-H), 5.18-3.74 (m, 14H, lactose unit), 2.10-1.88 (m, 21H, 7COCH 3 ).
2-N-hepta-O-acetyl-β-lactosyl-4-N-p-Cl-phenyl-5-phenylimino-1,2,4-Thiadiazolidin-3-one hydrochloride (3d): 1 HNMR (CDCl 3 ) (δ/ppm): δ 7.39-7.11 (m, 4H, Ar-H), 5.21-3.72 (m, 14H, lactose unit), 2.25-1.92 (m, 21H, 7COCH 3 ).
2-N-hepta-O-acetyl-β-lactosyl-4-N-o-tolyl-5-phenylimino-1,2,4-Thiadiazolidin-3-one hydrochloride (3e): 1 H NMR (CDCl 3 ) (δ/ppm): δ 7.46-7.20 (m, 4H, Ar-H), 5.36-3.75 (m, 14H, lactose unit), 2.24-1.97 (m, 21H, 7COCH 3 ).
2-N-hepta-O-acetyl-β-lactosyl-4-N-m-tolyl-5-phenylimino-1,2,4-Thiadiazolidin-3-one hydrochloride (3f): 1 H NMR (CDCl 3 ) (δ/ppm): δ 7.39-7.08 (m, 4H, Ar-H), 5.64-3.70 (m, 14H, lactose unit), 2.20 - 1.92 (m, 21H, 7COCH 3 ).
2-N-hepta-O-acetyl-β--lactosyl-4-N-p-tolyl-5-phenylimino-1,2,4-Thiadiazolidin-3-one hydrochloride (3g): IR (ν/cm -1 ): 1750 (C=O), 1515 (C=N), 1372 (C-N), 1230 (C-O), 906 and 1051 (lactose), 750 (C-S); 1 HNMR (CDCl 3 ) (δ/ppm): δ 7.42-7.01 (m, 4H, Ar-H), 5.52-3.77 (m, 14H, lactose unit), 2.24-1.96 (m, 21H, 7COCH 3 ); Mass ( m/z ): (M + ) 974, 901, 883, 619, 559, 331, 211, 169, 109.
Acknowledgements
Authors are thankful to RSIC, CDRI, Lucknow for providing spectral data. An author (ASD) also thanks Principal Dr. S. G. Bhadange for providing necessary facilities.
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