*Corresponding Author:
P. D. Mehta
Department of Pharmaceutical Chemistry, Maliba Pharmacy College, Tarsadi, Mahuva Road, Surat-394 350
E-mail: [email protected]
Date of Submission 1 October 2004
Date of Revision 15 April 2005
Date of Acceptance 20 February 2006
Indian J Pharm Sci, 2006, 68 (1):103-106  

Abstract

A series of 4-thiazolidinones and 2-azetidinones have been synthesized by condensation of 4,4'-diaminodiphenylsulphone with various aromatic or heterocyclic aldehydes to yield the Schiff's bases. Cyclocondensation of Schiff's bases with 2-mercaptopropionic acid afforded 4-thiazolidinone derivatives, and cyclocondensation of Schiff's bases with chloroacetylchloride in presence of triethylamine afforded 2-azetidinone derivatives. The structures of the newly synthesized compounds were confirmed by analytical and spectral (IR, NMR, and Mass) data. All these compounds were evaluated for their in vitro growth-inhibitory activity against several microbes. Compound 4b and 4c exhibited equipotent antibacterial activity with the reference standard ampicillin against Bacillus subtilis.

Dapsone (4,4’-diaminodiphenylsulphone), a sulphone analog, has been proved to be a powerful antimicrobial agent. 4-thiazolidinones are associated with antibacterial [1-7], antifungal [1-7], and antitubercular [8-11] activities and have diverse biological activities. β-lactam compounds are of interest due to the therapeutic significance of penicillin and cephalosporin antibiotics and possess significant antibacterial [3-7,12-19], antifungal [3-7,12-19] and antitubercular activities [12-14]. 4-thiazolidinone and 2-azetidinone derivatives occupy an important place in medicinal chemistry as they show a variety of microbiological activity. Therefore, an attempt was made to study the antibacterial, antifungal and antitubercular activities of 4- thiazolidinone and 2-azetidinone in present investigation.

4,4’-diaminodiphenylsulphone (1) was condensed with various aromatic or heterocyclic aldehydes in ethanol in the presence of concentrated sulphuric acid as a catalyst to yield the Schiff’s bases (2a-f). These Schiff”s bases on treatment with 2-mercaptopropionic acid yielded substituted 4-thiazolidinones (3a-f), and on treatment with chloroacetylchloride in the presence of triethylamine gave substituted 2-azetidinones (4a-f). The structural assignment of the products was based on their elemental, IR, NMR and Mass spectral data. The title compounds were screened for their antibacterial and antifungal activity.

All melting points were taken by open capillary tubes and were uncorrected. IR spectra recorded on a Perkin Elemer IR spectrophotometer, using KBr pellets, NMR on Bruker DRX 300 (300MHZ) NMR spectrophotometer in DMSO using TMS as internal standard and Mass spectra on Jeol SX 102 (FAB) Mass spectrophotometer.

To a mixture of 4,4’-diaminodiphenylsulphone (2.48 g, 0.01 mol) and p-methyl benzaldehyde (2.40 g, 0.02 mol) dissolved in ethanol, one drop of concentrated sulphuric acid was added. The reaction mixture was refluxed for 6 h. The reaction mixture was then poured into crushed ice. Separated solid was filtered, dried and re-crystallized from ethanol to give 4,4’-Bis (4-methylbenzylidene amino) diphenyl sulphone. The reaction was monitored by TLC.

To a mixture of compound 2b (4.52 g, 0.01 mol) in dry dioxane (10 ml), a solution of 2-mercaptopropionic acid (2.17 ml, 0.025 mol) in dry dioxane (10 ml) was added and the reaction mixture was refluxed for 24 h. The reaction mixture was then poured into crushed ice. The separated solid was neutralized by sodium bicarbonate to remove excess of 2-mercaptopropionic acid. Solid compound obtained was crystallized from ethanol to give 4,4’-Bis (2- (4-methyl phenyl)-5-methyl-1, 3-thiazolidin-4-one-3-yl) diphenyl sulphone. IR (KBr)cm-1 : 1693 (C=O), 1279 (SO2, Asymmetrical str.), 1141 (SO2, Symmetrical str.), 719 (C-SC), 1HNMR (CDCl3) δ: 3.58 (s, 2H, 2×S-CH-Ar), 3.30-3.50 (s, 6H, 2×Ar-CH3), 1.40-1.70 (d, 6H, 2×CH-CH3), 2.10-2.6 (qua, 2H, 2×CH-CH3), 5.90-8.60 (m,16H, 4×4 Ar-H); MS (m/z) 628 (M+), 598, 564, 538, 503, 439, 271. Anal Calcd for C34H32N2O4S3: C, 64.96; H, 5.09; N, 4.45. Found: C, 64.80; H, 5.03; N, 4.39.

To a mixture of compound 2b (4.52 g, 0.01 mol) in dry dioxane (10 ml), triethylamine (3.49 ml, 0.025 mol), was added chloroacetyl chloride (1.99 ml, 0.025 mol) drop-wise at 5-10°. The reaction mixture was stirred for 6 h. The reaction mixture was then poured into crushed ice. The solid separated was dried and re-crystallized from ethanol to give 4,4’-Bis (3-chloro-4-(4-methyl phenyl)-2-oxoazetidin- 1-yl) diphenyl sulphone. IR (KBr)cm-1 : 1683 (C=O), 1340 (SO2, Asymmetrical str.), 1150 (SO2, Symmetrical str.), 745 (C-S-C), 1H NMR (CDCl3) δ: 2.48- 2.60 (s, 2H, 2×CH-Cl), 4.22-4.40 (s, 2H, 2×CH-Ar), 2.80-2.93 (s, 6H, 2×Ar-CH3), 7.40-8.50 (m, 16H, 4×4 Ar-H); MS (m/ z) 604 (M+), 589, 575, 543, 534, 480, 423, 273. Anal Calcd for C34H32N2O4S3: C, 63.57; H, 4.30; N, 4.63. Found: C, 63.45; H, 4.29; N, 4.27. The synthetic route is represented in Scheme 1, and physical data of the synthesized compound are given in Table 1.

Compound R Molecular Formula (%) Yield M.P.(°)
2a Phenyl C26H20N2O2S 75 201-202
2b P-Methylphenyl C28H24N2O2S 70 205-206
2c P-Nitrophenyl C26H18N4O6S 80 215-216
2d P-Hydroxylphenyl C26H20N2O4S 85 96-97
2e Thiophene C22H16N2O4S 70 195-200
2f Furfural C22H16N2O4S 80 220-221
3a Phenyl C32H28N2O4S3 68 110-112
3b P-Methylphenyl C34H32N2O4S3 70 120-121
3c P-Nitrophenyl C32H26N4O8S3 65 113-114
3d P-Hydroxyphenyl C32H28N2O6S3 72 132-134
3e Thiophene C28H24N2O4S5 65 168-169
3f Furfural C28H24N2O6S3 69 169-171
4a Phenyl C30H22N2O4SCl2 64 172-173
4b P-Methylphenyl C32H26N2O4SCl2 72 160-161
4c P-Nitrophenyl C30H20N4O8SCl2 70 163-165
4d P-Hydroxylphenyl C30H22N2O6SCl2 69 174-175
4e Thophene C26H18N2O4S3Cl2 65 180-182
4f Furfural C26H18N2O6SCl2 69 220-222

Table 1: Physical data of the synthesized compounds

The compounds synthesized were screened for their antibacterial activity [4] using Staphylococcus aureus, concentration. Control experiment was carried out under similar condition by using ampicillin as a standard for comparison. The inhibition zone measure in mm showed that compounds 4b, 4c, 4e and 4f were more active than other compounds tested against the above microbes. Compounds 4b and 4c exhibited equipotent activity with the reference standard ampicillin against B. subtilis (Table 2).

Compound   Zone of inhibition in mm Concentration in µg/ml
  Bacteria     Fungi    Mycobacterium tuberculosis
  S. a B. s E. c.  P. a. A. n.  C. a. 100 µg 10 µg
3a 12 11 11 09 09 08 - +
3b 11 10 14 10 13 14 - +
3c 13 12 13 10 09 08 - +
3d 12 10 13 11 11 11 - +
3e 14 11 15 11 12 13 - -
3f 15 13 16 12 10 09 - +
4a 14 12 13 14 08 10 - +
4b 20 20 18 17 11 12 - -
4c 20 20 17 12 08 09 - +
4d 15 14 16 13 09 10 - +
4e 17 21 15 17 11 10 - -
4f 16 15 14 14 12 11 - +
Ampicillin 22 20 21 20 —- —- ——- ——
Griseofulvin —- —- —- —- 15 16 ——- ——-
Isoniazid —- —- —- —- —- —- - +

Table 2: Antimicrobial activity data of the title compounds

The antifungal activity [13] was tested against the fungal species Aspergilus niger and Candida albicans at 50 mg concentration. The antifungal data revealed that the compounds 3d, 3e, 4b, 4e and 4f were more active than other compounds tested against the above microbes, but none showed better or comparable activity to griseofulvin (Table 2).

The synthesized compounds were screened for antitubercular activity [9,14] at 1 mg, 10 mg and 100 mg concentration against the human strain H37Rv of M. tuberculosis. Isoniazid was used as the standard drug for comparison. The antitubercular data revealed that the compound 3e, 4b and 4e showed activity at 10 mg concentration, other compounds showed activity at 100 mg, while none of the compound showed activity at 1 g concentration (Table 2).

Escherichia coli, Pseudomonas aeruginosa and Bacillus subtilis as test organism. The activities of these compounds were tested using agar cup-plate method at 50 mg

Acknowledgements

We express our gratitude to RSIC, Lucknow and IISC, Bangalore for providing spectral and analytical data.

References