Note. Synthesis of 2-aryl-5-(benzofuran-2-yl)- thiazolo[3,2-b][1,2,4]triazoles, grinding. procedures and their antibacterial activity

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1 Indian Journal of Chemistry Vol. 51B, March 2012, pp ote Synthesis of 2-aryl-5-(benzofuran-2-yl)- thiazolo[3,2-b][1,2,4]triazoles using green procedures and their antibacterial activity Komal Jakhar & J K Makrandi* Department of Chemistry, Maharshi Dayanand University, Rohtak , India jkmakrandi_chem@rediffmail.com Received 8 October 2010; accepted (revised) 8 February Aryl-5-(benzofuran-2-yl)acylthio-1,2,4-triazoles 1a-h have been prepared by condensation of 2-(2-bromoacetyl)benzofurans and various 3-aryl-5-mercapto-1,2,4-triazoles under thermal conditions as well as using microwave irradiations and grinding technique. 3-Aryl-5-(benzofuran-2-yl)acylthio-1,2,4-triazoles on cyclisation using polyphosphoric acid under microwave irradiations give 2-aryl-5-(benzofuran-2-yl)-thiazolo[3,2-b][1,2,4]triazoles 2a-h. Preparation of compounds 1a-h using grinding technique and then cyclisation to 2a-h are in accordance to green procedures as these avoid use of hazardous organic solvents during the reaction as well as at its work-up stage. The antibacterial activity of these compounds has been described. Keywords: 3-Aryl-5-mercapto-1,2,4-triazoles, 2-(2-bromoacetyl)benzofurans, thiazolo[3,2-b][1,2,4]triazoles, grinding technique, antibacterial activity Triazoles derivatives constitute one of the most biologically active class of compounds 1-4 and thiazolo[3,2-b][1,2,4]triazoles have been known to exhibit significant pharmacological activities such as antibacterial 5, antifungal 6, insecticidal 7, COX-2 inhibitors 8, anti-inflammatory 9, analgesic 10 and anticancer 11. On the other hand many natural and synthetic benzofuran derivatives exhibit pharmacological, physiological and toxic properties and find applications as agrochemicals 12, pharmaceuticals 13,14, sedatives 15, cosmetics 16 and as building blocks of optical brighteners 17. Keeping this in view, synthesis of thiazolo[3,2-b][1,2,4]triazoles substituted with benzofuran moiety was taken up. ow-a-days much emphasis is being laid on the development of procedures based on principles of green chemistry 18 in order to protect the environment by avoiding the use of hazardous chemicals. The synthesis of the title compounds has been carried out using grinding technique and microwave irradiation avoiding the use of organic solvents. Results and Discussion 2-(2-Bromoacetyl)benzofuran 19 was condensed with 5-mercapto-3-(4-methoxyphenyl)-1,2,4-triazole 20 in absolute ethanol under reflux. The reaction was found to be completed in 35 min (TLC). The compound obtained (78%) after work-up in its IR exhibited a band at 3446 cm -1 which was attributed to -H stretching, 1667 cm -1 due to C=O stretching, 1614 cm -1 due to C= stretching, 1551 cm -1 due to C=C stretching and at 738 cm -1 corresponding to C-S stretching. In 1 H MR spectra the compound exhibited a singlet at δ 3.88 due to OCH 3 protons, a singlet at δ 4.86 due to CH 2 protons, a doublet at δ 7.02 (J = 8.9 Hz) due to two aromatic protons C 3'' -H and C 5'' -H, a multiplet at δ due to four aromatic protons C 4' -H, C 5' -H, C 6' -H and C 7' -H, a singlet at δ 7.61 for 4 -H proton, a singlet at δ 7.76 due to C 3' -H proton and a doublet at δ 8.05 (J = 8.9 Hz) due to two aromatic protons C 2'' -H and C 6'' -H. Based on its IR, 1 H MR and elemental analysis the compound was identified as 5-(benzofuran-2- yl)acylthio-3-(4-methoxyphenyl)-1,2,4-triazole 1a. The above reaction was repeated under microwave irradiation in dry DMF as well as using grinding technique in the presence of anhydrous barium hydroxide moistened with a few drops of ethanol at RT in an attempt to design a better procedure with higher yields. Both conditions for the reaction were found to be much more efficient in terms of time and yield. Using the above conditions, various 3-aryl-5- (benzofuran-2-yl)acylthio-1,2,4-triazoles were prepared (1a-h, Scheme I). The results of different methods have been compared in Table I. 5-(Benzofuran-2-yl)acylthio-3-(4-methoxyphenyl)-1,2,4-triazole 1a obtained above was then cyclised using polyphosphoric acid under microwave irradiation. The reaction was found to be completed in 1.5 min (9 10 sec). The compound obtained (79%) after work up in its IR exhibited a band at 1612 cm -1 due to C= stretching, 1509 cm -1 due to C=C stretching, 1472, 1176 cm -1 due to C- stretching and at 736 cm -1 due to C-S stretching. In 1 H MR spectra the compound exhibited a singlet at δ 3.88 due to OCH 3 protons, a doublet at δ 7.03 (J = 8.8 Hz) due to two aromatic protons C 3'' -H and C 5'' -H, a multiplet at δ due to four aromatic protons C 4' -H, C 5' -H, C 6' -H and

2 532 IDIA J. CHEM., SEC B, MARCH 2012 R 1 O O CH 2 Br + HS H R 2 R 3 R 1 = H, CH 3 R 2 = H, CH 3 ; R 3 = H, OCH 3, Cl, Br Method A: (Absolute Ethanol/reflux) Method B: (Dry DMF/MWI) Method C: (Ba(OH) 2, grinding, RT) R 1 6' 5' 7' 4' 1' 1 O 2' O 5 3' S 1a-h 2 2'' 3 1'' 4 H 6'' 5'' 3'' R 2 4'' R 3 PPA-MWI R 1 6' 5' 7' 4' 1' O 2' 5 3' 6 S 7 2a-h '' 1'' 2 6'' 5'' 3'' R 2 4'' R 3 Scheme I C 7' -H, a singlet at δ 7.60 due to C 3' -H proton, a singlet at δ 7.96 due to C 6 -H proton and a doublet at δ 8.19 (J = 8.8 Hz) due to two aromatic protons C 2'' -H and C 6'' - H. Based on its IR, 1 H MR and elemental analysis the compound was identified as 5-(benzofuran-2-yl)- 2-(4-methoxyphenyl)-thiazolo[3,2-b][1,2,4]triazole 2a. It is well established 6 that under these conditions of cyclisation, 2-aryl-5-(substituted)-thiazolo[3,2- b][1,2,4]triazoles are formed and not the other isomer i.e. 2-aryl-5-substituted-thiazolo[2,3-c][1,2,4]triazoles. Following the above procedure, differently substituted 2-aryl-5-(benzofuran-2-yl)-thiazolo[3,2- b][1,2,4]triazoles have been prepared (2a-h, Scheme I, Tables I and II). Biological activity The antibacterial activity of the compounds 2a-h were determined against gram-negative bacteria Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae, Salmonella typhii and one gram-positive bacteria Staphylococcus aureus at concentrations of 1000, 100 and 10 ppm using disc diffusion method 21 in nutrient agar medium. The test compounds were dissolved in,dimethylformamide to obtain solutions of 1000, 100 and 10 ppm concentration. The inhibition zones of microbial growth produced by different compounds were measured in millimeters at the end of incubation period of 24 hr at 37 C. DMF alone showed no zone of inhibition. Out of the three concentrations chosen, the best results were obtained at 10 ppm and hence this was the optimum concentration. All the compounds 2a-h was found to show strong activity against all the gram-negative bacteria. In case of gram-positive bacteria i.e. S. aureus only 2b and 2e were found to be inactive while the others showed moderate activity. The results are illustrated in Table III.

3 OTES 533 Table I Comparison of reaction time and yield of compounds 1a-h and 2a-h Compd R 1 R 2 R 3 m.p. (ºC) Method A Method B Method C (%)Yield/ (%)Yield/ (%)Yield/ Time a,b (min) Time (min) Time (min) 1a H H OCH /35 87/1.0 88/ b H CH 3 H /40 82/1.0 85/ c H H Cl /40 84/1.5 86/ d H H Br /40 83/1.5 85/ e CH 3 H OCH /35 86/1.0 87/ f CH 3 CH 3 H /40 81/1.5 83/ g CH 3 H Cl /35 82/1.0 84/ h CH 3 H Br /40 84/1.5 86/ a H H OCH /1.5-2b H CH 3 H /1.5-2c H H Cl /2.0-2d H H Br /2.0-2e CH 3 H OCH /1.5-2f CH 3 CH 3 H /2.0-2g CH 3 H Cl /2.0-2h CH 3 H Br /2.0 - a grinding time; b time for which reaction mixture was left at RT. Table II Elemental analysis of compounds 1a-h and 2a-h Compd Mol. formula 1a C 19 H 15 3 O 3 S ( b C 19 H 15 3 O 2 S ( c C 18 H 12 3 O 2 SCl ( d C 18 H 12 3 O 2 SBr ( e C 20 H 17 3 O 3 S ( f C 20 H 17 3 O 2 S ( g C 19 H 14 3 O 2 SCl ( h C 19 H 14 3 O 2 SBr ( a C 19 H 13 3 O 2 S ( b C 19 H 13 3 OS ( c C 18 H 10 3 OSCl ( d C 18 H 10 3 OSBr ( e C 20 H 15 3 O 2 S ( f C 20 H 15 3 OS ( g C 19 H 12 3 OSCl ( h C 19 H 12 3 OSBr (55.62 Elemental Analysis Found % (Calcd) C H ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) Experimental Section Melting points were determined in open capillary tubes and are uncorrected. IR spectra (KBr) were recorded in Perkin-Elmer Spectrum BX series FT-IR spectrophotometer, 1 H MR were obtained on Bruker Avance II 400 MHz spectrometer using TMS as an internal standard and elemental analysis on Perkin- Elmer 2400 CH elemental analyser. The reactions were carried out in a Samsung microwave oven (operating between W, Model o.ce745g) at 400 W power. All the solvents were distilled and dried according to the literature procedures. Synthesis of 5-(benzofuran-2-yl)acylthio-3-(4- methoxyphenyl)-1,2,4-triazole, 1a Method: A (Thermal Method) A mixture of 2-(2-bromoacetyl)benzofuran (0.72 g, 3.0 mmole) and 5-mercapto-3-(4-methoxyphenyl)- 1,2,4-triazole (0.62 g, 3.0 mmole) in absolute ethanol (30 ml) was refluxed in a 100 ml round bottom flask on a water bath. The progress of reaction was checked by TLC and the reaction was found to be complete in 35 min. The reaction mixture was diluted with ice cold water and the solid thus separated out was filtered under vacuum, washed with water and purified by recrystallization from DMF-ethanol (3:2) to give 5-(benzofuran-2-yl)acylthio-3-(4-methoxyphenyl)-1,2,4-triazole 1a. Method: B (MWI Method) A mixture of 2-(2-bromoacetyl)benzofuran (0.48 g, 2.0 mmole) and 5-mercapto-3-(4-methoxyphenyl)-

4 534 IDIA J. CHEM., SEC B, MARCH 2012 Table III Antibacterial activity data of compounds 2a-h at different concentrations (diameter of zone of inhibition in mm) Compd E. coli P. aeruginosa K. pneumoniae S. typhii S. aureus Conc (ppm) a b c d e f g h ,2,4-triazole (0.41 g, 2.0 mmole) in dry DMF (5 ml) was taken in a loosely stoppered 20 ml round bottom flask and was irradiated in a microwave oven at 400 W for 1.0 min (6 10 sec). The completion of reaction was checked by TLC. The reaction mixture was diluted with ice cold water, the solid thus separated out was filtered under vacuum, washed with water and purified by recrystallization from DMFethanol (3:2) to give 5-(benzofuran-2-yl)acylthio-3- (4-methoxyphenyl)-1,2,4-triazole 1a. Method: C (Grinding Method) A mixture of 2-(2-bromoacetyl)benzofuran (0.48 g, 2.0 mmole), 5-mercapto-3-(4-methoxyphenyl)-1,2,4- triazole (0.41 g, 2.0 mmole) and anhydrous barium hydroxide (2.0 g) moistened with 7 drops of ethanol was ground in a mortar by a pestle at RT for 10 min. The reaction mixture was left at RT for 10 min until the completion of the reaction which was checked by TLC. Crushed ice was added to the reaction mixture and acidified with conc. HCl. The solid thus separated out was filtered under vacuum, washed with water and purified by recrystallization from DMF-ethanol (3:2) to give 5-(benzofuran-2-yl)acylthio-3-(4-methoxyphenyl)-1,2,4-triazole 1a. 1a: IR (KBr): 3446 (-H), 1667 (C=O), 1614 (C=), 1551 (C=C), 738 cm -1 (C-S); 1 H MR (DMSO-d 6 ): δ 3.88 (s, 3H, OCH 3 ), 4.86 (s, 2H, CH 2 ), 7.02 (d, 2H, J = 8.9 Hz, C 3'' -H and C 5'' -H), (m, 4H, C 4' -H, C 5' -H, C 6' -H and C 7' -H), 7.61 (s, 1H, 4 -H), 7.76 (s, 1H, C 3' -H), 8.05 (d, 2H, J = 8.9 Hz, C 2'' -H and C 6'' -H). 1b: IR (KBr): 3330 (-H), 1674 (C=O), 1614 (C=), 1552 (C=C), 753 cm -1 (C-S); 1 H MR (DMSO-d 6 ): δ 2.37 (s, 3H, CH 3 ), 4.75 (s, 2H, CH 2 ), (m, 4H, C 4' -H, C 5' -H, C 6' -H and C 7' -H), 7.62 (s, 1H, 4 -H), 7.65 (s, 1H, C 3' -H), (m, 3H, C 4'' -H, C 5'' -H and C 6'' -H), 7.81 (s, 1H, C 2'' -H). 1c: IR (KBr): 3489 (-H), 1673 (C=O), 1610 (C=), 1557 (C=C), 737 cm -1 (C-S); 1 H MR (DMSO-d 6 ): δ 4.77 (s, 2H, CH 2 ), 7.40 (d, 2H, J = 8.6 Hz, C 3'' -H and C 5'' -H), (m, 6H, C 3' -H, C 4' -H, C 5' -H, C 6' -H, C 7' -H and 4 -H), 7.97 (d, 2H, J = 8.6 Hz, C 2'' -H and C 6'' -H). 1d: IR (KBr): 3324 (-H), 1672 (C=O), 1612 (C=), 1549 (C=C), 752 cm -1 (C-S); 1 H MR (DMSO-d 6 ): δ 4.80 (s, 2H, CH 2 ), (m, 4H, C 4' -H, C 5' -H, C 6' -H and C 7' -H), 7.43 (d, 2H, J = 8.4 Hz, C 3'' -H and C 5'' -H), 7.50 (s, 1H, 4 -H), 7.70 (s, 1H, C 3' -H), 8.00 (d, 2H, J = 8.4 Hz, C 2'' -H and C 6'' -H). 1e: IR (KBr): 3442 (-H), 1665 (C=O), 1611 (C=), 1548 (C=C), 737 cm -1 (C-S); 1 H MR (DMSO-d 6 ): δ 2.47 (s, 3H, CH 3 ), 3.88 (s, 3H, OCH 3 ), 4.84 (s, 2H, CH 2 ), 7.03 (d, 2H, J = 8.9 Hz, C 3'' -H and C 5'' -H), (m, 2H, C 6' -H and C 7' -H), 7.54 (s, 1H, C 4' -H), 7.64 (s, 1H, 4 -H), 7.75 (s, 1H, C 3' -H), 8.04 (d, 2H, J = 8.9 Hz, C 2'' -H and C 6'' -H). 1f: IR (KBr): 3450 (-H), 1658 (C=O), 1621 (C=), 1553 (C=C), 792 cm -1 (C-S); 1 H MR (DMSO-d 6 ): δ 2.39 (s, 3H, CH 3 ), 2.47 (s, 3H, CH 3 ), 4.87 (s, 2H, CH 2 ); (m, 4H, C 4'' -H, C 5'' -H, C 6' -H and C 7' -H), 7.55 (s, 1H, C 4' -H), 7.68 (s, 1H, 4 - H), 7.76 (s, 1H, C 3' -H), 7.85 (d, 1H, J = 7.5 Hz, C 6'' - H), 7.89 (s, 1H, C 2'' -H). 1g: IR (KBr): 3465 (-H), 1673 (C=O), 1609 (C=), 1553 (C=C), 799 cm -1 (C-S); 1 H MR (DMSO-d 6 ): δ 2.47 (s, 3H, CH 3 ), 4.81 (s, 2H, CH 2 ), 7.42 (d, 2H, J = 8.6 Hz, C 3'' -H and C 5'' -H), (m, 2H, C 6' -H and C 7' -H), 7.52 (s, 1H, 4 -H), 7.53 (s, 1H, C 4' -H), 7.71 (s, 1H, C 3' -H), 8.02 (d, 2H, J = 8.6 Hz, C 2'' -H and C 6'' -H).

5 OTES 535 1h: IR (KBr): 3419 (-H), 1653 (C=O), 1605 (C=), 1577 (C=C), 726 cm -1 (C-S); 1 H MR (DMSO-d 6 ): δ 2.59 (s, 3H, CH 3 ), 4.80 (s, 2H, CH 2 ), 7.00 (d, 2H, J = 8.8 Hz, C 3'' -H and C 5'' -H), (m, 3H, 4 -H, C 6' -H and C 7' -H), 7.76 (s, 1H, C 4' -H), 7.80 (s, 1H, C 3' -H), 8.10 (d, 2H, J = 8.8 Hz, C 2'' -H and C 6'' -H). Synthesis of 5-(benzofuran-2-yl)-2-(4-methoxyphenyl)-thiazolo[3,2-b][1,2,4]triazoles, 2a 5-(Benzofuran-2-yl)acylthio-3-(4-methoxyphenyl)- 1,2,4-triazole 1a (1.09 g, 3.0 mmole) was added to polyphosphoric acid (10 ml) in a 20 ml loosely stoppered round bottom flask and mixed properly to form uniform mixture. The mixture was irradiated in microwave at 400 W for 1.5 min (9 10 sec). The completion of reaction was checked by TLC. Crushed ice was added to the reaction mixture and neutralized by aqueous sodium carbonate (10%). The solid thus separated out was filtered under vacuum, washed with water and purified by recrystallization from DMFethanol (3:2) to give 5-(benzofuran-2-yl)-2-(4- methoxyphenyl)-thiazolo[3,2-b][1,2,4]triazoles 2a. 2a: IR (KBr): 1612 (C=), 1509 (C=C), 1472, 1176 (C-), 736 cm -1 (C-S); 1 H MR (DMSO-d 6 ): δ 3.88 (s, 3H, OCH 3 ), 7.03 (d, 2H, J = 8.8 Hz, C 3'' -H and C 5'' -H), (m, 4H, C 4' -H, C 5' -H, C 6' -H and C 7' -H), 7.60 (s, 1H, C 3' -H), 7.96 (s, 1H, C 6 -H), 8.19 (d, 2H, J = 8.8 Hz, C 2'' -H and C 6'' -H). 2b: IR (KBr): 1610 (C=), 1550 (C=C), 1460, 1167 (C-), 742 cm -1 (C-S); 1 H MR (DMSO-d 6 ): δ 2.47 (s, 3H, CH 3 ), (m, 6H, C 4' -H, C 5' -H, C 6' - H, C 7' -H, C 4'' -H and C 5'' -H), 7.73 (s, 1H, C 3' -H), 8.01 (s, 1H, C 6 -H), 8.08 (d, 1H, J = 8.8 Hz, C 6'' -H), 8.10 (s, 1H, C 2'' -H). 2c: IR (KBr): 1603 (C=), 1508 (C=C), 1471, 1171 (C-), 724 cm -1 (C-S); 1 H MR (DMSO-d 6 ): δ (m, 4H, C 4' -H, C 5' -H, C 6' -H and C 7' -H), 7.41 (d, 2H, J = 8.6 Hz, C 3'' -H and C 5'' -H), 7.43 (s, 1H, C 3' -H), 7.81 (s, 1H, C 6 -H), 8.16 (d, 2H, J = 8.6 Hz, C 2'' -H and C 6'' -H). 2d: IR (KBr): 1603 (C=), 1554 (C=C), 1448, 1168 (C-), 753 cm -1 (C-S); 1 H MR (DMSO-d 6 ): δ (m, 4H, C 4' -H, C 5' -H, C 6' -H and C 7' -H), 7.40 (d, 2H, J = 8.6 Hz, C 3'' -H and C 5'' -H), 7.66 (s, 1H, C 3' - H), 7.90 (s, 1H, C 6 -H), 8.14 (d, 2H, J = 8.6 Hz, C 2'' -H and C 6'' -H). 2e: IR (KBr): 1613 (C=), 1512 (C=C), 1473, 1169 (C-), 737 cm -1 (C-S); 1 H MR (DMSO-d 6 ): δ 2.41 (s, 3H, CH 3 ), 3.82 (s, 3H, OCH 3 ), 6.96 (d, 2H, J = 8.8 Hz, C 3'' -H and C 5'' -H), (m, 3H, C 4' -H, C 6' -H and C 7' -H), 7.43 (s, 1H, C 3' -H), 7.84 (s, 1H, C 6 - H), 8.15 (d, 2H, J = 8.8 Hz, C 2'' -H and C 6'' -H). 2f: IR (KBr): 1616 (C=), 1508 (C=C), 1453, 1125 (C-), 728 cm -1 (C-S); 1 H MR (DMSO-d 6 ): δ 2.49 (s, 3H, CH 3 ), 2.50 (s, 3H, CH 3 ), (m, 4H, C 6' -H, C 7' -H, C 4'' -H and C 5'' -H), 7.48 (s, 1H, C 4' -H), 7.54 (s, 1H, C 3' -H), 7.96 (s, 1H, C 6 -H), 8.10 (d, 1H, J = 8.9 Hz, C 6'' -H); 8.13 (s, 1H, C 2'' -H). 2g: IR (KBr): 1606 (C=), 1508 (C=C), 1472, 1141 (C-), 732 cm -1 (C-S); 1 H MR (DMSO-d 6 ): δ 2.10 (s, 3H, CH 3 ), (m, 2H, C 6' -H and C 7' -H), 7.35 (s, 1H, C 4' -H), 7.40 (d, 2H, J = 8.6 Hz, C 3'' -H and C 5'' -H), 7.68 (s, 1H, C 3' -H), 7.91 (s, 1H, C 6 -H), 8.16 (d, 2H, J = 8.6 Hz, C 2'' -H and C 6'' -H). 2h: IR (KBr): 1613 (C=), 1514 (C=C), 1467, 1174 (C-), 731 cm -1 (C-S); 1 H MR (DMSO-d 6 ): δ 2.40 (s, 3H, CH 3 ), 6.94 (d, 2H, J = 8.5 Hz, C 3'' -H and C 5'' -H), (m, 3H, C 4' -H, C 6' -H and C 7' -H), 7.40 (s, 1H, C 3' -H), 7.83 (s, 1H, C 6 -H), 8.08 (d, 2H, J = 8.5 Hz, C 2'' -H and C 6'' -H). Acknowledgement The authors are thankful to RSIC-SAIF, Punjab University, Chandigarh for recording IR and MR, and providing microanalysis of the compounds and to the authorities of M. D. University, Rohtak for providing research facilities. The author (KJ) also thanks CSIR, ew Delhi for providing research fellowship (SRF). References 1 Parmar S S, Gupta A K, Singh H H & Gupta T K, J Med Chem, 15, 1972, Ragenovic K C, Dimova V, Kakurinov V & Gobar D M, J Heterocycl Chem, 40, 2003, Demirbas, Karaoglu S A, Demirbas A & Sancak K, Eur J Med Chem, 39, 2004, Chu C H, Hui X P, Zhang Y, Zhang Z Y, Li Z C & Liao R A, J Chin Chem Soc, 48, 2001, Karthikeyan M S, Eur J Med Chem, 44, 2009, Kumar P, Mohan J & Makrandi J K, Indian J Chem, 46B, 2007, Sanemitsu Y, akayama Y, Yano T & Tanabe Y, Agric Biol Chem, 53, 1989, Manivannan E, Prasanna S & Chaturvedi S C, Indian J Biochem Biophys, 41, 2004, Tozkoparan B, Gokhan, Aktay G, Yesilada E & Ertan M, Eur J Med Chem, 35, 2000, Dogdas E, Tozkoparan B, Kaynak F B, Erikssan L, Kupali E, Yesilada E & Ertan M, Arzneim-Forsch, 57, 2007, Lesyk R, Vladzimirska O, Holota S, Zaprutko L & Gzella A, Eur J Med Chem, 42, 2007, Keay B A & Dibble P W, in Comprehensive Heterocyclic Chemistry II A Review of the literature (Pergamon, ew York), 2, 1996, Kumar D B A, Prakash G K, andeshwarappa B P, Kiran B M, Sherigara B S & Mahadevan K M, Indian J Pharm Sci, 68, 2006, 809.

6 536 IDIA J. CHEM., SEC B, MARCH Basawaraj R, aubade K & Sangapura S S, Indian J Heterocycl Chem, 17, 2008, asef M, El-aem S J A & El-Shbrawy O A, Egypt J Pharm Sci, 33, 1992, Leung A Y & Foster S, Encyclopedia of Common atural Ingredients used in Food, Drugs and Cosmetics (Wiley, ew York), Schmidt E, Ullmann, s Encyclopedia 6 th Edn, Optical Brighteners (Electronic Release), Clark J H, Green Chem, 1, 1999, Elliot E D, J Am Chem Soc, 73, 1951, Dhaka K S, Mohan J, Chadha V K & Pujari H K, Indian J Chem, 12, 1974, air R, Kalariya T & Chanda S, Turk J Biol, 29, 2005, 41.