Scientific paper
Construction of Some New Bioactive Building Block of Thiazolidines
Pushkal Samadhiya, Ritu Sharma,* Savitri D. Srivastava and Santosh K. Srivastava
Department of Chemistry, Dr. H. S. Gour University (A Central University), Sagar, M. P. India-470003 * Corresponding author: E-mail: ritusharmaic@rediffmail.com Received: 03-01-2012
Abstract
An efficient route for the synthesis of new series of N-[3-(1H-1,2,3-benzotriazol-1-yl)-propyl]-2-(substituted phenyl)-4-oxo-5-(substituted benzylidene)-1,3-thiazolidine-carboxamide has been devised; compounds 5a-j have been synthesized and characterized by IR, 1H NMR, 13C NMR, FAB-MS and chemical elemental analysis. All final compounds were screened for their antimicrobial activity against some selected bacteria and fungi and antituberculosis study against Mycobacterium tuberculosis and antiinflammatory activity on albino rats.
Keywords: Synthesis, benzotriazolo-4-oxo-thiazolidine, antimicrobial, antitubercular, antiinflammatory.
1. Introduction
Heterocyclic compounds have been under investigation for a long time because of their important pharmacological properties. Thiazolidines possess various remarkable biological activities such as antimicrobial,1 antibacterial,2'3 antifungal,4 antipsychotic,5 antiviral,6 antitubercular,7 anticancer8 and anti-HIV.9 1,2,3-Benzotriazole derivatives have been a topic of a substantial research interest and continue to be one of the most active areas of he-terocyclic chemistry, particularly due to their natural occurrence and pharmacological activities. The large numbers of benzotriazoles are at the fore as pharmacologically active leads compounds for drug development. Benzotria-zoles also occur widely in many natural products such as those from plants, fungi and marine organism. The biological and chemical properties of the benzotriazoles have attracted the attention of organic and medicinal chemists, biologists and pharmacists. Chemical and biological research has also presented a great challenge to synthesize and optimize highly efficient and economical synthetic routes to novel biologically active substances. At present there are thousands of compounds described, which include simple and more complexly substituted benzotriazoles. The simple benzotriazoles are comprised of triazole ring fused with benzene and more complex benzotriazole derivatives usually contain some additional fused rings. The
benzotriazole nucleus is pharmaceutical^ important and emerging heterocycle with broad spectrum of activities including antibacterial,10-12 antifungal,1314 antitubercular15 and anticancer.16 We have decided to explore some of these facets in our previous work.17 In the previous study !b-lactam derivatives of 1,2,3-benzotriazole have been synthesized and screened for their biological activity. In the recent study we are reporting synthesis and biological activities of 4-oxothiazolidine 4a-j and their 5-arylidene derivatives of 1,2,3-benzotriazole 5a-j. Compounds 1, 2 and 3a-j have been synthesized using similar method as described in the previous study (Scheme 1).
2. Results and Discussion: Synthesis
The 1,2,3-benzotriazole was used as the starting material for the synthesis of 1, 2 and 3a-j using similar method as described in our previous study.17 The compounds 3a-j on reaction with equimolar amount of thioglycolic acid in the presence of ZnCl2 gave the cycloaddition reaction and produced 4a-j. The compound 4a showed a characteristic absorption of the cyclic carbonyl group at 1672 cm-1 in the IR spectrum. The 1H NMR spectrum of 4a aroused our attention and clearly indicates the presence of the active methylene protons of the thiazolidine ring at S 3.37 ppm. The 13C NMR spectrum of 4a also supported
Comp.	Ar = Ar1	Comp.	Ar = Ar1
4a, 5a		4f, 5f	
4b, 5b		4g, 5g	
4c, 5c	CI -6	4h, 5h	
4d, 5d		4i, 5i	
4e, 5e		4j, 5j	
Scheme 1: Synthesis of compounds 4(a-j) and 5(a-j).
the fact that cyclic carbonyl group is present as a signal appeared at 8 168.7 ppm. All these facts are additionally supported by the disappearance of N=CH proton and appearance of N-CH proton at 8 5.15 ppm in the 1H NMR
spectrum of 4a. The compounds 4a-j underwent the Knoevenagel condensation reaction with substituted ben-zaldehydes in the presence of C2H5ONa to afford 5a-j. In the 1H NMR spectrum of 5a-j two methylene protons of
Table 1: Antibacterial, antifungal and antitubercular activities of compounds 5(a-j).
Comp.	Antibacterial activity	Antifungal activity	Antitubercular activity
	B. subtilis	E. coli	S. aureus	A. niger	A. flavus	C. albicans	M. tuberculosis
5a	12.5	9.25	12.50	20.25	21.25	20.25	12.5
5b	3.75	6.25	3.25	15.75	13.25	15.25	2.50
5c	6.25	3.75	6.25	12.75	12.50	12.75	2.75
5d	3.75	6.25	3.25	12.50	12.25	13.50	2.50
5e	3.25	3.75	3.25	13.25	12.25	13.75	2.75
5f	6.25	3.25	3.25	12.75	13.25	12.75	2.75
5g	4.75	6.25	4.50	16.25	14.50	15.75	6.25
5h	3.25	3.75	3.25	12.50	13.50	12.75	2.50
5i	3.25	3.25	3.75	12.25	12.75	13.5	2.50
5j	3.25	3.75	3.25	12.75	12.50	13.50	2.75
the mic values of standard streptomycin for all bacterial strain and griseofulvin for all fungal strain were in the range of 2.50-3.25 and 6.25-12.50 ng/ml respectively. Isoniazid and rifampicin were used as standards, mic values in the range of 1.25-2.50 ng/ml for m. tuberculosis.
4a-j have disappeared and a new signal for C=CH appeared in the range of 8 6.52-6.77 ppm in the :H NMR spectra and two new signals for C=CH and C=CH appeared in the range of 8 136.7-141.2 and 8 141.9-144.9 ppm, respectively, in the 13C NMR spectra of 5a-j. All these facts clearly confirmed the synthesis of all final products.
3. Results and Discussion: Biological Study
The results of the all described activities (antibacterial, antifungal, antitubercular and antiinflammatory) are summarized in Tables 1 and 2. The results of the antimicrobial screening data revealed that 5a-j showed considerable and varied activity against the selected microorganisms. A new series of N-[3-(1H-1,2,3-benzo-triazol-1-yl)-propyl]-2-(substituted phenyl)-4-oxo-5-(substituted benzylidene)-1,3-thiazolidine-carboxamide
Table 2: Antiinflammatory activity of compounds 5(a-j).
Compound Before carageenan Total increase Percent Code	admini- in paw volume inhibition
stration	after 5 hours
(mean ± SEM) (mean ± SEM)
5a	0.60 ± 0.02	0.16 ± 0.02	50.00
5b	0.64 ± 0.02	0.14 ± 0.02	56.25
5c	0.66 ± 0.02	0.13 ± 0.01	59.38
5d	0.68 ± 0.02	0.13 ± 0.02	59.38
5e	0.66 ± 0.03	0.14 ± 0.02	56.25
5f	0.65 ± 0.02	0.12 ± 0.01	62.50
5g	0.67 ± 0.02	0.13 ± 0.01	59.38
5h	0.64 ± 0.03	0.12 ± 0.01	62.50
5i	0.65 ± 0.02	0.10 ± 0.03	68.75
5j	0.67 ± 0.03	0.11 ± 0.02	65.63
Control	0.66 ± 0.02	0.32 ± 0.01	-
Standard;	0.68 ± 0.03	0.08 ± 0.02	75.00
phenylbutazone
5a-j were synthesized and screened for their antimicrobial, antitubercular and anti-inflammatory activities. Data (as shown in Table 1 and 2) revealed that all the synthesized compounds 5a-j have a structure activity relationship (SAR) because activities of compounds varies with substitution. Nitro group containing compounds (5h, 5i and 5j) showed higher activity than those containing chloro (5c, 5d) and bromo groups (5e, 5f). On the other hand, chloro and bromo derivatives have higher activity than other tested compounds. On the basis of SAR, it might be concluded that the activity of compounds depends on electron withdrawing nature of the substitutents.
The investigation of antimicrobial (antibacterial, an-tifungal and antitubercular) data revealed that the compounds 5c-f,h-j displayed high activity in the series, the compounds 5b and 5g showed moderate activity and the rest of the compounds showed lesser activity against all the strains compared with standard drugs. In the anti-inflammatory activity compounds 5c-f,h-j showed high activity while the rest of the compounds displayed moderate to low activity.
4. Conclusion
The research study reports the successful synthesis of a new series of 5a-j. The compounds 5a-j containing thiazolidine moiety possess moderate to good antibacterial, antifungal, antitubercular and anti-inflammatory activities.
5. Experimental: Synthesis
Melting points were determined in open capillaries and are uncorrected. Progress of reactions was monitored by silica gel-G coated TLC plates in MeOH:CHCl3 sys-
tem (1:9). Spots were visualized by exposing dry plates in iodine vapours. IR spectra were recorded as KBr discs on a Shimadzu 8201 PC, FTIR spectrophotometer (vmax in cm1) and 1H and 13C NMR spectra were measured on a Bruker DRX-300 spectrometer in CDCl3 at 300 and 75 MHz, respectively, using TMS as the internal standard. All chemical shifts are reported on scale. The FAB-MS spectra were recorded on a Jeol SX-102 mass spectrometer. Elemental analyses were performed on a Carlo Er-ba-1108 analyzer. The analytical data of all the compounds were highly satisfactory. For column chromato-graphic purification of the products Merck silica Gel 60 (230-400 mesh) was used. Antiinflammatory (in vivo) study has been approved by institutional ethical committee, Dr. H. S. Gour University, Sagar, India. The reagent grade chemicals were purchased from the commercial sources and further purified before use.
Synthesis of N-[3-(1_ff-1,2,3-Benzotriazol-1-yl)-propyl] -2-(phenyl)-4-oxo-1,3-thiazolidine-carboxamide (4a)
Mixture of 3a (0.016 mol) and thioglycolic acid (0.016 mol) in methanol (50 mL) in the presence of ZnCl2 was first stirred on a magnetic stirrer for about 2.30 h at room temperature followed by reflux on a steam bath for about 6.00 h. The completion of the reaction was monitored by silica gel-G coated TLC plates. The product was filtered, cooled and purified with column chromatography (silica gel packed column) using MeOH:CHCl3 (3:7 v/v) system as eluant (70 mL). The purified product was dried under vacuo and recrystallized from ethanol at room temperature to furnish compound 4a (Figure 1).
f.	3
Figure 1: Structure of compounds 4a-j.
45.1 (C-10), 47.3 (C-8), 61.7 (C-2''), 110.3 (C-4), 118.9 (C-7), 125.7 (C-5), 126.4 (C-12 and C-16), 128.4 (C-6), 129.8 (C-14), 130.1 (C-13 and C-15), 132.6 (C-3a), 136.4 (C-11), 145.9 (C-7a), 161.1 (C-2'), 168.7 (C-4''); FAB-MS (m/z): 381 [M+]; Anal. Calcd. for C19H19N5O2S: C, 59.82; H, 5.02; N, 18.35%. Found: C, 59.774; H, 4.97; N, 18.29%.
N-[3-(1#-1,2,3-BenzotriazoM-yl)-propyl]-2-(4-chlo-rophenyl)-4-oxo-1,3-thiazolidine-carboxamide (4b):
Yield: 64%; m.p. 95-96 °C; IR (cm-1): 672 (C-S-C), 761 (C-Cl), 1340 (C-N), 1485 (C=C), 1596 (N=N), 1670 (CO), 1745 (CO cyclic), 1442, 2836, 2933 (CH2), 2941 (S-CH2), 3024 (CH-Ar), 3378 (NH) (Figure 2); 1H NMR (300 MHz, CDCl3, TMS) 8: 2.15-2.21 (m, 2H, H-9), 3.40-3.45 (m, 2H, H-10), 3.46 (s, 2H, H-5''), 4.22 (t, 2H, J = 7.40 Hz, H-8), 5.46 (s, 1H, H-2''), 5.61 (s, 1H, H-1'), 7.29-7.82 (m, 8H, Ar-H); 13C NMR (75 MHz, CDCl3, TMS) 8: 35.2 (C-5''), 34.4 (C-9), 40.2 (C-10), 45.3 (C-8), 62.3 (C-2''), 116.2 (C-4), 120.9 (C-7), 123.7 (C-5), 127.7 (C-12 and C-16), 128.6 (C-6), 129.4 (C-13 and C-15), 132.8 (C-3a), 135.5 (C-14), 136.7 (C-11), 146.9 (C-7a),
164.1	(C-2'), 174.5 (C-4''); FAB-MS (m/z): 415 [M+]; Anal. Calcd. for C19H18ClN5O2S: C, 54.87; H, 4.36; N, 16.83%. Found: C, 54.82; H, 4.31; N, 16.78%.
N-[3-(1#-1,2,3-BenzotriazoM-yl)-propyl]-2-(3-chlo-rophenyl)-4-oxo-1,3-thiazolidine-carboxamide (4c):
Yield: 65%; m.p. 93-95 °C; IR (cm-1): 662 (C-S-C), 745 (C-Cl), 1343 (C-N), 1486 (C=C), 1580 (N=N), 1681 (CO), 1747 (CO cyclic), 1445, 2853, 2911 (CH2), 2944 (S-CH2), 3043 (CH-Ar), 3382 (NH); 1H NMR (300 MHz, CDCl3, TMS) 8: 2.29-2.33 (m, 2H, H-9), 3.35-3.39 (m, 2H, H-10), 3.45 (s, 2H, H-5''), 4.33 (t, 2H, J = 7.45 Hz, H-8), 5.41 (s, 1H, H-2''), 5.74 (s, 1H, H-1'), 7.31-7.85 (m, 8H, Ar-H); 13C NMR (75 MHz, CDCl3, TMS) 8: 34.9 (C-5''), 35.2 (C-9), 40.5 (C-10), 45.6 (C-8), 64.3 (C-2''),
114.2	(C-4), 118.4 (C-7), 124.3 (C-5), 126.7 (C-12),
128.3	(C-16), 129.1 (C-6), 129.9 (C-14), 131.4 (C-15),
134.4	(C-3a), 135.3 (C-13), 138.1 (C-11), 147.9 (C-7a), 164.3 (C-2'), 171.2 (C-4''); FAB-MS (m/z): 415 [M+]; Anal. Calcd. for C19H18ClN5O2S: C, 54.87; H, 4.36; N, 16.83%. Found: C, 54.80; H, 4.30; N, 16.75%.
Compounds 4b-j have been synthesized by using similar method as above.
N-[3-(1#-1,2,3-BenzotriazoM-yl)-propyl]-2-(phenyl)-4-oxo-1,3-thiazolidine-carboxamide (4a):
Yield: 62%; m.p. 81-82 °C; IR (cm-1): 668 (C-S-C), 1332 (C-N), 1478 (C=C), 1571 (N=N), 1672 (CO), 1740 (CO cyclic), 1438, 2843, 2903 (CH2), 2940 (S-CH2), 3032 (CH-Ar), 3373 (NH); 1H NMR (300 MHz, CDCl3, TMS) 8: 2.18-2.22 (m, 2H, H-9), 3.37 (s, 2H, H-5''), 3.40-3.44 (m, 2H, H-10), 4.10 (t, 2H, J = 7.35 Hz, H-8), 5.15 (s, 1H, H-2''), 5.80 (s, 1H, H-1'), 6.72-8.09 (m, 9H, Ar-H), 13C NMR (75 MHz, CDCl3, TMS) 8: 33.5 (C-5''), 36.6 (C-9),
N-[3-(1#-1,2,3-BenzotriazoM-yl)-propyl]-2-(2-chlo-rophenyl)-4-oxo-1,3-thiazolidine-carboxamide (4d):
Yield: 62 %; m.p. 90-91 °C; IR (cm-1): 656 (C-S-C), 738 (C-Cl), 1347 (C-N), 1490 (C=C), 1582 (N=N), 1683 (CO), 1746 (CO cyclic), 1447, 2851, 2909 (CH2), 2947 (S-CH2), 3041 (CH-Ar), 3380 (NH); 1H NMR (300 MHz, CDCl3, TMS) 8: 2.20-2.26 (m, 2H, H-9), 3.44-3.49 (m, 2H, H-10), 3.41 (s, 2H, H-5''), 4.25 (t, 2H, J = 7.40 Hz, H-8), 5.42 (s, 1H, H-2''), 5.65 (s, 1H, H-1'), 7.36-7.86 (m, 8H, Ar-H); 13C NMR (75 MHz, CDCl3, TMS) 8: 35.1 (C-5''), 36.8 (C-9), 39.7 (C-10), 47.4 (C-8), 64.2 (C-2''), 114.5 (C-4), 119.9 (C-7), 124.7
(C-5), 127.6 (C-15), 128.9 (C-6), 129.4 (C-13), 130.4 (C-14), 132.2 (C-16), 133.3 (C-3a), 135.1 (C-12), 137.9 (C-11), 147.4 (C-7a), 163.6 (C-2'), 173.7 (C-4'') FAB-MS (m/z): 415 [M+]; Anal. Calcd. for C19H18ClN5O2S: C, 54.87; H, 4.36; N, 16.83%. Found: C, 54.83; H, 4.33; N, 16.73%.
N-[3-(1#-1,2,3-Benzotriazol-1-yl)-propyl]-2-(4-bro-mophenyl)-4-oxo-1,3-thiazolidine-carboxamide (4e):
Yield: 66 %; m.p. 92-93 °C; IR (cm-1): 655 (C-S-C), 741 (C-Cl), 1338 (C-N), 1488 (C=C), 1577 (N=N), 1687 (CO), 1750 (CO cyclic), 1449, 2854, 2912 (CH2), 2946 (S-CH2), 3045 (CH-Ar), 3379 (NH); 1H NMR (300 MHz, CDCl3, TMS) 8: 2.21-2.25 (m, 2H, H-9), 3.47-3.53 (m, 2H, H-10), 3.40 (s, 2H, H-5''), 4.32 (t, 2H, J = 7.45 Hz, H-8), 5.47 (s, 1H, H-2''), 5.67 (s, 1H, H-1'), 7.38-7.83 (m, 8H, Ar-H); 13C NMR (75 MHz, CDCl3, TMS) 8: 35 (C-5''), 34.8 (C-9), 41.4 (C-10), 48.2 (C-8), 64.3 (C-2''), 112.4 (C-4), 119.4 (C-7), 123.9 (C-14), 124.5 (C-5), 128.6 (C-6), 130.8 (C-12 and C-16), 131.4 (C-13 and C-15), 132.6 (C-3a), 136.5 (C-11), 147.9 (C-7a), 164.2 (C-2'), 172.3 (C-4''); FAB-MS (m/z): 460 [M+]; Anal. Calcd. for C19H18BrN5O2S: C, 49.57; H, 3.94; N, 15.21%. Found: C, 49.51; H, 3.88; N, 15.19%.
N-[3-(1#-1,2,3-Benzotriazol-1-yl)-propyl]-2-(3-bro-mophenyl)-4-oxo-1,3-thiazolidine-carboxamide (4f):
Yield: 64 %; m.p. 81-82 °C; IR (cm-1): 679 (C-S-C), 749 (C-Cl), 1350 (C-N), 1484 (C=C), 1577 (N=N), 1684 (CO), 1745 (CO cyclic), 1452, 2848, 2909 (CH2), 2948 (S-CH2), 3040 (CH-Ar), 3383 (NH); 1H NMR (300 MHz, CDCl3, TMS) 8: 2.24-2.29 (m, 2H, H-9), 3.33-3.38 (m, 2H, H-10), 3.44 (s, 2H, H-5''), 4.31 (t, 2H, J = 7.55 Hz, H-8), 5.43 (s, 1H, H-2''), 5.76 (s, 1H, H-1'), 7.25-7.79 (m, 8H, Ar-H); 13C NMR (75 MHz, CDCl3, TMS) 8: 33.8 (C-5''), 37.1 (C-9), 41.9 (C-10), 46.5 (C-8), 60.9 (C-2''), 109.2 (C-4), 118.9 (C-7), 123.7 (C-13), 124.7 (C-5), 125.6 (C-16), 128.4 (C-6), 129.8 (C-12), 132.5 (C-15), 133.4 (C-14), 134.5 (C-3a), 140.3 (C-11), 145.6 (C-7a), 163.7 (C-2'), 172.6 (C-4''); FAB-MS (m/z): 460 [M+]; Anal. Calcd. for C19H18BrN5O2S: C, 49.57; H, 3.94; N, 15.21%. Found: C, 49^4; H, 3.87; N, 15.14%.
N-[3-(1#-1,2,3-Benzotriazol-1-yl)-propyl]-2-(2-bro-mophenyl)-4-oxo-1,3-thiazolidine-carboxamide (4g):
Yield: 67%; m.p. 85-87 °C, IR (cm-1): 659 (C-S-C), 1341 (C-N), 1481 (C=C), 1580 (N=N), 1682 (CO), 1748 (CO cyclic), 1446, 2853, 2916 (CH2), 2945 (S-CH2), 3042 (CH-Ar), 3385 (NH); 1H NMR (300 MHz, CDCl3, TMS) 8: 2.17-2.21 (m, 2H, H-9), 3.36-3.42 (m, 2H, H-10), 3.45 (s, 2H, H-5''), 4.38 (t, 2H, J = 7.50 Hz, H-8), 5.19 (s, 1H, H-2''), 5.78 (s, 1H, H-1'), 7.26-7.77 (m, 8H, Ar-H); 13C NMR (75 MHz, CDCl3, TMS) 8: 34.6 (C-5''), 37.4 (C-9), 42.2 (C-10), 46.8 (C-8), 59.9 (C-2''), 111.1 (C-4), 119.5 (C-7), 120.3 (C-12), 125.7 (C-5), 127.2 (C-15), 128.4
(C-6), 130.1 (C-16), 131.5 (C-14), 132.2 (C-3a), 133.2 (C-13), 142.6 (C-11), 147.9 (C-7a), 163.1 (C-2'), 172.5 (C-4''); FAB-MS (m/z): 460 [M+]; Anal. Calcd. for C19H18BrN5O2S: C, 49.57; H, 3.94; N, 15.21%. Found: C, 49^0; H, 3.822; N, 15.12%.
N-[3-(1#-1,2,3-Benzotriazol-1-yl)-propyl]-2-(4-nitrop-henyl)-4-oxo-1,3-thiazolidine-carboxamide (4h):
Yield: 61%; m.p. 90-91 °C; IR (cm-1): 655 (C-S-C), 865 (C-NO), 1322 (C-N), 1478 (N=O), 1486 (C=C), 1579 (N=N), 1682 (CO), 1752 (CO cyclic), 1450, 2853, 2913 (CH2), 2944 (S-CH2), 3044 (CH-Ar), 3381 (NH); 1H NMR2 (300 MHz, C2DCl3, TMS) 8: 2.30-2.34 (m, 2H, H-9), 3.31-3.36 (m, 2H, H-10), 3.49 (s, 2H, H-5''), 4.37 (t, 2H, J = 7.50 Hz, H-8), 5.16 (s, 1H, H-2''), 5.82 (s, 1H, H-1'), 7.26-7.84 (m, 8H, Ar-H); 13C NMR (75 MHz, CDCl3, TMS) 8: 36.7 (C-5''), 37.9 (C-9), 42.6 (C-10),
47.7	(C-8), 62.1 (C-2''), 112.2 (C-4), 118.5 (C-7), 122.6 (C-13 and C-15), 124.8 (C-5), 127.9 (C-12 and C-16), 128.3 (C-6), 132.4 (C-3a), 139.8 (C-11), 145.9 (C-7a), 147.9 (C-14), 163.7 (C-2'), 173.6 (C-4''). FAB-MS (m/z): 426 [M+]; Anal. Calcd. for C19H18N6O4S: C, 53.52; H, 4.25; N, 19.70%. Found: C, 53.-47; H, 4.22; N, 19.65%.
N-[3-(1_ff-1,2,3-Benzotriazol-1-yl)-propyl]-2-(3-nitrop-henyl)-4-oxo-1,3-thiazolidine-carboxamide (4i):
Yield: 65%; m.p. 87-89 °C; IR (cm-1): 660 (C-S-C), 867 (C-NO), 1328 (C-N), 1483 (C=C), 1502 (N=O), 1581 (N=N), 1679 (CO), 1754 (CO cyclic), 1448, 2850, 2915 (CH2), 2947 (S-CH2), 3048 (CH-Ar), 3384 (NH); 1H NMR2 (300 MHz, C2DCl3, TMS) 8: 2.25-2.31 (m, 2H, H-9), 3.33-3.38 (m, 2H, 3H-10), 3.47 (s, 2H, H-5''), 4.34 (t, 2H, J = 7.45 Hz, H-8), 5.21 (s, 1H, H-2''), 5.72 (s, 1H, H-1'), 7.29-7.81 (m, 8H, Ar-H); 13C NMR (75 MHz, CDCl3, TMS) 8: 35.4 (C-5''), 35.7 (C-9), 43.3 (C-10),
48.8	(C-8), 61.2 (C-2''), 113.3 (C-4), 118.9 (C-7), 122.7 (C-12), 124.8 (C-14), 125.9 (C-5), 128.8 (C-6), 129.4 (C-15), 132.6 (C-3a), 132.9 (C-16), 139.7 (C-11), 146.9 (C-7a), 147.9 (C-13), 163.1 (C-2'), 175.6 (C-4''); FAB-MS (m/z): 426 [M+]; Anal. Calcd. for C19H18N6O4S: C, 53.52; H, 4.25; N, 19.70%. Found: C, 53.45; H, 4.20; N, 19.60%.
N-[3-(1_ff-1,2,3-Benzotriazol-1-yl)-propyl]-2-(2-nitrop-henyl)-4-oxo-1,3-thiazolidine-carboxamide (4j):
Yield: 66 %; m.p. 86-88 °C; IR (cm-1): 657 (C-S-C), 872 (C-NO), 1324 (C-N), 1498 (N=O), 1489 (C=C), 1578 (N=N), 1683 (CO), 1751 (CO cyclic), 1449, 2848, 2910 (CH2), 2949 (S-CH2), 3043 (CH-Ar), 3382 (NH); 1H NMR (300 MHz, CDCl3, TMS) 8: 2.25-2.29 (m, 2H, H-9), 3.40-3.45 (m, 2H, H-10), 3.47 (s, 2H, H-5''), 4.28 (t, 2H, J = 7.55 Hz, H-8), 5.22 (s, 1H, H-2''), 5.73 (s, 1H, H-1'), 7.34-7.92 (m, 8H, Ar-H); 13C NMR (75 MHz, CDCl3, TMS) 8: 37.1 (C-5''), 36.3 (C-9), 43.7 (C-10), 49.4 (C-8), 64 (C-2''), 112.4 (C-4), 117.4 (C-7), 122.5 (C-13), 123.8 (C-5), 127.6 (C-16), 128.6 (C-6),
130.8 (C-14), 132.9 (C-3a), 133.5 (C-11), 135.3 (C-15), 145.7 (C-7a), 146.5 (C-12), 161.1 (C-2'), 174.5 (C-4'') FAB-MS (m/z): 426 [M+]; Anal. Calcd. for C19H18N6O4S C, 53.52; H, 4.25; N, 19.70%. Found: C, 53.492; H, 4.19 N, 19.62%.
Synthesis of N-[3-(1_ff-1,2,3-Benzotriazol-1-yl)-propyl] -2-(phenyl)-4-oxo-5-(benzylidene)-1,3-thiazolidine-carboxamide (5a)
Mixture of 4a (0.010 mol) and benzaldehyde (0.010 mol) in methanol (50 mL) in the presence of EtONa was first stirred on a magnetic stirrer for about 2.00 h at room temperature followed by reflux on a steam bath for about 4.00 h. The completion of the reaction was monitored by silica gel-G coated TLC plates. The product was filtered, cooled and purified with column chromatography (silica gel packed column) using MeOH: CHCl3 (3:7 v/v) system as eluant (90 mL). The purified product was dried under vacuo and recrystallized from ethanol at room temperature to furnish compound 5a (Figure 1).
Figure 1: Structure of compounds 5a-j.
Compounds 5 (b-j) have been synthesized by using similar method as above.
N-[3-(1ff-1,2,3-Benzotriazol-1-yl)-propyl]-2-(phenyl)-4-oxo-5-(benzylidene)-1,3-thiazolidine-carboxamide (5a):
Yield: 57%; m.p. 79-81 °C; NMR (300 MHz, CDCl3, TMS) 8: 2.24-2.29 (m, 2H, H-9), 3.48-3.53 (m, 2H, H-10), 4.37 (t, 2H, J = 7.50 Hz, H-8), 5.72 (s, 1H, H-1'), 5.27 (s, 1H, H-2''), 6.52 (H-17), 6.86-7.72 (m, 14H, Ar-H); 13C NMR (75 MHz, CDCl3, TMS) 8: 38.2 (C-9), 45.2 (C-10), 51.1 (C-8), 63.7 (C-2''), 110.3 (C-4), 118.9 (C-7), 125.7 (C-5), 126.4 (C-12 and C-16), 126.4 (C-19 and C-23), 128.4 (C-6), 129.8 (C-16), 129.8 (C-14), 130.1 (C-13 and C-15), 131.7 (C-20 and C-22), 132.6 (C-3a), 136.4 (C-11), 138.7 (C-18), 136.7 (C-17), 143.2 (C-5''), 145.9 (C-7a), 161.1 (C-2'), 168.7 (C-4''); IR (cm-1): 1560 (C=CH), 1336 (C-N), 1477 (C=C), 1544 (N=N), 1674 (CO), 1737 (CO cyclic), 1445, 2842, 2903 (CH2), 3034 (CH-Ar), 3375 (NH), 2850 (C=CH), 3339 (NH); FAB-MS (m/z): 469 [M+]; Anal. Calcd. for
C26H23N5O2S: C, 66.50; H, 4.93; N, 14.91%. Found: C, 6(5.46; H, 4.89; N, 14.87%.
N-[3-(1#-1,2,3-BenzotriazoM-yl)-propyl]-2-(4-chlo-rophenyl)-4-oxo-5-(4-chlorobenzylidene)-1,3-thiazoli-dine-carboxamide (5b):
Yield: 60%; m.p. 89-91 °C; 1H NMR (300 MHz, CDCl3, TMS) 8: 2.41-2.46 (m, 2H, H-9), 3.59-3.63 (m, 2H, H-10), 4.50 (t, 2H, J = 7.45 Hz, H-8), 5.79 (s, 1H, H-1'), 5.21 (s, 1H, H-2''), 6.71 (s, 1H, H-17), 6.86-7.72 (m, 12H, Ar-H); 13C NMR (75 MHz, CDCl3, TMS) 8: 39.7 (C-9), 42.9 (C-10), 50.4 (C-8), 62.2 (C-2"), 116.2 (C-4), 120.9 (C-7), 123.7 (C-5), 127.7 (C-12 and C-16), 128.0 (C-19 and C-23), 128.6 (C-6), 129.4 (C-13 and C-15),
130.3	(C-20 and C-22), 131.4 (C-16), 131.9 (C-14), 132.8 (C-3a), 136.7 (C-18), 136.7 (C-11), 137.2 (C-17), 143.5 (C-5''), 146.9 (C-7a), 164.1 (C-2'), 174.5 (C-4''); IR (cm-1): 732 (C-Cl), 1470 (C=CH), 2868 (C=CH), 1344 (C-NH), 1485 (C=C), 1546 (N=N), 1680 (CO), 1742 (CO cyclic), 1452, 2846, 2908 (CH2), 3039 (CH-Ar), 3381 (NH); FAB-MS (m/z): 538 [M+]; Anal. Calcd. for C26H21Cl2N5O2S: C, 57.99; H, 3.93; N, 13.00%. Found: C, 5754; H, 3.87; N, 12.94%.
N-[3-(1#-1,2,3-BenzotriazoM-yl)-propyl]-2-(3-chlo-rophenyl)-4-oxo-5-(3-chlorobenzylidene)-1,3-thiazoli-dine-carboxamide (5c):
Yield: 62%; m.p. 86-87 °C; 1H NMR (300 MHz, CDCl3, TMS) 8: 2.45-2.49 (m, 2H, H-9), 3.60-3.65 (m, 2H, H-10), 4.47 (t, 2H, J = 7.50 Hz, H-8), 5.95 (s, 1H, H-1'), 5.23 (s, 1H, H-2''), 6.68 (s, 1H, H-17), 6.86-7.72 (m, 12H, Ar-H); 13C NMR (75 MHz, CDCl3, TMS) 8: 38.6 (C-9), 43.6 (C-10), 47.3 (C-8), 61.9 (C-2"), 114.2 (C-4),
118.4	(C-7), 124.3 (C-5), 126.7 (C-12), 127.5 (C-19), 128.3 (C-16), 128.9 (C-23), 129.1 (C-6), 129.9 (C-14),
130.5	(C-21), 131.4 (C-13), 132.9 (C-22), 134.4 (C-3a), 135.3 (C-13), 136.6 (C-20), 138.1 (C-11), 139.7 (C-18),
140.1	(C-17), 143.2 (C-5''), 147.9 (C-7a), 164.3 (C-2'),
171.2	(C-4''); IR (cm-1): 738 (C-Cl), 1335 (N-C), 1474 (C=CH), 2862 (C=CH) 1489 (C=C), 1552 (N=N), 1685 (CO), 1747 (CO cyclic), 1452, 2854, 2914 (CH2), 3047 (CH-Ar), 3382 (NH); FAB-MS (m/z): 538 [M+]; Anal. Calcd. for C26H21Cl2N5O2S: C, 57.99; H, 3.93; N, 13.00%. Found: C, 577.922; H, 3.76; N, 12.91%.
N-[3-(1#-1,2,3-BenzotriazoM-yl)-propyl]-2-(2-chlo-rophenyl)-4-oxo-5-(2-chlorobenzylidene)-1,3-thiazoli-dine-carboxamide (5d):
Yield: 61; m.p. 82-83 °C; 1H NMR (300 MHz, CDCl3, TMS) 8: 2.37-2.43 (m, 2H, H-9), 3.53-3.59 (m, 2H, H-10), 4.44 (t, 2H, J = 7.55 Hz, H-8), 5.85 (s, 1H, H-1'), 5.29 (s, 1H, H-2''), 6.72 (s, 1H, H-17), 6.86-7.72 (m, 12H, Ar-H); 13C NMR (75 MHz, CDCl3, TMS) 8: 36.8 (C-9), 43.8 (C-10), 47.6 (C-8), 63.4 (C-2"), 114.5 (C-4), 119.9 (C-7), 124.7 (C-5), 127.6 (C-13), 128.2 (C-22), 128.9 (C-6), 129.4 (C-13), 130.1 (C-20), 130.4 (C-14),
131.6	(C-21), 132.2 (C-16), 132.2 (C-23), 133.3 (C-3a), 135.1 (C-12), 135.1 (C-19), 137.9 (C-11), 137.9 (C-8),
138.3	(C-17), 143.1 (C-5''), 147.4 (C-7a), 163.6 (C-2'),
173.7	(C-4''); IR (cm1): 742 (C-Cl), 1576 (C=CH), 2866 (C=CH) 1338 (C-NH), 1492 (C=C), 1549 (N=N), 1684 (CO), 1752 (CO cyclic), 1454, 2857, 2917 (CH2), 3046 (CH-Ar), 3388 (NH); FAB-MS (m/z): 538 [M+]; Anal. Calcd. for C26H21Cl2N5O2S: C, 57.99; H, 3.93; N, 13.00%. Found: C, 57.90; H, 3.85; N, 12.90%.
N-[3-(1#-1,2,3-Benzotriazol-1-yl)-propyl]-2-(4-bro-mophenyl)-4-oxo-5-(4-bromobenzylidene)-1,3-thiazo-lidine-carboxamide (5e):
Yield: 62%; m.p. 78-79 °C; 1H NMR (300 MHz, CDCl3, TMS) 8: 2.38-2.42 (m, 2H, H-9), 3.52-3.57 (m, 2H, H-10), 4.46 (t, 2H, J = 7.45 Hz, H-8), 5.92 (s, 1H, H-1'), 5.11 (s, 1H, H-2''), 6.77 (s, 1H, H-17), 6.86-7.72 (m, 12H, Ar-H); 13C NMR (75 MHz, CDCl3, TMS) 8: 39.4 (C-9), 43.8 (C-10), 47.6 (C-8), 63.4 (C-2"), 112.4 (C-4),
119.4	(C-7), 123.9 (C-14), 123.9 (C-21), 124.5 (C-5), 128.6 (C-6), 130.8 (C-12 and C-16), 131.2 (C-19 and C-23), 131.4 (C-13 and C-15), 131.8 (C-20 and C-22), 132.6 (C-3a), 136.5 (C-11), 137.7 (C-18), 138.8 (C-17), 141.9 (C-5''), 147.9 (C-7a), 164.2 (C-2'), 172.3 (C-4''); IR (cm-1): 561 (C-Br), 1472 (C=CH), 2856 (C=CH) 1346 (C-N), 1490 (C=C), 1553 (N=N), 1681 (CO), 1750 (CO cyclic), 1455, 2852, 2915 (CH2), 3042 (CH-Ar), 3385 (NH); FAB-MS (m/z): 627 [M+]; Anal. Calcd. for C26H21Br2N5O2S2: C, 49.77; H, 3.37; N, 11.16%. Found: C, 49.73; H, 3.33; N, 11.12%.
N-[3-(1#-1,2,3-Benzotriazol-1-yl)-propyl]-2-(3-bro-mophenyl)-4-oxo-5-(3-bromobenzylidene)-1,3-thiazo-lidine-carboxamide (5f):
Yield: 64%; m.p. 81-82 °C; 1H NMR (300 MHz, CDCl3, TMS) 8: 2.40-2.44 (m, 2H, H-9), 3.60-3.67 (m, 2H, H-10), 4.51 (t, 2H, J = 7.40 Hz, H-8), 5.89 (s, 1H, H-1'), 5.19 (s, 1H, H-2''), 6.68 (s, 1H, H-17), 6.86-7.72 (m, 12H, Ar-H); 13C NMR (75 MHz, CDCl3, TMS) 8: 37.5 (C-9), 44.3 (C-10), 49.3 (C-8), 64.6 (C-2"), 109.2 (C-4), 118.9 (C-7), 123.7 (C-13), 124.6 (C-20), 124.7 (C-5), 125.6 (C-16), 125.6 (C-23), 128.4 (C-6), 129.8 (C-12),
130.8	(C-19), 132.5 (C-13), 133.4 (C-22), 133.9 (C-14), 134.3 (C-21), 134.5 (C-3a), 140.3 (C-11), 140.8 (C-17),
142.5	(C-5''), 142.7 (C-18), 145.6 (C-7a), 163.7 (C-2'),
172.6	(C-4''); IR (cm-1): 568 (C-Br) 2852 (C=CH), 1475 (C=CH), 1347 (C-NH), 1484 (C=C), 1550 (N=N), 1679 (CO), 1745 (CO cyclic), 1450, 2848, 2909 (CH2), 3040 (CH-Ar), 3384 (NH); FAB-MS (m/z): 627 [M+]; Anal. Calcd. for C26H21Br2N5O2S: C, 49.77; H, 3.37; N, 11.16%. Found: C, 49.72; H, 3.34; N, 11.14%.
N-[3-(1#-1,2,3-Benzotriazol-1-yl)-propyl]-2-(2-bro-mophenyl)-4-oxo-5-(2-bromobenzylidene)-1,3-thiazo-lidine-carboxamide (5g):
Yield: 63%; m.p. 75-76 °C; 1H NMR (300 MHz,
CDCl3, TMS) 8: 2.40-2.45 (m, 2H, H-9), 3.55-3.61 (m, 2H, H-10), 4.49 (t, 2H, J = 7.50 Hz, H-8), 5.91 (s, 1H, H-1'), 5.17 (s, 1H, H-2''), 6.59 (s, 1H, H-17), 6.86-7.72 (m, 12H, Ar-H); 13C NMR (75 MHz, CDCl3, TMS) 8: 40.3 (C-9), 45.9 (C-10), 48.4 (C-8), 62.6 (C-2"), 111.1 (C-4), 119.5 (C-7), 120.3 (C-12), 122.6 (C-19), 125.7 (C-5), 126.5 (C-15), 127.2 (C-22), 128.4 (C-6), 129.3 (C-16), 130.1 (C-23), 131.3 (C-14), 132.8 (C-21), 133.2 (C-3a),
134.5	(C-13), 135.7 (C-20), 138.7 (C-17), 142.2 (C-5''),
142.6	(C-11), 144.2 (C-22), 147.9 (C-7a), 163.1 (C-2'), 172.5 (C-4''); IR (cm-1): 564 (C-Br), 1479 (C=CH), 2856 (C=CH), 1352 (C-NH), 1494 (C=C), 1551 (N=N), 1686 (CO), 1749 (CO cyclic), 1456, 2857, 2915 (CH2), 3045 (CH-Ar), 3386 (NH); FAB-MS (m/z): 627 [M+]; Anal. Calcd. for C26H21Br2N5O2S: C, 49.77; H, 3.37; N, 11.16%. Found6 C, 49.70; H, 3.30; N, 11.10%.
N-[3-(1#-1,2,3-Benzotriazol-1-yl)-propyl]-2-(4-nitrop-henyl)-4-oxo-5-(4-nitrobenzylidene)-1,3-thiazolidine-carboxamide (5h):
Yield: 60; m.p. 73-74 °C; 1H NMR (300 MHz, CDCl3, TMS) 8: 2.34-2.39 (m, 2H, H-9), 3.52-3.58 (m, 2H, H-10), 4.50 (t, 2H, J = 7.55 Hz, H-8), 5.13 (s, 1H, H-2''), 5.87 (s, 1H, H-1'), 6.61 (s, 1H, H-17), 6.81-7.71 (m,12H, Ar-H); 13C NMR (75 MHz, CDCl3, TMS) 8: 37.7 (C-9), 44.8 (C-10), 48.9 (C-8), 64.2 (C-2''), 112.2 (C-4),
118.5	(C-7), 122.6 (C-13 and C-15), 123.2 (C-20 and C-22), 124.8 (C-5), 126.9 (C-12 and C-16), 127.4 (C-19 and C-23), 128.3 (C-6), 132.4 (C-3a), 139.8 (C-11), 138.3 (C-17), 140.3 (C-18), 142.3 (C-5''), 145.9 (C-7a), 147.9 (C-14), 148.5 (C-21), 163.7 (C-2'), 173.6 (C-4''); IR (cm-1): 865 (C-NO), 1495 (N=O), 1578 (C=CH), 2857 (C=CH) 1345 (C-N), 1488 (C=C), 1547 (N=N), 1683 (CO), 1744 (CO cyclic), 1451, 2850, 2912 (CH2), 3045 (CH-Ar), 3387 (NH); FAB-MS (m/z): 559 [M+]; Anal. Calcd. for C26H21N7O6S: C, 5.80; H, 3.78; N, 17.52%. Found: C, 55.777; H, 3.772; N, 17.48%.
N-[3-(1_ff-1,2,3-Benzotriazol-1-yl)-propyl]-2-(3-nitrop-henyl)-4-oxo-5-(3-nitrobenzylidene)-1,3-thiazolidine-carboxamide (5i):
Yield: 64%; m.p. 81-82 °C; 1H NMR (300 MHz, CDCl3, TMS) 8: 2.43-2.48 (m, 2H, H-9), 3.50-3.54 (m, 2H, H-10), 4.48 (t, 2H, J = 7.50 Hz, H-8), 5.15 (s, 1H, H-2''), 5.90 (s, 1H, H-1'), 6.69 (s, 1H, H-17), 6.79-7.68 (m, 12H, Ar-H); 13C NMR (75 MHz, CDCl3, TMS) 8: 40.2 (C-9), 45.2 (C-10), 49.7 (C-8), 65.8 (C-2''), 113.3 (C-4), 118.9 (C-7), 121.8 (C-12), 122.7 (C-19), 123.6 (C-14),
124.8	(C-21), 125.9 (C-5), 128.8 (C-6), 129.4 (C-15), 130.4 (C-22), 132.6 (C-3a), 132.9 (C-16), 134.2 (C-23),
139.7	(C-11), 140.3 (C-17), 141.4 (C-18), 143.1 (C-5''),
146.9	(C-7a), 147.9 (C-13), 148.2 (C-20), 163.1 (C-2'),
175.6	(C-4''); IR (cm-1): 841 (C-NO), 1480 (C=CH), 1497 (N=O), 2864 (C=CH), 1350 (C-N), 1493 (C=C), 1548 (N=N), 1682 (CO), 1748 (CO cyclic), 1453, 2853, 2910 (CH2), 3044 (CH-Ar), 3384 (NH); FAB-MS (m/z):
559 [M+]; Anal. Calcd. for C26H21N7O6S: C, 55.80; H, 3.78; N, 17.52%. Found: C, 55.775; H, 3.773; N, 17.46%.
N-[3-(1_ff-1,2,3-Benzotriazol-1-yl)-propyl]-2-(2-nitrop-henyl)-4-oxo-5-(2-nitrobenzylidene)-1,3-thiazolidine-carboxamide (5j):
Yield: 62%; m.p. 84-85 °C; 1H NMR (300 MHz, CDCl3, TMS) 8: 2.34-2.40 (m, 2H, H-9), 3.60-3.65 (m, 2H, H-10), 4.53 (t, 2H, J = 7.45 Hz, H-8), 5.14 (s, 1H, H-2''), 5.83 (s, 1H, H-1'), 6.62 (s, 1H, H-17), 6.89-7.75 (m, 12H ,Ar-H); 13C NMR (75 MHz, CDCl3, TMS) 8: 38.6 (C-9), 45.5 (C-10), 50.9 (C-8), 63.8 (C-2''), 112.4 (C-4), 117.4 (C-7), 121.2 (C-13), 122.5 (C-20), 123.8 (C-5), 126.8 (C-16), 127.6 (C-23), 128.6 (C-6), 130.8 (C-14), 131.3 (C-21), 132.9 (C-3a), 133.5 (C-11), 134.8 (C-18), 135.3 (C-15), 136.7 (C-22), 141.2 (C-17), 144.9 (C-5''), 145.7 (C-7a), 146.5 (C-12), 147.9 (C-19), 161.1 (C-2'), 174.5 (C-4''); IR (cm-1): 852 (C-NO), 1478 (N=O), 1489 (C=CH), 2870 (C=CH), 1355 (C-NH), 1497 (C=C), 1553 (N=N), 1689 (CO), 1751 (CO cyclic), 1457, 2858, 2919 (CH2), 3047 (CH-Ar), 3387 (NH); FAB-MS (m/z): 559 [M+]; Anal. Calcd. for C26H21N7O6S: C, 55.80; H, 3.78; N, 17.52%. Found: C, 55.726; H, 3.74; N, 17.45%.
6. Experimental: Biological Study
6.1. Antibacterial, Antifungal and
Antitubercular Activities
Series of newly synthesized compounds were tested against selected microorganisms. The minimal inhibition concentrations (MIC) were determined using the filter paper disc diffusion method and the concentrations are given in ^g/mL. All the final synthesized 5a-j have been screened in vitro for their antibacterial activity against Bacillus subtilis, Escherichia coli and Staphylococcus au-reus and antifungal activity against Aspergillus niger, Aspergillus flavus and Candida albicans. Standards for antibacterial and antifungal activities streptomycin and gri-seofulvin, respectively, were used. The antitubercular activity screened against the Mycobacterium tuberculosis. For the antitubercular activity isoniazid and rifampicin were used as standard. Standards were screened under similar conditions for comparison. Results are given in Table 1.
6. 2. Anti-inflammatory Activity
Carageenan induced rat paw oedema method was employed for evaluating the antiinflammatory activity of compounds at a dose 50 mg/kg (bw) in albino rats (weighing 80-110 g, each group containing 5 animals) using phenylbutazone as a standard drug for comparison at a dose 30 mg/kg bw. The rate paw oedema was produced by the method of Winter et al. The percentage inhibition of inflammation was calculated by applying Newbould for-
mula. In vivo study has been approved by the institutional ethical committee, Dr. H. S. Gour University, Sagar. Results of 5a-j were given in Table 2.
7. Acknowledgement
The authors are thankful to SAIF, Central Drugs Research Institute, Lucknow (India) for providing spectral and analytical data of the compounds. We are also thankful to Head, Department of Chemistry, Dr. H. S. Gour, University, Sagar (India) for giving the facilities to carry out the work.
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Povzetek
Razvili smo učinkovito sintezno pot nove serije N-[3-(1_ff-1,2,3-benzotriazol-1-il)-propil]-2-(substituiran fenil)-4-okso-5-(substituiran benziliden)-1,3-tiazolidin-karboksamidov; sintetizirali smo spojine 5a-j in jih karakterizirali z IR, NMR, 13C NMR, FAB-MS in kemijsko elementno analizo. Vse končne produkte smo testirali na antimikrobno aktivnost proti nekaterim izbranim bakterijam in glivam ter za antituberkulozno aktivnost proti Mycobacterium tuberculosis ter za proti vnetno aktivnost pri albino podganah.