INTRODUCTION:
Thiazoles are important class of heterocyclic compounds, found in many potent biologically bioactive compounds such as Sulfathiazol (antimicrobial drug), Ritonavir (antiretroviral drug), Abafungin (antifungal drug) with trade name Abasol cream and Bleomycine and Tiazofurin1 (antineoplastic drug). The applications of thiazoles were found in drug development for the treatment of allergies2, hypertension3, inflammation4, schizophrenia5, bacterial6, HIV infections7, hypnotics8 and more recently for the treatment of pain9, as fibrinogen receptor antagonists with antithrombotic activity10 and as new inhibitors of bacterial DNA gyrase B11. Many thiazole derivatives are bioactive and several are useful clinically prescribed drugs; thus, thiazole nucleus has long been recognized as a good pharmacophore.
The synthetic approach for the synthesis of targeted compound 2-(2-arylaminothiazol-5-oyl)benzofuran is given Scheme I.
The retro synthetic approach shows that the desired compounds can obtain from bromoacetylbenzofuran and imidoylthiourea. The required imidoylthiourea can be obtained from a thiourea amine and N,N-dimethylformamide dimethylacetal.
MATERIALS AND METHOD:
The reagents and solvents used were of AR grade. All chemicals were purchased from Merck Specialties Pvt. Ltd and Sigma - Aldrich. The spectra were recorded on Bruker Avance III, 400MHz NMR spectrometer (400MHz for 1H and 400MHz for 13C NMR spectra), Waters UPLC - TQD mass spectrometer (ESI – MS and APCI - MS) for ESI mass spectra and Nicolet 400D FTIR spectrometer. Melting points were uncorrected. Elemental analysis was done at the Central Drug Research Institute, Lucknow, India.
Preparation of 1-arylamino-3-(N,N-dimethylimidoyl)thioureas:
The arylamino-3-(N,N-dimethylimidoyl)thioureas 4 were prepared by the reaction between N,N-dimethylformamide dimethylacetal 3 and arylthiourea 2 is given Scheme II. The 1-arylthiourea derivative was prepared by the reaction between 3,5-dimethyl-1-thiocarboxamidopyrazole 1 and an amine12. This reaction involves a thiocarbamoyl transfer agent. This reagent was prepared from acetylacetone and thiosemicarbazide. This transfer agent on reaction with aryl/alkyl amine afforded the desired thiourea.
Preparation of 2–acetylbenzofuran13:
Salicylaldehyde (0.1mol), bromoacetone (0.1mol) and anhydrous acetone (35mL) were taken in dried round bottomed flask and refluxed for 10 hours in a water bath. The reaction mixture was then cooled and treated with anhydrous potassium carbonate, filtered and evaporated to give pure white crystals of 2-acetylbenzofuran. Yield: 12.3g (76.9%), m. p. 75°C.
Preparation of 2–bromoacetylbenzofuran13:
A solution of bromine (7.5mmol) in acetic acid was added drop wise with stirring to a solution of 2-acetylbenzofuran (7.5mmol) in acetic acid after complete addition of bromine, the mixture was stirred for 45 min and allowed to stand for 30 minutes, then the mixture was decanted in crushed ice, the solid separated was collected and crystallized from ethanol as light green crystals. Yield: 18.6g (77.8%), m. p. 94°C.
Synthesis of 1-arylamino-3-(N,N-dimethylimidoyl) thioureas12 , 14:
The 1-arylamino-3-(N,N-dimethylimidoyl)thioureas were prepared by the reaction between N,N-dimethylformamide dimethylacetal and 1-arylthiourea. The 1-arylthiourea derivative 2 was prepared by the reaction between 3,5-dimethyl-1-thiocarboxamidopyrazole 1 and an amine. This reaction involves a thiocarbamoyl transfer agent. This reagent was prepared from acetylacetone and thiosemicarbazide. This transfer agent on reaction with aryl/alkyl amine afforded the desired thiourea.
Synthesis of 2-(2-arylaminothiazol-5-oyl)benzofuran 3a-e:
To a solution of 1-aryl-3-(N,N-dimethylimidoyl)thiourea
(1mmol) in DMF, 2-(2-bromoacetyl)benzofuran (1mmol) was added. The reaction
mixture was heated at 80-85°C on a
water bath for 5 min. To this triethylamine (1mmol) was added and heating was
continued for another 10 min. The reaction mixture was then cooled and poured
into ice-cold water with stirring. The yellow precipitate obtained was
filtered, washed with water and dried. The crude product was crystallized from
methanol-water (2:1).
2-(2-phenylaminothiazol-5-oyl)benzofuran 3a:
Yield 61.1%, m.p. 223-227, Analysis found: C, 67.14: H, 3.44: N, 8.51%: Calc. for C18H12N2O2S (320.3)7: C, 67.48: H, 3.78: N, 8.74%: IR (KBr) cm-1: 3580, 3550, 3527, 3506, 3427, 3404, 3315, 3278, 3054, 2924, 2423, 1644, 1560, 1534, 1527, 1547, 1020, 942, 867, 713, 692. 1H NMR: (400 MHz, DMSO-d6) 7.00(t, 7.2 Hz, 1H, ArH), 7.12(t, 8.4 Hz, 1H, H-5), 7.21(s, 1H, H-4 of thiazole), 7.24-7.42(m, 4H, H-3, H-6, 2ArH), 7.48(d, 7.6 Hz, 2H, 2ArH), 7.61(d, 8Hz, 1H, H-4), 7.69(d, 7.4 Hz, 1H, H-7), 9.77(s, 1H, NH).
2-[2-(4-chlorophenylamino)thiazol-5-oyl]benzofuran 3b:
Yield 60.2%, m.p. 185-187, Analysis found: C, 61.03: H, 3.14: N, 7.93%: Calc. for C18H11N2O2SCl (354.81): C, 60.93: H, 3.12: N, 7.90%: IR (KBr) cm-1: 3577, 3566, 3529, 3447, 3422, 3371, 3296, 3062, 2362, 1641, 1591, 1557, 1541, 1529, 1515, 1588, 1571, 1525, 1506, 1536, 1546, 1582, 1538, 1015, 966, 825, 746, 673, 615. 1H NMR: (400 MHz, DMSO-d6) 7.23(s, 1H, H-4 of thiazole), 7.21-7.42(m, 4H, H-5, H-6, 2ArH), 7.43-7.53(m, 3H, H-3, 2ArH), 7.61-7.80(m, 2H, H-4, H-7), 9.74(s, 1H, NH).
2-[2-(4-methoxyphenylamino)thiazol-5-oyl]benzofuran 3c:
Yield 67.3%, m.p. 244-247, Analysis found: C, 65.43: H, 3.77: N, 8.11%: Calc. for C19H14N2O3S (350.39): C, 65.13: H, 4.03: N, 7.99%: IR (KBr) cm-1: 3474, 3428, 3404, 3157, 3078, 3045, 2958, 2926, 2456, 1715, 1695, 1672, 1666, 1645, 1566, 1514, 1502, 1529, 1532, 1547, 1574, 1026, 923, 826, 746, 671. 1H NMR: (400 MHz, DMSO-d6) 3.88(s, 3H, OCH3), 7.05-7.43 (m, 6H, H-3, H-5, H-6, H-4 of thiazole, 2ArH), 7.48(d, 7.6 Hz, 2H, 2ArH), 7.59-7.70 (m, 2H, H-4, H-7), 9.77(s, 1H, NH)
2-(2-(4-ethoxyphenylamino)thiazol-5-oyl]benzofuran 3d:
Yield 64.6%, m.p. 258-262, Analysis found: C, 65.02: H, 4.11: N, 7.61%: Calc. for C20H16N2O3S (364.42): C, 65.92: H, 4.43: N, 7.69%: IR (KBr) cm-1: 3583, 3464, 3449, 3423, 3394, 3277, 3251, 3340, 3221, 3301, 2978, 2456, 1560, 1523, 1515, 1523, 1500, 1544, 1515, 1047, 968, 921, 823, 748, 688, 624. 1H NMR: (400 MHz, DMSO-d6) 1.17(t, 7.0Hz, 3H, CH3), 4.00(q, 7.2Hz, 2H, CH2), 7.20(s, 1H, H-4 of thiazole), 7.23-7.47(m, 5H, H-3, H-5, H-6, 2ArH), 7.61-7.79 (m, 4H, H-4, H-7, 2ArH), 9.46(s, 1H, NH)
2-[2-(4-methylphenylamino)thiazol-5-oyl]benzofuran 3e:
Yield 55.5%, m.p. 249-253, Analysis found: C, 68.18: H, 4.26: N, 8.31%: Calc. for C19H14N2O2S (334.39): C, 68.24: H, 4.22: N, 8.38%: IR (KBr) cm-1: 3459, 3426, 3403, 3286, 3224, 3150, 3062, 3037, 3010, 2924, 1566, 1554, 1537, 1519, 1527, 1517, 1551, 1518, 1045, 1020, 746, 631. 1H NMR: (400 MHz, DMSO-d6) 2.35(s, 3H, CH3), 7.18(s, 1H, H-4 of thiazole), 7.22-7.40 (m, 4H, H-5, H-6, 2ArH), 7.42-7.70(m, 5H, H-3, H-4, H-7, 2ArH), 9.89(s, 1H, NH)
RESULT AND DISCUSSION:
The reaction of 2-(2-bromoacetyl)benzofuran with 1-aryl-3-(N,N-dimethylimidoyl)thiourea in the presence of triethylamine, afforded an orange yellow solid. Crystallization from methanol-water (2:1) gave an orange yellow crystalline compound. As a representative example, the reaction of 2-(2-bromoacetyl)benzofuran with 3-(N,N-dimethylimidoyl)-1-phenylthiourea is described below in detail. The reaction yielded an orange yellow crystalline compound.
The elemental analysis showed that the molecular composition of the compound was C18H12N2O2S. The IR (KBr) spectrum of the compound shows peaks15 at 3580cm-1, 3550cm-1 and 3427cm-1, which are assignable to nN-H bands. The peak at 3054cm-1 is attributed to aromatic nC-H vibration. The highly conjugated carbonyl group gives rise to a nC=O band at 1644cm-1. In the 1H NMR (400 MHz, DMSO-d6) spectrum, the aromatic hydrogen para to NH group shows a one-hydrogen triplet at d 7.00. The one hydrogen triplet at d 7.12 has been attributed to H-5 of the benzofuran ring. The one hydrogen singlet at d 7.21 has been attributed to H-4 of the thiazole ring. The multiplet at d 7.24-7.42 has been attributed to H-3 and H-6 of the benzofuran ring and two aryl hydrogens. The one hydrogen doublet at d 7.48 has been attributed to two aryl hydrogens. The one hydrogen singlet at d 7.61 has been attributed to H-4 of the benzofuran ring. The H-7 of the benzofuran ring forms doublet at d 7.69. The amino hydrogen appears as singlet at d 9.77. From the above evidences, the compound was formulated as 2-(2-phenylaminothiazol-5-oyl)benzofuran 3a.
The next reaction was performed between 1-(4-methoxyphenyl)-3-(N,N-dimethylimidoyl)thiourea and 2-(2-bromoacetyl)benzofuran. The reaction afforded an orange yellow crystalline compound. The elemental analysis showed that the molecular composition was C19H14N2O3S. . The IR (KBr) spectrum of the compound shows peaks at 3474cm-1, 3428cm-1 and 3404cm-1, which are assignable to nN-H bands. The peak at 3045cm-1 is attributed to aromatic nC-H vibration. The highly conjugated carbonyl group gives rise to a nC=O band at 1672cm-1.
In the 1H NMR (400 MHz, DMSO-d6) spectrums consists of a three-hydrogen singlet d 3.88 due to the presence of the methoxy group. The multiplet at d 7.05-7.43 has been attributed to H-3, H-5 and H-6 of the benzofuran ring, H-4 of thiazole ring and two aryl hydrogens. The one hydrogen doublet at d 7.48 has been attributed to two aryl hydrogens. The H-4 and H-7 of the benzofuran ring forms the multiplet at d 7.59-7.70. The amino hydrogen appears as singlet at d 9.77. The ESI-Mass spectrum showed MH+ peak at 351, which confirms the molecular mass of the compound to be 350 in accordance with the elemental analysis data. The 13C NMR gives nineteen peaks corresponding to the nineteen carbons. Hence the compound is formulated as 2-[2-(4-methoxyphenylamino)thiazol-5-oyl]benzofuran 3c.
We have performed the similar reaction using other 1-aryl-3-(N,N-dimethylimidoyl)thiourea to obtain 2-[2-(4-chlorophenylamino)thiazol-5-oyl]benzofuran 3b 2-[2-(4-ethoxyphenylamino)thiazol-5-oyl]benzofuran 3d and 2-[2-(4-methylphenylamino)thiazol-5-oyl]benzofuran 35e. The structure assignment is based on the physical data, elemental analysis data IR 1H NMR and 13C NMR spectral data. The reaction can be depicted as follows scheme III.
Compd. |
Ar |
|
3a 3b 3c 3d 3e |
phenyl 4-chlorophenyl 4-methoxyphenyl 4-ethoxyphenyl 4-methylphenyl |
Antioxidant studies:
The newly synthesis compounds were screened for their antioxidant studies, DPPH (1mg) in methanol was prepared in 250mL standard flask (10-5mol) with different concentrations (0.1, 0.25, 0.5, 0.75 and 1mM) were prepared. Standard solutions of different concentrations (0.1, 0.25, 0.5, 0.75 and 1mM) were prepared. The absorbance of the control and the test solutions were recorded at 517nm. By following similar procedure the absorbance will be measured for BHA solutions. From the absorbance values, percentage of inhibition was calculated. The percentage of reduction and IC50 were calculated. The IC50 value indicates that compound with less IC50 has more antioxidant capacity. The standard BHA shows the IC50 value of 624µM.
Control Absorbance – Sample absorbance
% Inhibition =--------------------------------- X 100
Control Absorbance
Table 1. Antioxidant studies of 2-(2-arylaminothiazol-5-oyl)benzofurans
|
Compd. |
IC50 Value (μM) |
|
3a |
308 |
|
3b |
132 |
|
3c |
214 |
|
3d |
210 |
|
3e |
166 |
|
BHA(std) |
624 |
The results of antioxidant potential of the compounds were classified into excellent (IC50 = 1-100mM), very good (IC50 = 101-200mM), good (IC50 = 201-300mM) and moderate (IC50 = 301-624mM).
The results of antioxidant study (Table 1) shows that the compounds 2-[2-(4-chlorophenylamino)thiazol-5-oyl]benzofuran 3b, 2-[2-(4-methylphenylamino)-thiazol-5-oyl]benzofuran 3e, has IC50 value 132μM, 166μM, and has very good antioxidant activity. The compounds 2-[2-(4-methoxyphenylamino)thiazol-5-oyl]ben-zofuran 3c and 2-[2-(4-ethoxyphenylamino)thiazol-5-oyl]benzofuran 3d, have IC50 values 214μM and 210μM respectively and hence they have good antioxidant activities. The 2-(2-phenylaminothiazol-5-oyl)benzofuran 3a have IC50 values 308μM and hence it has moderate antioxidant activities. All synthesized compounds showed low to moderate antioxidant activity.
Anti-bacterial activities:
Method used:
The stock cultures of bacteria were revived by inoculating in broth media and grown at 37ºC for 18 hrs. The agar plates (20g in 1L distilled water) of the above media were prepared and wells were made in the plate. Each plate was inoculated with 18 h old cultures (100μL, 104CFU) and spread evenly on the plate. After 20 min, the wells were filled with compound and antibiotic at different concentrations. All the plates were incubated at 37ºC for 24 h and the diameter of inhibition zone were noted.
Newly synthesized compounds have been screened for antibacterial activity against Gram-positive Staphylococcus aureus, Bacillus subtilis and Gram-negative Escherichia coli, Pseudomonas aeruginosa. As a reference, Ciprofloxacin is used and a comparison of the data obtained from the study shows that almost all the new compounds now screened appeared to have remarkable antibacterial activity. These are classified into highly active (inhibition zone > 15mm), fairly active (inhibition zone > 10mm), moderately active (inhibition zone > 8mm) and somewhat active (inhibition zone = 6mm). The antibacterial activities of 2-(2-arylaminothiazol-5-oyl)benzofuran are presented in the
Table 2: Anti-bacterial activities of 2-(2-arylaminothiazol-5-oyl)benzofurans
|
Compd. |
Zone of inhibition (mm) |
|||
|
Staphylococcus aureus |
Bacillus subtilis |
Escherichia coli |
Pseudomonas aeruginosa |
|
|
3a |
5 |
10 |
4 |
- |
|
3b |
15 |
21 |
15 |
10 |
|
3c |
2 |
15 |
6 |
- |
|
3d |
3 |
5 |
- |
3 |
|
3e |
20 |
26 |
18 |
6 |
|
Gentamycin |
27 |
39 |
32 |
29 |
The compound 2-(2-phenylaminothiazol-5-oyl)benzofuran 3a, is somewhat active against Staphylococcus aureus and Escherichia coli and fairly activity against Bacillus subtilis. The compound 2-[2-(4-methoxyphenylamino)thiazol-5-oyl]benzofuran 3c, is somewhat active against Staphylococcus aureus and Escherichia coli, highly active against Bacillus subtilis. The compound 2-[2-(4-ethoxyphenylamino)thiazol-5-oyl]benzofuran 3d is somewhat active against Staphylococcus aureus, Bacillus subtilis and Pseudomonas aeruginosa, The compound 2-[2-(4-chlorophenylamino)thiazol-5-oyl]benzofuran 3b is highly active against Staphylococcus aureus, Bacillus subtilis and Escherichia coli, fairly active against Pseudomonas aeruginosa. The compound 2-[2-(4-methylphenylamino)thiazol-5-oyl]benzofuran 3e, highly active against Staphylococcus aureus, Escherichia coli and Bacillus subtilis and somewhat active against Pseudomonas aeruginosa.
CONCLUSION:
The newly synthesized novel compounds were established on the basis of elemental analysis, IR, 1H NMR, 13C NMR and mass spectral data and tested for in vitro antimicrobial activity. It may be concluded that the newly synthesized compound 2-[2-(4-chlorophenylamino)thiazol-5-oyl]benzofuran 3b has very good antioxidant activity., also compound 2-[2-(4-chlorophenylamino)thiazol-5-oyl]benzofuran 3b and 2-[2-(4-methylphenylamino)thiazol-5-oyl]benzofuran 3e is highly active against Bacillus subtilis in antibacterial studies.
ACKNOWLEDGEMENT:
T.F. Abbs Fen Reji thanks University Grants Commission, New Delhi for Financial Assistance in the form of Major Research project [F.No.41-229/2012 (SR)]. The authors thank NIIST, Trivandrum and CDRI, Lucknow for spectral and analytical data
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Received on 27.08.2017 Modified on 26.09.2017
Accepted on 21.10.2017 © AJRC All right reserved
Asian J. Research Chem. 2017; 10(6): 798-802.
DOI: 10.5958/0974-4150.2017.00133.X