SYNTHESIS AND ANTIMICROBIAL ACTIVITY OF 1-(4-ARYL-2-THIAZOLYL) – AND 1-(4-ARYL-2-OXAZOLYL)-3, 5-DIARYL Δ2-PYRAZOLINE DERIVATIVES
HTML Full TextSYNTHESIS AND ANTIMICROBIAL ACTIVITY OF 1-(4-ARYL-2-THIAZOLYL) - AND 1-(4-ARYL-2-OXAZOLYL)-3, 5-DIARYL Δ2-PYRAZOLINE DERIVATIVES
Nadia T. A. Dawood
Chemistry Department, Faculty of Science, Girl's, Al-Azhar University, Nasr City, Cairo, Egypt
ABSTRACT
A series of nine 1-(4-aryl-2-thiazolyl)-3, 5- diaryl and six of 1- (4- aryl- 2-oxazolyl)-3, 5- diaryl- 2- pyrazolin derivatives were prepared by reacting 3, 5-diaryl-1- thiocarbamoyl-/or 3, 5- diaryl- 1- carbamoyl- D2- pyrazolines with substituted phenacyl bromide in ethanol. The structures of the synthesized derivatives were confirmed by IR, 1H-NMR, 13C-NMR as well as EIMS spectral data. Some of these derivatives were screened for their antimicrobial activity against Gram-positive, Gram- negative and pathogenic fungi, and showed a significant activity.
Keywords:
D2-pynazolines, Thiazoles, Oxazoles, Synthesis, |
Antimicrobial activity
INTRODUCTION: Heterocyclic compounds have played an invaluable role in pharmaceutical and agrochemical discovery processes. In recent years a substantial number of substituted pyrazolines have been reported to possess various pharmacological activities such as antimicrobial 1-3, anti-inflammatory 4, antihypertensive 5, antiamoebic 6, 7, antimycobacterial 8, 9, antitumor 10, antidepressant 11 and antidiabetic 12, and since the combat against bacterial infections has resulted in the development of a wide variety of antibiotics, therefore, recent efforts have been directed toward exploring novel antibacterial agents 13.
Apart from this, during the past 20 years an increase of invasive fungal infections has been observed, particularly in immunosuppressed patients, which are now, cause of morbidity and mortality. Since the discovery of amphotericin B a number of different classes of antifungal agents have been discovered, however, there is still a critical need for new antifungal agents to treat life threatening invasive mycoses 14.
In order to overcome the rapid development of drug resistance, new agents should preferably consist of chemical characteristics that clearly differ from those existing agents. Certain small heterocyclic molecules act as highly functionalized scaffolds and are known pharmacophores of a number of biologically active and medicinally useful molecules 15, 16. Electron-rich nitrogen heterocycles play an important role in diverse biological activities. Second nitrogen in the five membered rings also influences the antibacterial or pharmacokinetic properties 17-19.
On the other hand, sulphur and/or nitrogen heterocycles that possess pharmaceutical activities widely occur in nature in the form of alkaloids, vitamins, pigments and as constituents of plant and animal cells. Penicillins containing a thiazole ring system (thiazolidine) 20 are also important naturally occurring products. Thiazoles and their derivatives are found to be associated with various biological activities such as antimicrobial 21, 22, antituberculosis 23, and anti-HIV 24 activities.
In the interest of the above suggestion, the present investigation was planned to synthesize a system that combines together two biolabile components that are 2-pyrazolines and thiazoles or oxazole, to give a compact structure like the title compounds.
Chemistry: The synthetic routes of 1-(4-aryl-2-thiazolyl)-3, 5-diaryl pyrazolines (6a-i) and 1-(4-aryl-2-oxazolyl)-3, 5-diaryl pyrazolines (8a-f) are outlined in schemes 1, 2 and 3.
SCHEME 1
In the present work, 1-phenyl-1-(4-bromophenyl), 1-(2-thienyl) and 1-(4-pyridyl)-3-aryl-2-propen-1-ones (3a-e) were prepared by reacting acetophenone, 4-bromoacetophenone, 2-acetylthiophene and/or 4-acetylpyridine (1a-d) with aromatic aldehydes namely, benzaldehyde, 4-chlorobenzaldehyde and/or 4-nitrobenzaldehyde (2a-c) according to the method described in the literature 25, They were then subjected to reaction with thiosemicarbazide and/or semicarbazide followed by reaction with phenacyl bromide derivative (5a-d) to give the corresponding 2-thiazolyl- and 2-oxazolyl-pyrazoline derivatives (6a-i) and (8a-f), respectively.
RESULTS, DISCUSSION AND CONCLUSION: In the present investigation a series of 9 and 6 new compounds were prepared. Thus, starting with 1, 3-(diphenyl)-, 1-(4-bromophenyl)-3-(phenyl)-, 1-(4-bromophenyl)-3-(4-chlorophenyl), 1-(2-thienyl)-3-(4-chlo-rophenyl)-and/or-1-(4-pyridyl)-3-(4-nitrophenyl)-2-propen-1-ones (3a-e) prepared according to the literature 25 were cyclized to the corresponding 3, 5-diaryl- 1- thiocarbamoyl- 2- pyrazolines (4a-e) by treatment with thiosemicarbazide in boiling ethanol containing aqueous NaOH. Treatment of (4a-e) with phenacylbromide derivatives (5a, b) in boiling ethanol affected cyclization to the corresponding title compounds (6a-i), respectively (c.f. Scheme 2)
SCHEME 1
The presence of a strong electron withdrawing group at the para position of the phenacyl bromide such as Br played an important role in the thiazole formation since it appears to increase its polar character and therefore its tendency to undergo cyclocondensation in the para position of the benzene ring since it enhances the reaction to the forward and so gave higher yield compared to other derivative which didn’t contain it (c.f. Tables 1, 2). In a similar manner, the interaction of 1, 3-diaryl-propen-1-one (3a-e) with semicarbazide in ethanolic NaOH gave the corresponding 3, 5-diaryl-1-carbamoyl-2-pyrazolines (7a-d). Compounds (8a-f) were obtained by reacting compounds (7a-d) with phenacylbromide derivatives (5c, d) in boiling ethanol (Scheme 3).
SCHEME 2
On the other hand, the presence of an electron-releasing group at the para position of the phenacyl bromide derivative such as –OCH3, in (5c) and a strong electron-withdrawing group such as Br in the para position in (5d) affected strongly the cyclization of 1-carbamoyl-3, 5-diaryl-2 pyrazolines (7a-f) as the yields of the formed oxazoles (8a-e) differ completely than the oxazoles (8b-d, 8f) (c.f. Table 2).
* Where EtOH = absolute ethanol; AcOH = acetic acid and P.E. = Petroleum ether (B.P. 60-80°C)
The structures of compounds (6a-i) and (8a-f) were confirmed by their IR, 1H-NMR, 13C-NMR and EIMS spectral data (c.f. Tables 2). The IR spectra of (6a-i) has shown strong absorption bands at the region 1591-1623cm-1 for uC=N, at the region 1061-1071cm-1 for uC=N–N–C and at the region 1100-1159cm-1 for uN=C–X (X=S).
The IR spectra of (8a-f) has shown characteristic absorption bands in the region 1601-1623cm–1 for uC=N, at the region 1069-1073cm–1 for uC=N–N–C and at the region 1097-1176 for uC–C–X (X=O).
The 1H–NMR spectra of compounds (6a-i) have shown the CH2 protons of the pyrazoline ring resonated as a pair of doublets of doublets at the region d2.8-3.76ppm (Hb), the CH (Hx) proton appeared as a doublet of doublets at the region d3.25-3.96ppm due to vicinal coupling with the two magnetically non-equivalent protons of the methylene group at position 4 of the pyrazoline ring (Jab = 17.1-17.6 Hz, Jax = 7.0-7.5 H2 and Jbx=12.0-12.1 Hz). The H5-proton of the thiazole and/or the oxazole is observed as a singlet between d6.7-6.89ppm.
All the other aromatic and aliphatic protons were observed at the expected regions. The 13C–NMR chemical shift values of the carbon atoms were measured at d42.25-44.93ppm. (C–4), at d62.96-66.29ppm (C–5), at the region d50.79-152.96ppm (C–3), which supported the D2-pyrazoline character confirmed by the 1H–NMR data (c.f. Table 2). The EIMS spectra of the prepared compounds (6a–i) were also in agreement with the proposed structures. The analytical as well as physical and spectral data of compounds (6a-i) and compounds (8a-f) which confirmed the structure of these compounds are listed in Table 1, 2.
TABLE 1: PHYSICAL DATA OF THE THIAZOLYLPYRAZOLINES (6a-i) AND OXAZOLYLPYRAZOLINES (8a-f)
Compd. No | IR u Cm-1 | 1H-NMR d ppm | 13C NMR d ppm | Ms m/z (%) |
6a | 2928,2826 (uCH), 1623(uC=N), 1061(C–N) | 2.23 (dd, 1H), 2.91 (dd, 1H),
3.25 (dd, 1H), 6.70(s, 1H, CH), 6.95–7.61 (m, 15H, Ar–H) |
40.72(CH2), 66.1(CH), 1017(CH), 126.8(2CH), 127.0(2CH), 128.6(2CH), 128.9(2CH), 129.2(2CH), 131.1(CH), 134.0(CH), 143.5(C), 151.8(C), 173(C). | 382(2.7), 381(17.2), 221(8.7), 215(12.7), 201(33.1), 174(4.9), 161(23.7), 130(19.2), 103(11.4), 77(100), 72(59.3), 67(37.1), 59(19.2), 58(13.4), 54(12.2). |
6b | 3010,2928,2880(uCH),
1619(uC=N), 1069(C–N), 529(C–Br). |
2.81 (dd, 1H), 3.12 (dd, 1H), 3.91 (dd, 1H), 6.72 (s, 1H, CH) 7.08-7.59( m,14H,Ar–H) | 462(1.8), 461(17.3), 460(22.1), 446(19.7), 384(11.3), 366(7.1), 306(1.1), 304(15.2), 303(12.9), 290(25.3), 277(61.1), 234(1.7) 226(33.7), 215(16.3)156(100), 151(23.1), 83(16.3), 67(11.1), 77(51.9), 76(2.1). | |
6c | 3030,2967,2889(uC–H),
1615(uC=N), 1071(C–N), 518(uC–Br). |
2.89(dd,1H), 3.39(dd, 1H), 3.95(dd,1H), 6.80 (s, 1H, CH),7.19-8.13 (m,13H,Ar–H) | 42.6(CH2), 67.3(CH), 102.1(CH), 119.3(CH), 125.4(2CH), 128.2 (2CH), 128.7(CH), 131.4(CH), 131.8(2CH), 132.3(CH), 1331.0(CH), 143.5(C), 151.8(C), 173.2(C). | |
6d | 3010, 2922, 2886(uCH), 1619(uC=N), 1061(C–N), 879(uC–Cl), 519((uC–Br). | 2.81(dd, 1H), 3.15(dd, 1H), 3.90(dd, 1H), 3.90 (dd, 1H) 6.81 (s, 1H, CH), 7.02-7.89 (m, 13H, Ar–H) | 497(1.1), 496(12.9), 495(13.3), 458(21.3), 414(53.1), 379(50.3),339(37.2),327(18.2), 326(35.1),313(12.6), 238(27.4), 225(21.5), 223(14.3), 211(1.6), 201(19.6), 179(22.2), 161(89.1),156(89.1),151(43.3), 145(16.1), 143(1.1), 112(7.1), 76(23.3), 68(100), 55(56.1). | |
6e | 3053, 2986, 2822(uCH), 1618(uC=N), 1071(C–N), 881(uC–Cl), 529(uC–Br). | 3.32(dd, 1H), 3.76(dd, 1H), 3.96(dd, 1H), 6.89(s, 1HCH) 7.03-8.12 (m, 12H, Ar–H). | ||
6f | 3003, 2928, 2826(uCH), 1601(uC=N), 1069(C–N), 872(uC–Cl). | 2.80(dd, 1H), 3.12(dd, 1H), 3.90 (dd, 1H), 6.82 (s, 1H, CH), 7.06-7.28 (m, 12H, Ar–H). | 37.8(CH2), 66.9(CH), 103.2 (CH), 117(2CH), 122.3 (2CH), 128.4(2CH), 128.7(2CH), 137(CH), 139.0(C), 141.6(C), 149.4(C), 173.2(C). | |
6g | 2986, 2886, 2828(uCH), 3.19, 1591(uC=N), 1071 (C–N), 867(uC–Cl), 528 (uC–Br). | |||
8a
|
3030,2928,2828 (uCH),1601(uC=N), 1027(uO–C–N) | 3.07 (dd, 1H), 3.41 (s,3H,Ar-OCH3, 1H), 3.81 (dd, 1H), 5.4 (dd, 1H), 6.13(s,1H,CH),7.01–7.85 (m,14H,Ar–H) | 40.37(CH2), 68.1(CH), 104.1(CH), 111.8(2CH), 121.9(2CH), 128.4(2CH), 128.7(2CH), 137.8(CH), 39.9(H), 142.7(H), 153.7(C), 174.1(C).
|
395(18.1), 396(3.3), 397(1.2), 263(19.1), 185(23.3), 109(50.1), 108(23.1), 107(16.5), 106(27.2), 94(17.9), 83(17.3), 77(100), 67(7.1), 53(14.9).
|
8b | 3010, 2928, 2818(uCH), 1619(uC=N), 1072(uO–C–N).
|
3.08 (dd, 1H), 3.82 (dd, 1H),
5.45 (dd, 1H), 6.76 (s, 1H, CH), 7.15-7.91(m,14H,Ar–H) |
||
8c | 3008,2928,2828(uC–H),1622 (uC=N),1076(uO–C–N),
|
3.21(dd,1H), 3.84(dd,1H),
5.45(dd,1H), 6.76(s,1H,CH), 7.19-7.85(m, 13H, Ar–H) |
523(11.1),524(7.7),525(1.4),342(19.3)278 (11.2),272(12.1),264(1.3),224(11.3)197(35.4),135(20.9),123(11.1),109(71.3),83(100),77(55.1),76(24.9),69(13.9),67(1.3). | |
8d | 3055, 2928, 2818 (uCH), 1623(uC=N), 1176(uO–C–N).
|
3.08(dd,1H), 3.80(dd, 1H),
5.41(dd,1H), 6.65(s, 1H, CH), 7.09-7.89 (m, 11H, Ar–H) |
44.3(CH2), 69.01(CH), 114.3 (CH), 118.7(2CH), 121.9(2CH), 128.7(2CH), 129.1(2C), 137.9 (CH), 141.1(C), 142.7(C), 154.3(C), 163.9(C), 174.9(C). | |
8e | 308653, 2928, 28282uCH), 1619(uC=N), 1648(uNO2), 1068(uO–C–N). | 3.07(dd,1H),3.43(s,3H,ArOCH3),
3.82(dd, 1H), 6.39(dd, 1H), 6.79-7.80(m, 12,Ar-H). |
441(17.1), 442(9.7), 443(3.2), 425(11.1), 409(17.2), 355(23.1), 324(14.2), 318(19.2),313(2.4), 266(21.3), 251(20.4), 249(15.3), 212(11.3), 185(30.4), 159(1.3), 145(17.9), 118(12.3), 90(15.4), 79(58.1), 77(20.3), 76(12.9), 68(11.1), 66(100), 51(98.1)
|
|
8f | 3065, 2928, 2828(uCH), 1622 (uC=N), 1660 (uNO2), 1080((uO–C–N). | 3.10(dd, 1H), 3.81(dd, 1H), 5.43 (dd, 1H), 6.67 (s, 1H, CH), 7.04-7.80 (m, 12H, Ar–H). | 37.9(CH2), 66.7(CH), 103.9(CH), 114.7(2CH), 118.1(2CH), 121.4 (2CH), 127.9(2CH), 129.4 (CH), 131.3(CH), 133.4(C), 139.1(C), 141.3(C).151.1(C), 163.2(C).
|
TABLE 2: IR; 1H–NMR; 13CNMR AND MS OF THIAZOLYL- AND/OR OXAZOLYL-PYRAZOLINES (6a-i) AND (8a-f)
Antimicrobial Activity:
Biology: The new compounds (6a-i) and (8a-f) were screened for their antibacterial activity by disk-diffusion technique(26) against two Gram – positive bacteria namely, Staphylococcus aureus and Pseudomonas aeruginosa, two Gram-negative bacteria namely, Bacillus subtillis and Escherichia coli and four pathogenic fungi namely, Syncephalastrum racemosum, Aspergillus fumigatus, Candida albicans and Geotrichum candidum at three concentrations 5,2.5 and 1.25µg/ml. Chloramphenicol was used as standard antibacterial agent and fluconazole was used as standard antifungal agent. The minimal inhibitory concentrations (MIC) of the compounds are listed in Table 3.
MIC'S were recorded as the minimum concentration of a compound that inhibits the growth of tested microorganisms. All of the compounds tested have shown significant antibacterial and antifungal activity as compared with the reference drugs. The antibacterial assessment revealed that most of the tested compounds possess weak to moderate activity. The MIC values are generally within the range 3.9-250µg/ml against all the tested strains.
In comparing the MIC values with the references chloramphenicol, it is obvious that most of the compounds are effective against P. aeruginosa, A. fumigatus, C. albicans and G. eandidum. Compound 6a has shown a relatively high activity against S. aureus, P. aeruginosa, S. racemosum, A. fumigatus and B. subtilis. Compounds 6d were highly active against S. aureus, B. subtilis, P. aeruginosa, S. racemosum and A. fumigatus.
Compounds 6a-i and 8a-f have shown no activity towards E. coli. Compound 6a has shown the highest activity towards E.coli. Compound 6a has shown the highest activity towards S. aureus as compared to the references, while the activity of compounds 8a was the same as the references chloramphenicol.
Compounds 6a, 6d have shown the same moderate activity against B. subtilis. Compound 6i has shown the highest activity towards P. aeruginosa, while compounds 6b-e, 8a and 8d have shown the same moderate activity and compound 6a showed the same activity as the standard reference. Compound 6a, 8a, have shown the same activity against S. racemosum and A. fumigatus, while compounds 6d, 8b-d have shown the same moderate activity. Compounds 6c, 8a-d have shown high activity towards C. albicans, while compounds 6c,d and 8a-d have shown the same high level of activity towards G. eandidum (c.f. Table 3). The results are summarized in Table 3. Most of the compounds have shown good antifungal activity, when compared to Fluconazole, 4 compounds were more active (MIC < 250µg/ml).
TABLE 3: MIC VALUES (mg/ml) OF COMPOUND 6a-i AND 8a-f.
Compound | A | B | C | D | E | F | G | H |
6a | 250 | 15.6 | 62.5 | 31.25 | 31.25 | 31.25 | 250 | 250 |
6b | 250 | 125 | 125 | 62.5 | 250 | 125 | 125 | 125 |
6c | 125 | 125 | 125 | 62.5 | 250 | 125 | 62.5 | 62.5 |
6d | 125 | 62.5 | 62.5 | 62.5 | 62.5 | 62.5 | 125 | 62.5 |
6e | 125 | 125 | 125 | 62.5 | 250 | 125 | 125 | 125 |
6f | 250 | 125 | 250 | 250 | 250 | 250 | 250 | 250 |
6g | 250 | 125 | 125 | 125 | 250 | 250 | 125 | 125 |
6h | 250 | 250 | 125 | 250 | 250 | 125 | 125 | 125 |
6i | 250 | 250 | 250 | 3.9 | 125 | 250 | 250 | 250 |
8a | 250 | 31.25 | 125 | 62.5 | 125 | 31.25 | 62.5 | 62.5 |
8b | 125 | 250 | 125 | 125 | 250 | 62.5 | 62.5 | 62.5 |
8c | 125 | 250 | 125 | 125 | 250 | 62.5 | 62.5 | 62.5 |
8d | 125 | 125 | 125 | 62.5 | 250 | 62.5 | 62.5 | 62.5 |
8e | 125 | 250 | 250 | 250 | 250 | 125 | 125 | 125 |
8f | 125 | 250 | 250 | 250 | 500 | 125 | 125 | 125 |
Reference-1 | 15.60 | 31.25 | 31.25 | 31.25 | –– | –– | –– | –– |
Reference-2 | –– | –– | –– | –– | 250 | 125 | 250 | 250 |
Reference 1: Chloramphenicol, Reference-2 fluconazole where:
A: Escherichia coli (RCMB 000103), B: Staphylococcus aureus (RCMB 000106), C: Bacillus subtilis (RCMB 000107), D: Pseudomonas aeruginosa (RCMB 000102), E: Syncephalastrum racemosum (RCMB 005003), F: Aspergillus fumigatus (RCMB 002003), G: Candida albicans (RCMB 005002), H: Geotrichum eandidum.
Experimental:
Chemistry: Melting points were determined by using Gallen camp digital meeting point apparatus in capillary tubes and were uncorrected. 1H-NMR and 13C NMR spectra (DMSO-d4) using TMS as internal standard were recorded at 400 and 1000 MHZ with a Bruker apparatus. MS spectra were performed with apparatus Jeol JMS-D300 at 70eV.
General procedure for the synthesis of the compounds:
1, 3-diaryl-2-propen-1-ones(3a-e): A mixture of acetophenone, 4-bromoacetophenon,2-acetyl-thiophene and/or 4-acetyl pyridine (0.02mol) (1a-d), aromatic aldehyde namely, benzaldehyde, 4-chlorobenzaldehyde and/or 4-nitrobenzaldehyde (0.02 mol) (2a-c) and 10% aqueous sodium hydroxide (10 ml) in ethanol (30ml) was stirred while cooling (0-5ºC) for 3h; The resulting solid was collected, washed well and recrystallized from ethanol as 3a-e 25.
1, 4- diaryl- 1- thiocarbamoyl- or- carbamoyl- 2-pyrazolines (4a-e) and (7a-d): A mixture of 1,3-diaryl-2-propen-1-one derivatives (3a-e) (0.01mol), aqueous sodium hydroxide [(1g, 0.025mol), dissolved in 1m1 of water] in 30ml of absolute ethanol and thiosemicarbazide (0.01 mol, 0.9g)/or semicarbazide (0.01mol, 0.7g) was refluxed for 6h. The product was poured into cold water and the solid product was collected, washed well and recrystallized from the proper solvent as 4a-e and 7a-d.
1-(4-aryl-2-thiazolyl)-3, 5-diaryl-2-pyrazolines (6a-i): A mixture of 4a-e (0.01mol), phenacylbromide derivatives (5a, b) (0.01mol) in 25ml of absolute ethanol was heated under reflux for 3h. The product that separated after concentration and cooling was collected and recrystallized from the proper solvent as (6a-i).
1-(4-aryl-2-oxazolyl)-3, 5-diaryl-2-pyrazolines (8a-f): A mixture of 7a-d (0.01mol), phenacylbromide derivatives (5c, b) (0.01mol) in 25ml of absolute ethanol was heated under reflux for 3h and the products were treated as above to give (8a-f).
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Article Information
20
2368-2375
707
1033
English
Ijpsr
Nadia T. A. Dawood
Chemistry Department, Faculty of Science, Girl's, Al-Azhar University, Nasr City, Cairo, Egypt
20 May, 2011
21 August, 2011
23 August, 2011
http://dx.doi.org/10.13040/IJPSR.0975-8232.2(9).2368-75
01 September, 2011