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Arch. Pharm. Chem. Life Sci. 2013, 346, 860–864
Full Paper Facile Regioselective Synthesis of Novel bis-Thiazole Derivatives and Their Antimicrobial Activity Nosrat O. Mahmoodi1, Jafar Parvizi2, Bahman Sharifzadeh1, and Mehdi Rassa3 1 2 3
Faculty of Sciences, Department of Organic Chemistry, University of Guilan, Rasht, Iran Chemistry Department, Islamic Azad University, Rasht Branch, Iran Faculty of Sciences, Department of Biology, University of Guilan, Rasht, Iran
The design and synthesis of several new bis-thiazoles 4a–h serving as bis-drugs in comparison with monoheterocyclic analogs are described. These bis-drugs present superior medicinal and pharmacological activities against both gram-negative (Pseudomonas aeruginosa and Escherichia coli) and gram-positive (Micrococcus luteus and Bacillus subtilis) bacteria, which are in general more sensitive to compounds with higher hydrophobicity. Compounds with higher hydrophobicity (4d and 4h) exhibited some activity against the gram-negative bacteria. Keywords: Aminothiazole / Antibacterial / bis-Drugs / Regioselectivity Received: May 19, 2013; Revised: August 20, 2013; Accepted: August 29, 2013 DOI 10.1002/ardp.201300187
Introduction Thiazole and its derivatives are very helpful in various fields of organic chemistry, medicine, agriculture, and structure of natural compounds, and are used as an intermediate for synthetic drugs, fungicides, and dyes [1]. Substituted groups like NH2 have very important function in a multitude of these properties, as heretofore many biological activities of aminothiazoles have been well recognized [2]. They have broad application in the treatment of bacterial infections [3], schizophrenia [4], hypertension [5], allergies [6], inflammation [7], and HIV [8]. Recently they have been utilized for the treatment of pain [9], as fibrinogen receptor antagonists with anti-thrombotic activity [10], ligands of estrogen receptors [11], and as a novel class of adenosine receptor antagonists [12], with antitumor and cytotoxic activity [13]. In contribution to our previous design and synthesis of bisintelligent heterocyclic compounds [14–21], here we report the synthesis of bis-thiazoles competent serving as bis-drugs. The reports describing some bis-heterocyclic compounds being compared with their mono-heterocyclic analogs, which
Correspondence: Nosrat Ollah Mahmoodi, Faculty of Sciences, Department of Organic Chemistry, University of Guilan, PO Box 41335-1914, Rasht, Iran. E-mail: [email protected], [email protected] Fax: þ981313233262
ß 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
present superior medicinal and pharmacological activities [22], prompted us to design and synthesize bis-thiazoles 4a–h. The structural evaluations, properties, and synthetic routes toward bis-thiazoles have been reported in limited sources [23, 24].
Results and discussion Chemistry Synthetic efforts toward bis-acetophenones 3a–h commenced with exploration of SN2 reaction of 2 equiv. hydroxy acetophenones with 1 equiv. dihaloalkane or dihalobenzyl in DMF using K2CO3 as catalyst (Scheme 1). The formation of bis-phenacylbromides was confirmed by the change of a red solution to yellow. The thiazole formation is followed by nucleophilic substitution of boromines prepared in situ by S-atom of thiourea, and subsequently cyclocondensation and H2O elimination led to the target compounds 4a–h (Scheme 1). The literature shows that bis-thiazoles 4a–h have not been reported previously. All of the new compounds have been characterized by IR, 1H NMR, 13C NMR, and elemental analyses. The IR spectra of bis-thiazole derivatives 4a–h revealed the presence of stretching vibration for amine bands at n ¼ 3482–3123 cm1, absorption bands in the region of 1509–1610 cm1 corresponding to C –– N attributable to the ring closure, and bands in the regions of 1355–1365 and
Arch. Pharm. Chem. Life Sci. 2013, 346, 860–864
COCH3 Y Y = Cl, Br
Y+
2
R2
Antimicrobial Activity of New bis-Thiazoles
O
K2CO3 DMF
R1 1) R1 = OH, R2 = H
H3COC
O 3a_3d
= (CH2)4
3b, 3f, 4b & 4f ;
= (CH2)5
3c, 3g, 4c & 4g ; 3d, 3h, 4d & 4h ;
O
COCH3
3e_3h
2) Thiourea / EtOH - Reflux
O
= (CH2)6 =
O
1) Br2 / CHCl3
2) R1 = H, R2 = OH
3a, 3e, 4a & 4e ;
H3COC + COCH3
861
S H2N
O
H2N S
N
4a_4d
N
+
S N
O
NH2
O
S N
NH2
4e_4h
Scheme 1. Process of synthesis of bis-thiazoles 4a–h.
1055–1096 cm1, which indicate the presence of C–S and C–N groups. The 1H NMR spectra of bis-thiazoles 4a–h showed a sharp singlet at d 7–8 ppm due to the protons of thiazole rings and sharp singlets at d 9.6 and 10.4 due to the NH2 protons. The etheric –OCH2 protons demonstrate signals at d 4.0–4.5 ppm as triplet. Regarding compounds 4d and 4h, etheric –OCH2 protons appeared as signals at d 4.8–5.5 ppm. Protons of the aromatic ring (HC –– CH) and aliphatic linkages (CH2) were observed within the expected chemical shift regions and exhibited the expected integral values. The 13C NMR spectra of bis-thiazoles 4a–h showed signals at 169.2–170.8 ppm assigned to C2 of the thiazole rings. C4 of these rings displayed a signal at 158–160 ppm for all of the compounds. The signals due to the aromatic and aliphatic carbon groups resonate at their usual positions (see Experimental section).
Antibacterial activity The biological activity of 4a–h against four bacteria was determined using the minimum inhibitory concentration (MIC) method. The bacteria used were Pseudomonas aeruginosa (Psa) and Escherichia coli (Ec) as gram-negative, and Micrococcus luteus (Ml) and Bacillus subtilis (Bs) as gram-positive. The results of antibacterial MIC assays are shown in Table 1, M. luteus was sensitive to all of the synthesized compounds at very low concentrations, with MIC being between 0.93 and 1.87 mg/mL. B. subtilis was sensitive to most but not all of the compounds, although at several-fold higher concentrations, between 7.5 and 15 mg/mL. It may be significant that both these bacteria are gram-positive. E. coli was less sensitive compared to the first two bacteria, with MIC being exhibited only between 15 and 60 mg/mL. P. aeruginosa was the most resistant bacterium, with MIC being shown by compounds 4d, ß 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
4e, and 4h, only at very high concentrations (60 mg/mL). It can be argued that both gram-negative (Psa and Ec) and grampositive bacteria were more sensitive to compounds with higher hydrophobicity. In addition, compounds with higher hydrophobicity (4d and 4h) exhibited some antibacterial activity toward the gram-negatives, which is in accordance with their higher cell wall lipid content. For comparison, tetracycline was used as a positive control and DMSO as a negative control.
Experimental 1
H NMR (400 MHz) and 13C NMR (100 MHz) spectra were run with a Bruker 400 DRX-Avance NMR spectrometer. The compounds were diluted in deuterated DMSO as solvent, and the solvent is indicated for each compound. The IR data were obtained with a Shimadzu 470 spectrometer. Melting points of crystalline compounds were measured with an electrothermal melting point apparatus and have not been corrected. The purification of crystalline compounds was performed by recrystallization. All chemicals were purchased from Aldrich Chemical Company, Merck, and Fluka. Tetracycline was used as a positive control and DMSO as a negative control.
General procedure for the synthesis of bis-thiazoles The bis-acetophenones 3a–h was prepared according to a standard procedure [11]. In 5 mL of CHCl3, bis-acetophenones 3a–h (1 mmol) were dissolved. Then, 5 mL of bromine–CHCl3 (2%) was added dropwise to bis-acetophenones solution, while stirring at RT. After 5–10 min, the bromine color was discharged and a yellow solution remained. At this point, an additional 0.5–1 mL of the bromine–CHCl3 solution was added. When the bromine color remained for longer than 30 min, the completion of the reaction was monitored through thin-layer chromatography (TLC), and the solution was evaporated under vacuum. The white solid bisphenacyl bromide was purified by washing with cooled EtOH solution. To these solids thiouria (2 mmol) and dry EtOH were added and refluxed for the required reaction time (about 6 h). The www.archpharm.com
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Arch. Pharm. Chem. Life Sci. 2013, 346, 860–864
Table 1. Results of antibacterial screening of compounds expressed as MIC (mg/mL). Minimum inhibitory concentration (mg/mL) Entry
Compound O S
4a
N
N
N
N
S
N
N
7.5
60
1.87
–
–
60
0.93
–
7.5
30
0.93
60
7.5
15
1.78
60
–
–
0.93
–
15
–
0.93
–
7.5
30
0.93
60
7.5
15
– 5
– 23
– 16
– 18
NH2
S
S
O
N
H2N
–
O
H2N
4d
1.87
NH2 O
S
Ec
O
H2N
4c
Bs
NH2
S O
S
Psa
O
H2N
4b
Ml
S
O
N
NH2
S
4e
H 2N
O
N
N
O
S
4f
O
S
O N
N
H2N
NH2
S NH2
S H2N
4g
O
N
O N
O
4h
NH2
O
N H2N
N S
S
S
NH2
DMSO Tetracycline
progress of reaction was monitored by TLC (EtOAc/n-hexane 1:3). After completion, the reaction solution was cooled to RT. The precipitate was filtered out and purified by washing with EtOH several times.
General procedure for in vitro antibacterial evaluation of compounds 4a–h expressed as MIC (mg/mL) The isolates were grown either in 3 mL of nutrient broth (Merck) or overnight at 37°C on nutrient agar plates (Merck). ß 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
To test the sensitivity of the bacteria to different compounds, each compound, dissolved in DMSO, was added to the molten nutrient agar at a certain concentration, and after the plates had solidified, 50 mg/L of bacterial suspension in nutrient broth was added to the plate. The inoculum was evenly spread on the agar surface using a sterile spreader and left at 37°C overnight. If bacterial growth was present, the experiment was repeated, but with double the concentration of the test compound, until the MIC was observed. If there was no bacterial growth, the www.archpharm.com
Arch. Pharm. Chem. Life Sci. 2013, 346, 860–864
concentration of the compound was halved till the MIC was observed.
4,4 0 -((Butane-1,4-diylbis(oxy))bis(4,1-phenylene))bis(thiazol-2-amine) (4a) Yield: 72%; m.p.: 231–234°C, FT-IR (KBr): 3379, 3271 (N–H stretch), 3080 (aromatic C–H stretch), 2937, 2866 (aliphatic C–H stretch), 1625 (C –– N stretch), 1606, 1577, 1510 (aromatic C–C stretch), 1469 (C–H bending, CH2), 1251, 1012 (C–O stretch), 1186 (C–N stretch), 833 (aromatic C–H out of plane bending) cm1. 1 H NMR (400 MHz, DMSO-d6): d 7.93 (d, J ¼ 8.8 Hz, 2H), 7.71 (d, J ¼ 8.8 Hz, 2H), 7.04 (dd, J ¼ 8.8, 1.6 Hz, 2H), 6.98 (s, 1H), 6.93 (d, J ¼ 8.8 Hz, 2H,), 6.83 (s, 1H,), 4.19 (s, 2H), 4.06 (s, 2H), 1.92 (s, 2H), 1.90 (s, 2H) ppm. 13C NMR (100 MHz, DMSO-d6): d 170.3, 163.0, 159.8, 131.1, 127.3, 114.9, 103.3, 68.0, 26.3 ppm. Anal. calcd. for C22H22N4O2S2: C, 60.25; H, 5.06; N, 12.78. Found: C, 60.23; H, 5.04; N, 12.77.
4,4 0 -((Pentane-1,5-diylbis(oxy))bis(4,1-phenylene))bis(thiazol-2-amine) (4b) Yield: 80%; m.p.: 229–232°C, FT-IR (KBr): 3363, 3267 (N–H stretch), 3109 (aromatic C–H stretch), 2939, 2884 (aliphatic C–H stretch), 1625 (C –– N stretch), 1577, 1539, 1506 (aromatic C–C stretch), 1463 (C–H bending, CH2), 1255 (C–O stretch), 1182 (C–N stretch), 831 (aromatic C–H out of plane bending) cm1. 1H NMR (400 MHz, DMSO-d6): d 7.72 (d, J ¼ 8.4 Hz, 1H), 7.65 (d, J ¼ 8.8 Hz, 3H), 7.20 (d, J ¼ 8.8 Hz, 1H), 7.12 (s, 1H), 7.06–7.02 (m, 3H), 4.15–4.02 (m, 4H), 1.83 (m, 4H), 1.65–1.59 (m, 2H) ppm. 13C NMR (100 MHz, DMSO-d6): d 170.3, 159.8, 150.0, 130.4, 127.7, 114.3, 109.8, 68.07, 28.6, 22.5 ppm. Anal. calcd. for C23H24N4O2S2: C, 61.04; H, 5.35; N, 12.38. Found: C, 61.03; H, 5.34; N, 12.37.
4,4 0 -((Hexane-1,6-diylbis(oxy))bis(4,1-phenylene))bis(thiazol-2-amine) (4c) Yield: 80%; m.p.: 230–232°C, FT-IR (KBr): 3379, 3271 (N–H stretch), 3080 (aromatic C–H stretch), 2937, 2866 (aliphatic C–H stretch), 1625 (C –– N stretch), 1606, 1577, 1510 (aromatic C–C stretch), 1469 (C–H bending, CH2), 1251, 1012 (C–O stretch), 1186 (C–N stretch), 833 (aromatic C–H out of plane bending) cm1. 1H NMR (400 MHz, DMSO-d6): d 7.92 (d, J ¼ 8.8 Hz) and 7.65 (d, J ¼ 8.6, 2.2 Hz), 7.07–7.01 (m, 6H), 4.09–4.02 (m, 4H), 1.76 (s, 4H), 1.49 (s, 4H) ppm. 13 C NMR (100 MHz, DMSO-d6): d 169.4, 162.5, 152.0, 130.9, 129.4, 115.1, 90, 69.6, 26.9, 14.5 ppm. Anal. calcd. for C24H26N4O2S2: C, 61.78; H, 5.62; N, 12.01. Found: C, 61.75; H, 5.61; N, 12.01.
4,4 0 -(((1,4-Phenylenebis(methylene))bis(oxy))bis(4,1-phenylene))bis(thiazol-2-amine) (4d) Yield: 78%; m.p.: 232–234°C, FT-IR (KBr): 3421, 3330 (N–H stretch), 3068 (aromatic C–H stretch), 2921, 2866 (aliphatic C–H stretch), 1674 (C –– N stretch), 1600, 1508 (aromatic C–C stretch), 1467 (C–H bending, CH2), 1249, 1045 (C–O stretch), 1172 (C–N stretch), 825 (aromatic C–H out of plane bending) cm1. 1H NMR (400 MHz, DMSO-d6): d 9.29, 9.08, 8.53, 8.33 (s, 4H), 7.93 (d, J ¼ 8.4 Hz), 7.58 (s, 1H), 7.62–7.40 (m, 7H), 7.12 (d, J ¼ 8.4 Hz, 3H), 6.87 (s, 1H) ppm. 13 C NMR (100 MHz, DMSO-d6): d 170.6, 163.0, 159.9, 139.6, 130.9, 130.1, 127.7, 121.7, 115.3, 114.7, 100.9, 68.2 ppm. Anal. calcd. for C26H22N4O2S2: C, 64.18; H, 4.56; N, 11.51. Found: C, 64.16; H, 4.55; N, 11.50. ß 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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863
4,4 0 -((Butane-1,4-diylbis(oxy))bis(3,1-phenylene))bis(thiazol-2-amine) (4e) Yield: 78%; m.p.: 229–231°C, FT-IR (KBr): 3440, 3274 (N–H stretch), 3109 (aromatic C–H stretch), 2923, 2854 (aliphatic C–H stretch), 1635 (C –– N stretch), 1558 (aromatic C–C stretch), 1471 (C–H bending, CH2), 1232, 1035 (C–O stretch), 1174 (C–N stretch), 854, 811, 740 (aromatic C–H out of plane bending) cm1. 1H NMR (400 MHz, DMSO-d6): d 7.65 (d, J ¼ 8.8 Hz, 2H), 7.403 (t, J ¼ 7.8 Hz, 1H), 7.30 (t, J ¼ 7.6 Hz, 1H), 7.20 (d, J ¼ 1.6 Hz, 2H), 7.07–7.02 (m, 8H) ppm. 13C NMR (100 MHz, DMSO-d6): d 169.6, 158.3, 138.0, 135.4, 134.5, 129.8, 118.3, 112.4, 107.6, 68.2, 25.6 ppm. Anal. calcd. for C22H22N4O2S2: C, 60.25; H, 5.06; N, 12.78. Found: C, 60.23; H, 5.05; N, 12.74.
4,4 0 -((Pentane-1,5-diylbis(oxy))bis(3,1-phenylene))bis(thiazol-2-amine) (4f) Yield: 80%; m.p.: 230–232°C, FT-IR (KBr): 3425, 3369 (N–H stretch), 3109 (aromatic C–H stretch), 2925, 2854 (aliphatic C–H stretch), 1633 (C –– N stretch), 1573 (aromatic C–C stretch), 1479 (C–H bending, CH2), 1232, 1035 (C–O stretch), 1174 (C–N stretch), 854, 811, 732 (aromatic C–H out of plane bending) cm1. 1H NMR (400 MHz, DMSO-d6): d 7.63 (d, J ¼ 8.8 Hz, 1H), 7.37 (t, J ¼ 8 Hz, 2H), 7.32–7.30 (m, 3H), 7.24 (s, 2H), 7.20 (d, J ¼ 2.8 Hz, 2H), 7.06–6.97 (m, 4H, He, H), 4.06 (t, J ¼ 6.4 Hz, 4H), 1.86–1.79 (m, 4H), 1.65–1.61 (m, 2H) ppm. 13C NMR (100 MHz, DMSO-d6): d 170.2, 159.4, 141.1, 134.5, 138.6, 118.3, 115.6, 112.2, 103.4, 68.1, 26.8, 22.7 ppm. Anal. calcd. for C23H24N4O2S2: C, 61.04; H, 5.35; N, 12.38. Found: C, 61.02; H, 5.33; N, 12.35.
4,4 0 -((Hexane-1,6-diylbis(oxy))bis(3,1-phenylene))bis(thiazol-2-amine) (4g) Yield: 75%; m.p.: 230–233°C, FT-IR (KBr): 3419, 3265 (N–H stretch), 3099 (aromatic C–H stretch), 2933, 2858 (aliphatic C–H stretch), 1635 (C –– N stretch), 1558, 1523 (aromatic C–C stretch), 1461 (C–H bending, CH2), 1232, 1039 (C–O stretch), 1174 (C–N stretch), 848, 810 (aromatic C–H out of plane bending) cm1. 1HNMR (400 MHz, DMSO-d6): d 7.69–7.61 (m, 4H), 7.17 (d, J ¼ 2.8 Hz, 2H), 7.08 (s, 4H), 7.06–7.02 (m, 4H), 4.02 (t, J ¼ 6.2 Hz, 4H), 1.74 (s, 4H), 1.47 (s, 4H) ppm. 13C NMR (100 MHz, DMSO-d6): d 169.7, 158.4, 137.5, 134.5, 131.4, 128.1, 118.3, 115.6, 107.7, 68.7, 28.9, 25.6 ppm. Anal. calcd. for C24H26N4O2S2: C, 61.78; H, 5.62; N, 12.01. Found: C, 61.76; H, 5.59; N, 12.01.
4,4 0 -(((1,4-Phenylenebis(methylene))bis(oxy))bis(3,1-phenylene))bis(thiazol-2-amine) (4h) Yield: 70%; m.p.: 231–234°C, FT-IR (KBr): 3313, 3176 (N–H stretch), 3068 (aromatic C–H stretch), 1625 (C –– N stretch), 1541 (aromatic C–C stretch), 1425 (C–H bending, CH2), 1242, 1076 (C–O stretch), 1145 (C–N stretch), 898, 819, 763, 671 (aromatic C–H out of plane bending) cm1. 1H NMR (400 MHz, DMSO-d6): d 8.30–6.63 (m, 18H), 4.15 (s, 4H) ppm. 13C NMR (100 MHz, DMSO-d6): d 169.3, 162.9, 159.0, 140.8, 139.6, 135.3, 129.8, 121.0, 115.3, 114.7, 100.9, 68.0 ppm. Anal. calcd. for C26H22N4O2S2: C, 64.18; H, 4.56; N, 11.51. Found: C, 64.17; H, 4.54; N, 11.50.
The partial support of this research by the Research Committee of University of Guilan is gratefully acknowledged.
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References [1] S. J. Kashyap, V. K. Garg, P. K. Sharma, N. Kumar, R. Dudhe, J. K. Gupta, Med. Chem. Res. 2012, 21, 2123–2132. [2] M. J. Gorczynski, R. M. Leal, S. L. Mooberry, J. H. Bushweller, M. L. Brown, Bioorg. Med. Chem. 2004, 12, 1029–1036. [3] K. Tsuji, H. Ishikawa, Bioorg. Med. Chem. Lett. 1994, 4, 1601–1606. [4] J. C. Jaen, L. D. Wise, B. W. Caprathe, H. Tecle, S. Bergmeier, C. C. Humblet, T. G. Effner, L. T. Meltzner, T. A. Pugsley, J. Med. Chem. 1990, 33, 311–317. [5] W. C. Patt, H. W. Hamilton, M. D. Taylor, M. J. Ryan, D. G. Taylor, Jr., C. J. C. Connolly, M. Doherty, S. R. Klutchko, I. Sircar, B. A. Steinbaugh, B. L. Batley, C. A. Painchaud, S. T. Rapundalo, B. M. Michniewicz, S. C. J. Olson, J. Med. Chem. 1992, 35, 2562–2572. [6] M. Ohkubo, A. Kuno, I. Nakanishi, H. Takasugi, Chem. Pharm. Bull. 1995, 43, 1497–1504. [7] R. N. Sharma, F. P. Xavier, K. K. Vasu, S. C. Chaturvedi, S. S. Pancholi, J. Enzyme Inhib. Med. Chem. 2009, 24, 890– 897. [8] T. K. Venkatachalam, E. A. Sudbeck, C. Mao, F. M. Uckum, Bioorg. Med. Chem. Lett. 2001, 11, 523–528. [9] K. J. Wilson, C. R. Illig, N. Subasinghe, J. B. Hoffman, M. J. Rudolph, R. Soll, C. Molloy, R. Bone, D. Green, T. Randall, M. Zhang, F. A. Lewandowski, Z. Zhou, C. Sharp, D. Maguire, B. Grasberger, R. L. DesJarlais, J. Spurlino, Bioorg. Med. Chem. Lett. 2001, 11, 915–918. [10] A. Badorc, M. F. Bordes, P. De Cointet, P. Savi, A. Bernat, A. Lale, M. Petitou, J. P. Maffrand, J. M. Herbert, J. Med. Chem. 1997, 40, 3393–3401.
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[11] B. A. Fink, D. S. Mortensen, S. R. Stauffer, Z. D. Aron, J. A. Katzenellenbogen, Chem. Biol. 1999, 6, 205–219. [12] J. E. Van Muijlwijk-Koezen, H. Timmerman, R. C. Vollinga, J. F. Von Drabbe Kunzel, M. De Groote, S. Visser, A. P. Ijzerman, J. Med. Chem. 2001, 44, 749–762. [13] E. Gulsory, N. U. Guzeldemirci, Eur. J. Med. Chem. 2007, 42, 320–326. [14] N. O. Mahmoodi, M. A. Zanjanchi, H. Kiyani, J. Chem. Res. 1997, 6, 438–440. [15] N. O. Mahmoodi, H. Kiyani, K. Tabatabaeian, M. A. Zanjanchi, M. Arvand, B. Sharifzadeh, Russ. J. Org. Chem. 2010, 46, 884– 889. [16] N. O. Mahmoodi, H. Kiyani, Bull. Korean Chem. Soc. 2004, 25, 1417–1420. [17] N. O. Mahmoodi, M. R. Yazdanbakhsh, H. Kiyani, J. Chin. Chem. Soc. 2007, 54, 635–641. [18] N. O. Mahmoodi, M. Arvand, M. Moghimi, A. Afshari, Anal. Chin. Acta 2006, 579, 102–108. [19] N. O. Mahmoodi, M. A. Zanjanchi, M. Arvand, A. Islamnezhad, Talanta 2007, 74, 125–131. [20] N. O. Mahmoodi, H. Kiyani, K. Tabatabaeian, M. A. Zanjanchi, J. Phys. Org. Chem. 2009, 22, 559–567. [21] N. O. Mahmoodi, H. Kiyani, K. Tabatabaeian, M. A. Zanjanchi, Mendeleev Commun. 2009, 19, 203–205. [22] N. O. Mahmoodi, A. Rineh, M. Abdollahi, A. Foroumadi, M. Sorkhi, A. Shafiee, Arch. Pharm. Chem. Life Sci. 2007, 340, 409–415. [23] H. T. Fahmy, A. A. Bekhit, Pharmazie 2002, 12, 800–803. [24] A. Shockravi, M. Kamali, A. Ziyaei Halimehjani, R. Jafari, J. Heterocyclic Chem. 2013, 50, 209–215.
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Arch. Pharm. Chem. Life Sci. 2013, 346, 860–864
Full Paper Facile Regioselective Synthesis of Novel bis-Thiazole Derivatives and Their Antimicrobial Activity Nosrat O. Mahmoodi1, Jafar Parvizi2, Bahman Sharifzadeh1, and Mehdi Rassa3 1 2 3
Faculty of Sciences, Department of Organic Chemistry, University of Guilan, Rasht, Iran Chemistry Department, Islamic Azad University, Rasht Branch, Iran Faculty of Sciences, Department of Biology, University of Guilan, Rasht, Iran
The design and synthesis of several new bis-thiazoles 4a–h serving as bis-drugs in comparison with monoheterocyclic analogs are described. These bis-drugs present superior medicinal and pharmacological activities against both gram-negative (Pseudomonas aeruginosa and Escherichia coli) and gram-positive (Micrococcus luteus and Bacillus subtilis) bacteria, which are in general more sensitive to compounds with higher hydrophobicity. Compounds with higher hydrophobicity (4d and 4h) exhibited some activity against the gram-negative bacteria. Keywords: Aminothiazole / Antibacterial / bis-Drugs / Regioselectivity Received: May 19, 2013; Revised: August 20, 2013; Accepted: August 29, 2013 DOI 10.1002/ardp.201300187
Introduction Thiazole and its derivatives are very helpful in various fields of organic chemistry, medicine, agriculture, and structure of natural compounds, and are used as an intermediate for synthetic drugs, fungicides, and dyes [1]. Substituted groups like NH2 have very important function in a multitude of these properties, as heretofore many biological activities of aminothiazoles have been well recognized [2]. They have broad application in the treatment of bacterial infections [3], schizophrenia [4], hypertension [5], allergies [6], inflammation [7], and HIV [8]. Recently they have been utilized for the treatment of pain [9], as fibrinogen receptor antagonists with anti-thrombotic activity [10], ligands of estrogen receptors [11], and as a novel class of adenosine receptor antagonists [12], with antitumor and cytotoxic activity [13]. In contribution to our previous design and synthesis of bisintelligent heterocyclic compounds [14–21], here we report the synthesis of bis-thiazoles competent serving as bis-drugs. The reports describing some bis-heterocyclic compounds being compared with their mono-heterocyclic analogs, which
Correspondence: Nosrat Ollah Mahmoodi, Faculty of Sciences, Department of Organic Chemistry, University of Guilan, PO Box 41335-1914, Rasht, Iran. E-mail: [email protected], [email protected] Fax: þ981313233262
ß 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
present superior medicinal and pharmacological activities [22], prompted us to design and synthesize bis-thiazoles 4a–h. The structural evaluations, properties, and synthetic routes toward bis-thiazoles have been reported in limited sources [23, 24].
Results and discussion Chemistry Synthetic efforts toward bis-acetophenones 3a–h commenced with exploration of SN2 reaction of 2 equiv. hydroxy acetophenones with 1 equiv. dihaloalkane or dihalobenzyl in DMF using K2CO3 as catalyst (Scheme 1). The formation of bis-phenacylbromides was confirmed by the change of a red solution to yellow. The thiazole formation is followed by nucleophilic substitution of boromines prepared in situ by S-atom of thiourea, and subsequently cyclocondensation and H2O elimination led to the target compounds 4a–h (Scheme 1). The literature shows that bis-thiazoles 4a–h have not been reported previously. All of the new compounds have been characterized by IR, 1H NMR, 13C NMR, and elemental analyses. The IR spectra of bis-thiazole derivatives 4a–h revealed the presence of stretching vibration for amine bands at n ¼ 3482–3123 cm1, absorption bands in the region of 1509–1610 cm1 corresponding to C –– N attributable to the ring closure, and bands in the regions of 1355–1365 and
Arch. Pharm. Chem. Life Sci. 2013, 346, 860–864
COCH3 Y Y = Cl, Br
Y+
2
R2
Antimicrobial Activity of New bis-Thiazoles
O
K2CO3 DMF
R1 1) R1 = OH, R2 = H
H3COC
O 3a_3d
= (CH2)4
3b, 3f, 4b & 4f ;
= (CH2)5
3c, 3g, 4c & 4g ; 3d, 3h, 4d & 4h ;
O
COCH3
3e_3h
2) Thiourea / EtOH - Reflux
O
= (CH2)6 =
O
1) Br2 / CHCl3
2) R1 = H, R2 = OH
3a, 3e, 4a & 4e ;
H3COC + COCH3
861
S H2N
O
H2N S
N
4a_4d
N
+
S N
O
NH2
O
S N
NH2
4e_4h
Scheme 1. Process of synthesis of bis-thiazoles 4a–h.
1055–1096 cm1, which indicate the presence of C–S and C–N groups. The 1H NMR spectra of bis-thiazoles 4a–h showed a sharp singlet at d 7–8 ppm due to the protons of thiazole rings and sharp singlets at d 9.6 and 10.4 due to the NH2 protons. The etheric –OCH2 protons demonstrate signals at d 4.0–4.5 ppm as triplet. Regarding compounds 4d and 4h, etheric –OCH2 protons appeared as signals at d 4.8–5.5 ppm. Protons of the aromatic ring (HC –– CH) and aliphatic linkages (CH2) were observed within the expected chemical shift regions and exhibited the expected integral values. The 13C NMR spectra of bis-thiazoles 4a–h showed signals at 169.2–170.8 ppm assigned to C2 of the thiazole rings. C4 of these rings displayed a signal at 158–160 ppm for all of the compounds. The signals due to the aromatic and aliphatic carbon groups resonate at their usual positions (see Experimental section).
Antibacterial activity The biological activity of 4a–h against four bacteria was determined using the minimum inhibitory concentration (MIC) method. The bacteria used were Pseudomonas aeruginosa (Psa) and Escherichia coli (Ec) as gram-negative, and Micrococcus luteus (Ml) and Bacillus subtilis (Bs) as gram-positive. The results of antibacterial MIC assays are shown in Table 1, M. luteus was sensitive to all of the synthesized compounds at very low concentrations, with MIC being between 0.93 and 1.87 mg/mL. B. subtilis was sensitive to most but not all of the compounds, although at several-fold higher concentrations, between 7.5 and 15 mg/mL. It may be significant that both these bacteria are gram-positive. E. coli was less sensitive compared to the first two bacteria, with MIC being exhibited only between 15 and 60 mg/mL. P. aeruginosa was the most resistant bacterium, with MIC being shown by compounds 4d, ß 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
4e, and 4h, only at very high concentrations (60 mg/mL). It can be argued that both gram-negative (Psa and Ec) and grampositive bacteria were more sensitive to compounds with higher hydrophobicity. In addition, compounds with higher hydrophobicity (4d and 4h) exhibited some antibacterial activity toward the gram-negatives, which is in accordance with their higher cell wall lipid content. For comparison, tetracycline was used as a positive control and DMSO as a negative control.
Experimental 1
H NMR (400 MHz) and 13C NMR (100 MHz) spectra were run with a Bruker 400 DRX-Avance NMR spectrometer. The compounds were diluted in deuterated DMSO as solvent, and the solvent is indicated for each compound. The IR data were obtained with a Shimadzu 470 spectrometer. Melting points of crystalline compounds were measured with an electrothermal melting point apparatus and have not been corrected. The purification of crystalline compounds was performed by recrystallization. All chemicals were purchased from Aldrich Chemical Company, Merck, and Fluka. Tetracycline was used as a positive control and DMSO as a negative control.
General procedure for the synthesis of bis-thiazoles The bis-acetophenones 3a–h was prepared according to a standard procedure [11]. In 5 mL of CHCl3, bis-acetophenones 3a–h (1 mmol) were dissolved. Then, 5 mL of bromine–CHCl3 (2%) was added dropwise to bis-acetophenones solution, while stirring at RT. After 5–10 min, the bromine color was discharged and a yellow solution remained. At this point, an additional 0.5–1 mL of the bromine–CHCl3 solution was added. When the bromine color remained for longer than 30 min, the completion of the reaction was monitored through thin-layer chromatography (TLC), and the solution was evaporated under vacuum. The white solid bisphenacyl bromide was purified by washing with cooled EtOH solution. To these solids thiouria (2 mmol) and dry EtOH were added and refluxed for the required reaction time (about 6 h). The www.archpharm.com
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Arch. Pharm. Chem. Life Sci. 2013, 346, 860–864
Table 1. Results of antibacterial screening of compounds expressed as MIC (mg/mL). Minimum inhibitory concentration (mg/mL) Entry
Compound O S
4a
N
N
N
N
S
N
N
7.5
60
1.87
–
–
60
0.93
–
7.5
30
0.93
60
7.5
15
1.78
60
–
–
0.93
–
15
–
0.93
–
7.5
30
0.93
60
7.5
15
– 5
– 23
– 16
– 18
NH2
S
S
O
N
H2N
–
O
H2N
4d
1.87
NH2 O
S
Ec
O
H2N
4c
Bs
NH2
S O
S
Psa
O
H2N
4b
Ml
S
O
N
NH2
S
4e
H 2N
O
N
N
O
S
4f
O
S
O N
N
H2N
NH2
S NH2
S H2N
4g
O
N
O N
O
4h
NH2
O
N H2N
N S
S
S
NH2
DMSO Tetracycline
progress of reaction was monitored by TLC (EtOAc/n-hexane 1:3). After completion, the reaction solution was cooled to RT. The precipitate was filtered out and purified by washing with EtOH several times.
General procedure for in vitro antibacterial evaluation of compounds 4a–h expressed as MIC (mg/mL) The isolates were grown either in 3 mL of nutrient broth (Merck) or overnight at 37°C on nutrient agar plates (Merck). ß 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
To test the sensitivity of the bacteria to different compounds, each compound, dissolved in DMSO, was added to the molten nutrient agar at a certain concentration, and after the plates had solidified, 50 mg/L of bacterial suspension in nutrient broth was added to the plate. The inoculum was evenly spread on the agar surface using a sterile spreader and left at 37°C overnight. If bacterial growth was present, the experiment was repeated, but with double the concentration of the test compound, until the MIC was observed. If there was no bacterial growth, the www.archpharm.com
Arch. Pharm. Chem. Life Sci. 2013, 346, 860–864
concentration of the compound was halved till the MIC was observed.
4,4 0 -((Butane-1,4-diylbis(oxy))bis(4,1-phenylene))bis(thiazol-2-amine) (4a) Yield: 72%; m.p.: 231–234°C, FT-IR (KBr): 3379, 3271 (N–H stretch), 3080 (aromatic C–H stretch), 2937, 2866 (aliphatic C–H stretch), 1625 (C –– N stretch), 1606, 1577, 1510 (aromatic C–C stretch), 1469 (C–H bending, CH2), 1251, 1012 (C–O stretch), 1186 (C–N stretch), 833 (aromatic C–H out of plane bending) cm1. 1 H NMR (400 MHz, DMSO-d6): d 7.93 (d, J ¼ 8.8 Hz, 2H), 7.71 (d, J ¼ 8.8 Hz, 2H), 7.04 (dd, J ¼ 8.8, 1.6 Hz, 2H), 6.98 (s, 1H), 6.93 (d, J ¼ 8.8 Hz, 2H,), 6.83 (s, 1H,), 4.19 (s, 2H), 4.06 (s, 2H), 1.92 (s, 2H), 1.90 (s, 2H) ppm. 13C NMR (100 MHz, DMSO-d6): d 170.3, 163.0, 159.8, 131.1, 127.3, 114.9, 103.3, 68.0, 26.3 ppm. Anal. calcd. for C22H22N4O2S2: C, 60.25; H, 5.06; N, 12.78. Found: C, 60.23; H, 5.04; N, 12.77.
4,4 0 -((Pentane-1,5-diylbis(oxy))bis(4,1-phenylene))bis(thiazol-2-amine) (4b) Yield: 80%; m.p.: 229–232°C, FT-IR (KBr): 3363, 3267 (N–H stretch), 3109 (aromatic C–H stretch), 2939, 2884 (aliphatic C–H stretch), 1625 (C –– N stretch), 1577, 1539, 1506 (aromatic C–C stretch), 1463 (C–H bending, CH2), 1255 (C–O stretch), 1182 (C–N stretch), 831 (aromatic C–H out of plane bending) cm1. 1H NMR (400 MHz, DMSO-d6): d 7.72 (d, J ¼ 8.4 Hz, 1H), 7.65 (d, J ¼ 8.8 Hz, 3H), 7.20 (d, J ¼ 8.8 Hz, 1H), 7.12 (s, 1H), 7.06–7.02 (m, 3H), 4.15–4.02 (m, 4H), 1.83 (m, 4H), 1.65–1.59 (m, 2H) ppm. 13C NMR (100 MHz, DMSO-d6): d 170.3, 159.8, 150.0, 130.4, 127.7, 114.3, 109.8, 68.07, 28.6, 22.5 ppm. Anal. calcd. for C23H24N4O2S2: C, 61.04; H, 5.35; N, 12.38. Found: C, 61.03; H, 5.34; N, 12.37.
4,4 0 -((Hexane-1,6-diylbis(oxy))bis(4,1-phenylene))bis(thiazol-2-amine) (4c) Yield: 80%; m.p.: 230–232°C, FT-IR (KBr): 3379, 3271 (N–H stretch), 3080 (aromatic C–H stretch), 2937, 2866 (aliphatic C–H stretch), 1625 (C –– N stretch), 1606, 1577, 1510 (aromatic C–C stretch), 1469 (C–H bending, CH2), 1251, 1012 (C–O stretch), 1186 (C–N stretch), 833 (aromatic C–H out of plane bending) cm1. 1H NMR (400 MHz, DMSO-d6): d 7.92 (d, J ¼ 8.8 Hz) and 7.65 (d, J ¼ 8.6, 2.2 Hz), 7.07–7.01 (m, 6H), 4.09–4.02 (m, 4H), 1.76 (s, 4H), 1.49 (s, 4H) ppm. 13 C NMR (100 MHz, DMSO-d6): d 169.4, 162.5, 152.0, 130.9, 129.4, 115.1, 90, 69.6, 26.9, 14.5 ppm. Anal. calcd. for C24H26N4O2S2: C, 61.78; H, 5.62; N, 12.01. Found: C, 61.75; H, 5.61; N, 12.01.
4,4 0 -(((1,4-Phenylenebis(methylene))bis(oxy))bis(4,1-phenylene))bis(thiazol-2-amine) (4d) Yield: 78%; m.p.: 232–234°C, FT-IR (KBr): 3421, 3330 (N–H stretch), 3068 (aromatic C–H stretch), 2921, 2866 (aliphatic C–H stretch), 1674 (C –– N stretch), 1600, 1508 (aromatic C–C stretch), 1467 (C–H bending, CH2), 1249, 1045 (C–O stretch), 1172 (C–N stretch), 825 (aromatic C–H out of plane bending) cm1. 1H NMR (400 MHz, DMSO-d6): d 9.29, 9.08, 8.53, 8.33 (s, 4H), 7.93 (d, J ¼ 8.4 Hz), 7.58 (s, 1H), 7.62–7.40 (m, 7H), 7.12 (d, J ¼ 8.4 Hz, 3H), 6.87 (s, 1H) ppm. 13 C NMR (100 MHz, DMSO-d6): d 170.6, 163.0, 159.9, 139.6, 130.9, 130.1, 127.7, 121.7, 115.3, 114.7, 100.9, 68.2 ppm. Anal. calcd. for C26H22N4O2S2: C, 64.18; H, 4.56; N, 11.51. Found: C, 64.16; H, 4.55; N, 11.50. ß 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Antimicrobial Activity of New bis-Thiazoles
863
4,4 0 -((Butane-1,4-diylbis(oxy))bis(3,1-phenylene))bis(thiazol-2-amine) (4e) Yield: 78%; m.p.: 229–231°C, FT-IR (KBr): 3440, 3274 (N–H stretch), 3109 (aromatic C–H stretch), 2923, 2854 (aliphatic C–H stretch), 1635 (C –– N stretch), 1558 (aromatic C–C stretch), 1471 (C–H bending, CH2), 1232, 1035 (C–O stretch), 1174 (C–N stretch), 854, 811, 740 (aromatic C–H out of plane bending) cm1. 1H NMR (400 MHz, DMSO-d6): d 7.65 (d, J ¼ 8.8 Hz, 2H), 7.403 (t, J ¼ 7.8 Hz, 1H), 7.30 (t, J ¼ 7.6 Hz, 1H), 7.20 (d, J ¼ 1.6 Hz, 2H), 7.07–7.02 (m, 8H) ppm. 13C NMR (100 MHz, DMSO-d6): d 169.6, 158.3, 138.0, 135.4, 134.5, 129.8, 118.3, 112.4, 107.6, 68.2, 25.6 ppm. Anal. calcd. for C22H22N4O2S2: C, 60.25; H, 5.06; N, 12.78. Found: C, 60.23; H, 5.05; N, 12.74.
4,4 0 -((Pentane-1,5-diylbis(oxy))bis(3,1-phenylene))bis(thiazol-2-amine) (4f) Yield: 80%; m.p.: 230–232°C, FT-IR (KBr): 3425, 3369 (N–H stretch), 3109 (aromatic C–H stretch), 2925, 2854 (aliphatic C–H stretch), 1633 (C –– N stretch), 1573 (aromatic C–C stretch), 1479 (C–H bending, CH2), 1232, 1035 (C–O stretch), 1174 (C–N stretch), 854, 811, 732 (aromatic C–H out of plane bending) cm1. 1H NMR (400 MHz, DMSO-d6): d 7.63 (d, J ¼ 8.8 Hz, 1H), 7.37 (t, J ¼ 8 Hz, 2H), 7.32–7.30 (m, 3H), 7.24 (s, 2H), 7.20 (d, J ¼ 2.8 Hz, 2H), 7.06–6.97 (m, 4H, He, H), 4.06 (t, J ¼ 6.4 Hz, 4H), 1.86–1.79 (m, 4H), 1.65–1.61 (m, 2H) ppm. 13C NMR (100 MHz, DMSO-d6): d 170.2, 159.4, 141.1, 134.5, 138.6, 118.3, 115.6, 112.2, 103.4, 68.1, 26.8, 22.7 ppm. Anal. calcd. for C23H24N4O2S2: C, 61.04; H, 5.35; N, 12.38. Found: C, 61.02; H, 5.33; N, 12.35.
4,4 0 -((Hexane-1,6-diylbis(oxy))bis(3,1-phenylene))bis(thiazol-2-amine) (4g) Yield: 75%; m.p.: 230–233°C, FT-IR (KBr): 3419, 3265 (N–H stretch), 3099 (aromatic C–H stretch), 2933, 2858 (aliphatic C–H stretch), 1635 (C –– N stretch), 1558, 1523 (aromatic C–C stretch), 1461 (C–H bending, CH2), 1232, 1039 (C–O stretch), 1174 (C–N stretch), 848, 810 (aromatic C–H out of plane bending) cm1. 1HNMR (400 MHz, DMSO-d6): d 7.69–7.61 (m, 4H), 7.17 (d, J ¼ 2.8 Hz, 2H), 7.08 (s, 4H), 7.06–7.02 (m, 4H), 4.02 (t, J ¼ 6.2 Hz, 4H), 1.74 (s, 4H), 1.47 (s, 4H) ppm. 13C NMR (100 MHz, DMSO-d6): d 169.7, 158.4, 137.5, 134.5, 131.4, 128.1, 118.3, 115.6, 107.7, 68.7, 28.9, 25.6 ppm. Anal. calcd. for C24H26N4O2S2: C, 61.78; H, 5.62; N, 12.01. Found: C, 61.76; H, 5.59; N, 12.01.
4,4 0 -(((1,4-Phenylenebis(methylene))bis(oxy))bis(3,1-phenylene))bis(thiazol-2-amine) (4h) Yield: 70%; m.p.: 231–234°C, FT-IR (KBr): 3313, 3176 (N–H stretch), 3068 (aromatic C–H stretch), 1625 (C –– N stretch), 1541 (aromatic C–C stretch), 1425 (C–H bending, CH2), 1242, 1076 (C–O stretch), 1145 (C–N stretch), 898, 819, 763, 671 (aromatic C–H out of plane bending) cm1. 1H NMR (400 MHz, DMSO-d6): d 8.30–6.63 (m, 18H), 4.15 (s, 4H) ppm. 13C NMR (100 MHz, DMSO-d6): d 169.3, 162.9, 159.0, 140.8, 139.6, 135.3, 129.8, 121.0, 115.3, 114.7, 100.9, 68.0 ppm. Anal. calcd. for C26H22N4O2S2: C, 64.18; H, 4.56; N, 11.51. Found: C, 64.17; H, 4.54; N, 11.50.
The partial support of this research by the Research Committee of University of Guilan is gratefully acknowledged.
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References [1] S. J. Kashyap, V. K. Garg, P. K. Sharma, N. Kumar, R. Dudhe, J. K. Gupta, Med. Chem. Res. 2012, 21, 2123–2132. [2] M. J. Gorczynski, R. M. Leal, S. L. Mooberry, J. H. Bushweller, M. L. Brown, Bioorg. Med. Chem. 2004, 12, 1029–1036. [3] K. Tsuji, H. Ishikawa, Bioorg. Med. Chem. Lett. 1994, 4, 1601–1606. [4] J. C. Jaen, L. D. Wise, B. W. Caprathe, H. Tecle, S. Bergmeier, C. C. Humblet, T. G. Effner, L. T. Meltzner, T. A. Pugsley, J. Med. Chem. 1990, 33, 311–317. [5] W. C. Patt, H. W. Hamilton, M. D. Taylor, M. J. Ryan, D. G. Taylor, Jr., C. J. C. Connolly, M. Doherty, S. R. Klutchko, I. Sircar, B. A. Steinbaugh, B. L. Batley, C. A. Painchaud, S. T. Rapundalo, B. M. Michniewicz, S. C. J. Olson, J. Med. Chem. 1992, 35, 2562–2572. [6] M. Ohkubo, A. Kuno, I. Nakanishi, H. Takasugi, Chem. Pharm. Bull. 1995, 43, 1497–1504. [7] R. N. Sharma, F. P. Xavier, K. K. Vasu, S. C. Chaturvedi, S. S. Pancholi, J. Enzyme Inhib. Med. Chem. 2009, 24, 890– 897. [8] T. K. Venkatachalam, E. A. Sudbeck, C. Mao, F. M. Uckum, Bioorg. Med. Chem. Lett. 2001, 11, 523–528. [9] K. J. Wilson, C. R. Illig, N. Subasinghe, J. B. Hoffman, M. J. Rudolph, R. Soll, C. Molloy, R. Bone, D. Green, T. Randall, M. Zhang, F. A. Lewandowski, Z. Zhou, C. Sharp, D. Maguire, B. Grasberger, R. L. DesJarlais, J. Spurlino, Bioorg. Med. Chem. Lett. 2001, 11, 915–918. [10] A. Badorc, M. F. Bordes, P. De Cointet, P. Savi, A. Bernat, A. Lale, M. Petitou, J. P. Maffrand, J. M. Herbert, J. Med. Chem. 1997, 40, 3393–3401.
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[11] B. A. Fink, D. S. Mortensen, S. R. Stauffer, Z. D. Aron, J. A. Katzenellenbogen, Chem. Biol. 1999, 6, 205–219. [12] J. E. Van Muijlwijk-Koezen, H. Timmerman, R. C. Vollinga, J. F. Von Drabbe Kunzel, M. De Groote, S. Visser, A. P. Ijzerman, J. Med. Chem. 2001, 44, 749–762. [13] E. Gulsory, N. U. Guzeldemirci, Eur. J. Med. Chem. 2007, 42, 320–326. [14] N. O. Mahmoodi, M. A. Zanjanchi, H. Kiyani, J. Chem. Res. 1997, 6, 438–440. [15] N. O. Mahmoodi, H. Kiyani, K. Tabatabaeian, M. A. Zanjanchi, M. Arvand, B. Sharifzadeh, Russ. J. Org. Chem. 2010, 46, 884– 889. [16] N. O. Mahmoodi, H. Kiyani, Bull. Korean Chem. Soc. 2004, 25, 1417–1420. [17] N. O. Mahmoodi, M. R. Yazdanbakhsh, H. Kiyani, J. Chin. Chem. Soc. 2007, 54, 635–641. [18] N. O. Mahmoodi, M. Arvand, M. Moghimi, A. Afshari, Anal. Chin. Acta 2006, 579, 102–108. [19] N. O. Mahmoodi, M. A. Zanjanchi, M. Arvand, A. Islamnezhad, Talanta 2007, 74, 125–131. [20] N. O. Mahmoodi, H. Kiyani, K. Tabatabaeian, M. A. Zanjanchi, J. Phys. Org. Chem. 2009, 22, 559–567. [21] N. O. Mahmoodi, H. Kiyani, K. Tabatabaeian, M. A. Zanjanchi, Mendeleev Commun. 2009, 19, 203–205. [22] N. O. Mahmoodi, A. Rineh, M. Abdollahi, A. Foroumadi, M. Sorkhi, A. Shafiee, Arch. Pharm. Chem. Life Sci. 2007, 340, 409–415. [23] H. T. Fahmy, A. A. Bekhit, Pharmazie 2002, 12, 800–803. [24] A. Shockravi, M. Kamali, A. Ziyaei Halimehjani, R. Jafari, J. Heterocyclic Chem. 2013, 50, 209–215.
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