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Synthesis and Antidiabetic Evaluation of Benzothiazole Derivatives
Synthesis and Antidiabetic Evaluation of Benzothiazole Derivatives
Journal of the Korean Chemical Society. 2012. Apr, 56(2): 251-256
Copyright © 2012, The Korean Chemical Society
  • Received : February 18, 2012
  • Accepted : March 27, 2012
  • Published : April 20, 2012
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About the Authors
G Mariappan
gmariappanhpi@yahoo.co.in
P Prabhat
L Sutharson
J Banerjee
U Patangia
S Nath

Abstract
A novel series of benzothiazole derivatives were synthesized and assayed in vivo to investigate their hypoglycemic activity by streptozotocin-induced diebetic model in rat. These derivatives showed considerable biological efficacy when compared to glibenclamide, a potent and well known antidiabetic agent as a reference drug. All the compounds were effective, amongst them 3d showed more prominent activity at 100 mg/kg p.o. The experimental results are statistically significant at p<0.01 and p<0.05 level.
Keywords
INTRODUCTION
Benzothiazole ring system is present in various marine and terrestrial natural compounds, which have useful biological activities. 1 - 4 2-Aminobenzothiazoles are highly reactive compounds and extensively utilized as reactants or reaction intermediates since the NH 2 and endocyclic N functions are suitably situated to enable reactions with various reactants to form a variety of fused heterocyclic compounds. Medicinal chemist attention was drawn to this series when the pharmacological profile of Riluzole 5 was observed as clinically available anticonvulsant drug. These derivatives are reported in the literature for the treatment of epilepsy, 6 - 12 inflammation, 13 , 14 analgesia, 15 , 16 amyotrophic lateral sclerosis, 17 and viral infections. 18 They also exhibit antitumour, 19 - 33 antitubercular, 34 , 35 antibacterial, 36 antifungal, 37 antimalarial, 38 antihelmintic. 39 2-aryl substituted benzothiazoles have emerged in recent years as an important pharmacophore in non-invasive diagnosis of alzheimer’s disease. 40 Benzothiazole derivatives have been evaluated as potential amyloid-binding diagnostic agents in neurodegenerative disease 41 , 42 and selective fatty acid amide hydrolase inhibitors. 43 They are broadly found in bio organic and medicinal chemistry with applications in drug discovery and development for the treatment of diabetes. 44 - 52 Diabetes has become an increasing concern to the world’s population. In view of these literatures, it was of considerable interest to synthesize the title compound with a hope to obtain potent biologically active and safe oral anti diabetic agents.
RESULT AND DISCUSSION
- Chemistry
A congeneric series of benzothiazole derivatives were synthesized as illustrated in 1 . The starting material 2-amino-5-chloro benzothiazole 1 was prepared by the reaction of 4-chloro aniline and potassium thiocyanate in glacial acetic acid. The compound 1 was refluxed with chloroacetyl chloride in presence of potassium carbonate and chloroform to yield 2-chloroacetamido-5-chloro-benzothiazole 2 . The condensation of compound 2 with various primary and secondary amines in absolute alcohol and HCl afforded the final compounds 3 (a-j) . Their structures have been elucidated from UV, IR, 1 H NMR, mass spectral data and elemental analysis. The physicochemical data of the synthesized compounds are given in 1 .
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Synthesis of benzothiazole derivatives.
Physical data of the synthesized compounds3(a-j)
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Physical data of the synthesized compounds 3(a-j)
- Spectral Analysis
A sharp singlet at 2.52-3.40 ppm ascertained the presence of CH 2 proton (aliphatic) and a characteristic signal at 7.14-7.60 ppm is assigned to NH proton (benzothiazole) in all the synthesized compounds. A multiplet observed at 6.52-8.15 ppm indicated the presence of aromatic proton in all the compounds. In addition to this, two OH proton of compound 3c exhibited a sharp singlet at 2.48 ppm. The two sharp singlet signals of morpholine were observed at 2.52 and 3.55 ppm corresponding to two types of CH 2 proton in compound 3e . The appearance of signals at 1.53 ppm and 2.50 ppm ascertained the presence of CH 2 of piperidine. A sharp singlet at 4.06 ppm, 4.46 ppm and 4.49 ppm demonstrated the existence of NH proton (benzene) for the compounds 3f , 3g and 3j respectively. The NHproton of pyridine ring in 3h and 3i are assigned by singlet at 3.37 and 4.47 ppm respectively. Hence, the compounds synthesized were in conformity with the structures postulated.
- Antidiabetic Evaluation
The LD 50 values of the synthesized compounds were estimated to be in the range of 100-1000 mg/kg b.w. STZ causes diabetes by the rapid depletion of β-cells and thereby bring about a reduction of insulin release 4 . The results summarized in 2 revealed that all the synthesized compounds exhibited anti diabetic response at the end of ten-day experimental period. From 2 , it has been found that oral administration of synthesized compounds 3c , 3d , 3e and 3j caused a more significant reduction in blood glucose than other compounds in diabetic rats. However, the compound 3d at 100 mg/kg b.w. exerted maximum glucose lowering effects whereas 3g showed minimum glucose lowering effects. The maximum glucose lowering effects of compound 3d may be due to the presence of heterocyclic amine (morpholine).
Effect of synthesized test compounds3(a-j)on diabetic rats
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All the values were expressed as m±S.E.M (n=6). *p<0.05 and **p<0.01
The fundamental mechanism underlying hyperglycemia in diabetes mellitus involves over-production and decreased utilization of glucose by the tissues. The plausible mechanism by which benzothiazole derivatives brought about its hypoglycemic action in diabetic rats might be by potentiating the effect of insulin in plasma by increasing either the pancreatic secretion of insulin from existing beta cells or by its release from bound form. In STZ induced diabetes, induction of diabetes with STZ is associated with characteristic loss of body weight, which is due to increased muscle wasting in diabetes. 5 The present study has indicated the fact that benzothiazole derivatives have anti diabetic property and further exploitation of benzothiazole core may afford a safe anti diabetic drug.
- Pharmacological Evaluation
Acute toxicity studies:
Groups of six albino mice, weighing 20-25 g were fasted overnight and treated per orally with test compounds. The dosage was varied from 100 to 1000 mg kg -1 body weight. The animals were observed for 24 h for any signs of acute toxicity such as increased or decreased motor activity, tremors, convulsion, sedation, lacrimation etc. No such signs, symptoms and mortality were observed even after 24 h. Hence the LD 50 cut off value of the test compounds was fixed at 100 mg/kg. b.w and the same dose was considered for evaluation of anti diabetic activity. All the animal experiments were conducted by the approval of Institutional Animal Ethics Committee, Himalayan Pharmacy Institute, East Sikkim, India. During the study period, guidelines of Committee for the Purpose of Control and Supervision of Experiments on Animals (CPCSEA), Institutional Animal Ethics Committee (IAEC) were followed for the maintenance of animals.
- Antidiabetic Activity
Induction of experimental diabetes by Streptozotocin (STZ):
The rats were injected intraperitoneally with streptozotocin dissolved in sterile normal saline at a dose of 60 mg kg -1 b.w. The animals showing blood glucose range of 200-300 mg dL -1 were used for the experiment and the hyperglycemia was confirmed after 72 hours of streptozotocin injection.
- Experimental Design
Animals were divided into 12 groups of 6 animals in each (n=6). Group 1 diabetic animals received 0.5% carboxy methyl cellulose (CMC) (1 ml); Group 2 diabetic animals received glibenclamide 20 mg/kg. Groups (3-12) diabetic animals received compounds 3a-3j in a single dose of 100 mg/kg b.w p.o respectively for 7 days continuously.
- Blood Glucose Measurement
Blood was withdrawn from the tail vein each time. At the end of 0, 3 rd , 7 th and 10 th day, blood sample was withdrawn from a tail vein by snipping the tip of the tail and the blood glucose level was measured by Accu Sure Blood Glucose Monitoring System (Dr. Gene Health & Wellness).
- Statistical Analysis
Values are expressed as mean ± SEM. Data were analyzed using analysis of variance and group means were compared with Tukey-Kramer Post ANOVA test. The values were considered to be significant at p <0.05 and p <0.01 level.
EXPERIMENTAL SECTION
All the chemicals were of synthetic grade and commercially procured from Qualigen, Mumbai, India. Melting points were determined in open capillary method and are uncorrected. IR spectra were recorded on FT-IR8400S, Fourier Transform (Shimadzu) Infrared Spectrophotometer using KBr disc method. The 1 H-NMR were recorded on BRUKER ADVANCE-II 400 NMR spectrophotometer in DMSO- d 6 as a solvent and TMS as an internal standard. Mass spectra were recorded on a PEP-SCIUX-APIQ pulsar (electron pre-ionisation) mass spectrometer. Elemental analyses were performed on Perkin-Elmer EAL-240 elemental analyzer.
- General procedure for the synthesis of 6-chloro-1, 3-benzothiazol-2-amine 1
To a required amount of chilled glacial acetic acid, KSCN and 4-chloroaniline were added and placed in freezing mixture. The solution was stirred mechanically with dropwise addition of Br 2 in glacial acetic acid at such a rate that temperature does not rise above 5 ℃. The stirring was continued for an additional 3 hr at 0-10 ℃ and the separated hydrochloride salt was filtered, washed with acetic acid and dried. It was dissolved in hot water and neutralized with aqueous ammonia solution (25%). The resulting precipitate was filtered, washed with water and recrystallized from methanol to obtain pure 6-chloro-1, 3-benzothiazol-2-amine.
- Synthesis of 2-chloro-N-(6-chlorobenzothiazol-2-yl) acetamide 2
Equimolar quantity of compound 1 and chloroacetyl chloride in sufficient quantity of chloroform was refluxed in the presence of K 2 CO 3 for about 10 hours. Excess solvent was removed in vacuum and the residue thus obtained was washed with 5% NaHCO 3 and subsequently with water. The resulting crude product was dried and recrystallized from ethanol to furnish white crystal.
- Synthesis of N-(6-chlorobenzothiazol-2-yl)-2-(substituted amino) acetamide 3(a-j)
To a solution of compound 2 (0.01 mol) in 25 ml of absolute alcohol was added different secondary and primary amine (0.01 mol). The mixture was refluxed on water bath for 4-6 hours and the completion of reaction was checked by TLC. The crude product thus obtained was filtered, dried and recrystallized from aqueous alcohol.
N-(6-chlorobenzo[d]thiazol-2-yl)-2-(dimethylamino) acetamide (3a):
Colorless crystal; UV (nm) 225; IR (KBr, cm -1 ) 3460 (N-H), 3063 (C-H str of CH 2 ), 1531 (C=O), 1444(C=N); 1 HNMR (400Hz, DMSO- d 6 ): δ 7.61(s, 1H, NH), δ 2.50 (s, 2H, CH 2 ), δ 3.37(s, 6H, (CH 3 ) 2 ), δ 7.19-7.76 (m, 3H, Ar-H); Mass (m/z) 269; Ana. Calcd. C 11 H 12 ClN 3 OS C, 48.98; H, 4.48; N, 15.58, found C, 49.38; H, 4.58; N, 15. 48%.
N-(6-chlorobenzo[d]thiazol-2-yl)-2-(diethylamino) acetamide (3b):
Colorless crystal; UV (nm) 225; IR (KBr, cm -1 ) 3456 (N-H), 3091 (CH str of CH 2 ), 1637 (C=O), 1533(C=N); 1 H NMR (400 Hz, DMSO- d 6 ): δ 7.61 (s, IH, NH), δ 2.50 (s, 4H, (CH 2 ) 2 ), δ 3.38(s, 6H, (CH 3 ) 2 ) 7.19-7.76 (m, 3H, Ar-H); Mass (m/z) 298; Ana. Calcd. C 13 H 16 ClN 3 OS C, 52.43; H, 5.42; N, 14.11, found C, 52.83; H, 5.12; N, 14.51%.
N-(6-chlorobenzo[d]thiazol-2-yl)-2-(bis (2-hydroxyethyl) amino) acetamide (3c):
Colorless crystal; UV (nm) 226; IR (KBr, cm -1 ) 3458 (O-H), 3271(N-H), 3093 (C-H str of CH 2 ), 1637 (C=O), 1533(C=N); 1 H NMR (400 Hz, DMSO- d 6 ): δ 7.60 (s, 1H, NH), δ 3.39 (s, 2H, CH 2 ), δ 2.49 (s, 8H, 2×(CH 2 ) 2 ), δ 2.48 (s, 2H, 2×OH), δ 7.17-7.74 (m, 3H, Ar-H); Mass (m/z) 329; Ana. Calcd. C 13 H 16 ClN 3 O 3 S C, 47.34; H, 4.89; N, 12.74; found C, 47.74; H, 4.99; N, 12.64%.
N-(6-chlorobenzo[d]thiazol-2-yl)-2-morpholinoacetamide (3d):
Colorless crystal; UV (nm) 215; IR (KBr,cm -1 ) 3329 (N-H), 3080 (C-H str of CH 2 ),1695 (C=O), 1599 (C=N); 1 H NMR (400 Hz, DMSO- d 6 ): δ 7.14(s, 1H, NH), δ 3.62 (s, 2H, CH 2 ), δ 2.52 (s, 4H, 2×CH 2 of morpholine), δ 3.55 (s, 4H, 2×CH 2 of morpholine), δ 7.42-8.12 (m, 3H, Ar-H); Mass (m/z) 312; Ana. Calcd. C 13 H 14 ClN 3 O 2 S C, 50.08; H, 4.53; N, 13.48; found C, 50.48; H, 4.83; N, 13.28%.
N-(6-chlorobenzo[d]thiazol-2-yl)-2-(piperidin-1-yl) acetamide (3e):
Pale yellow powder; UV (nm) 224; IR (KBr, cm -1 ) 3460 (N-H), 3265 (C-H str of CH 2 ), 1639 (C=O), 1433 (C=N), 1 H NMR (400 Hz, DMSO- d 6 ): δ 7.60 (s,1H, NH), δ 3.35 (s, 2H, CH 2 ), δ 1.53 (s, 8H, 4×CH 2 of piperidine), δ 2.50 (s, 2H, CH 2 of piperidine), δ 7.19-7.77 (m, 3H, Ar-H); Mass (m/z) 309; Ana. Calcd. C 14 H 16 ClN 3 OS C, 54.27; H, 5.21; N, 13.56; found C, 54.67; H, 4.81; N, 13.76%.
N-(6-chlorobenzo[d]thiazol-2-yl)-2-(4-fluorophenylamino) acetamide (3f):
Colorless powder; UV (nm) 218; IR (KBr, cm -1 ) 3365 (N-H), 3178 (C-H str of CH 2 ), 1600 (C=O), 1521 (C=N); 1 H NMR (400Hz, DMSO- d 6 ): δ 8.13 (s, 1H, NH), δ 3.36 (s, 2H, CH 2 ), 4.06 (s, 1H, Ar-NH), δ 6.55-8.13 (m, 3H, Ar-H), δ 7.73-7.43 (m, 4H, Ar-H); Mass (m/z) 336; Ana. Calcd. C 15 H 11 ClFN 3 OS C, 53.65; H, 3.30; N, 12.51; found C, 53.25; H, 3.6; N, 12.91%.
N-(6-chlorobenzo[d]thiazol-2-yl-2-(3-chlorophenylamino) acetamide (3g):
Colorless powder; UV (nm) 282; IR (KBr, cm -1 ), 3379 (N-H), 3176 (C-H str of CH 2 ), 1668 (C=O), 1541 (C=N); 1 H NMR (400 Hz, DMSO- d 6 ): δ 7.73 (s, 1H, NH), δ 4.04 (s, 2H, CH 2 ), δ 4.46 (s, IH, Ar-NH), δ 6.52-8.14 (m, 7H, Ar-H); Mass (m/z) 352; Ana. Cald. C 15 H 11 Cl 2 N 3 OS C, 51.15; H, 3.15; N, 11.93; found C, 51.05; H, 3.45; N, 11.73%.
N-(6-chlorobenzo[d]thiazol-2-yl)-2-(pyridin-4-ylamino) acetamide (3h):
Colorless crystal; UV (nm) 224; IR (KBr, cm -1 ), 3456 (N-H), 3269 (C-H str of CH 2 ), 1637 (C=O), 1533 (C=N); 1 H NMR (400 Hz, DMSO- d 6 ): δ 7.61 (s, 1H, NH), δ 2.51 (s, 2H, CH 2 ), δ 3.37 (s, 1H, pyridine-NH), δ 7.19-7.22 (m, 3H, Ar-H), δ 7.28-7.77 (m, 4H, Het. Ar-H); Mass (m/z) 318; Ana. Cald. C 14 H 11 ClN 4 OS C, 52.75; H, 3.48; N, 17.58; found C, 51.43; H, 3.52; N, 17.43%.
N-(6-chlorobenzo[d]thiazol-2-yl)-2-(pyridin-2-ylamino) acetamide (3i):
Brick red powder; UV (nm) 224; IR (KBr, cm -1 ), 3454 (N-H), 3416 (C-H str of CH 2 ), 1699 (C=O), 1535 (C=N); 1 H NMR (400 Hz, DMSO- d 6 ): δ 7.60 (s, 1H, NH), δ 3.36 (s, 2H, CH 2 ), δ 4.47 (s, 1H, pyridine-NH), δ 7.19-7.31 (m, 3H, Ar-H), δ 7.46-8.15 (m, 4H, Het. Ar-H); Mass (m/z) 318; Ana. Cald C 14 H 11 ClN 4 OS C, 52.75; H, 3.48; N, 17.58; found C, 52.43; H, 3.48; N, 17.43%.
N-(6-chlorobenzo[d]thiazol-2-yl)-2-(4-sulfanilido) acetamide (3j):
Colorless crystal; UV (nm) 281; IR (KBr, cm -1 ), 3180 (N-H), 2993 (C-H str of CH 2 ), 1668 (C=O), 1541 (C=N); 1 H NMR (400 Hz, DMSO- d 6 ): δ 8.15 (s, 1H, NH), δ 3.38 (s, 2H, CH 2 ), δ 4.49 (s, 1H, NH), δ 7.46 (m, 2H, SO 2 NH 2 ), δ7.75-8.15 (m, 7H, Ar-H); Mass (m/z) 397; Ana. Cald C 15 H 13 ClN 4 O 3 S 2 C, 45.40; H, 3.30; N, 14.12; found C, 45.43; H, 3.44; N, 14.22%.
Acknowledgements
The authors are thankful to the Dr. H.P.Chhetri, Director, Himalayan Pharmacy Institute, Majhitar, East Sikkim, India who provided the facilities to carry out the research work. The authors are also grateful to Director, IICB for providing spectral data.
References
Geewananda G. P. , Shigeo K. , Sarath P. G. , Oliver J. M. , Frank E. K. 1988 J. Am. Chem. Soc. 110 (14) 4856 -    DOI : 10.1021/ja00222a071
Geewananda G. P. , Shigeo K. , Neal S.B. 1989 Tetrahedron Lett. 30 4359 -    DOI : 10.1016/S0040-4039(00)99360-2
Gunawardana G. P. , Koehn F. E. , Lee A. Y. , Clardy J. , He H. Y. , Faulkenr J. D. 1992 J. Org. Chem. 57 (5) 523 -    DOI : 10.1021/jo00031a035
Carroll A. R. , Scheuer P. J. 1990 J. Org. Chem. 55 (14) 4426 -    DOI : 10.1021/jo00301a040
Bryson M. , Fulton B. , Benfield P. 1996 Drugs. 52 549 -    DOI : 10.2165/00003495-199652040-00010
Chopade R. S. , Bahekar R. H. , Khedekar P. B. , Bhusari K. P. , Rao A.R.R. 2002 Arch. Pharm. Pharm. Med. Chem. 8 381 -    DOI : 10.1002/1521-4184(200211)335:8<381::AID-ARDP381>3.0.CO;2-S
Yogeeswari P. , Srisam D. , Suniljit L. , Kumar S. , Stables J. 2002 Eur. J. Med. Chem. 37 231 -    DOI : 10.1016/S0223-5234(02)01338-7
Yogeeswari P. , Sriram D. , Mehta S. , Nigam D. , Kumar M. , Murugesan S. 2005 J. Stables II, Farmaco. 60 1 -    DOI : 10.1016/j.farmac.2004.09.001
Siddiqui N. , Pandeya S. , Khan S. , Stables J. , Rana A. , Alam M. , Arshad M. , Bhat M. 2007 Bioorg. Med. Chem. Lett. 17 255 -    DOI : 10.1016/j.bmcl.2006.09.053
Siddiqui N. , Rana A. , Khan S. , Bhat M. , Haque S. 2007 Bioorg. Med. Chem. Lett. 17 4178 -    DOI : 10.1016/j.bmcl.2007.05.048
Hays S. J. , Rice M. J. , Ortwine D. F. , Johnson G. , Schwartz R. D. , Boyd D. K. , opeland L. F. , Vartanian M. G. , Boxer P. A. 1994 J. Pharm. Sci. 83 1425 -    DOI : 10.1002/jps.2600831013
He Y. , Benz A. , Fu T. , Wang M. , Covey D. F. , Zorumski C. F. , Mennick S. 2002 Neuropharmacology 42 199 -    DOI : 10.1016/S0028-3908(01)00175-7
Gurupadayya B. M. , Gopal M. , Padmashali B. , Vaidya V. P. 2005 Int. J. Heterocyclic Chem. 15 169 -
Sawhney S. N. , Arora S. K. , Singh J. V. , Bansal O. P. , Singh S. P. 1978 Indian J. Chem. 16B 605 -
Foscolos G. , Tsatsas G. , Champagnac A. , Pommier M. 1977 Ann. Pharm. Fr. 35 295 -
Siddiqui N. , Alam M. , Siddiqui A. A. 2004 Asian. J. Chem. (b) Bensimon, G.; Lacomblez, L.; Meininger, V. New Engl. J. Med. 1994, 330, 585. 16 1005 -
Bensimon G. , Lacomblez L. , Meininger V. 1994 New Engl. J. Med. 330 585 -    DOI : 10.1056/NEJM199403033300901
Paget C. J. , Kisner K. , Stone R. L. , Delong D. C. 1969 J. Med. Chem. 12 1016 -    DOI : 10.1021/jm00306a011
Vicini P. , Gernonikaki A. , Incerti M. , Busonera B. , Poni G. , Cabras C. A. , Colla P. L. 2003 Bioorg. Med. Chem. 11 4785 -    DOI : 10.1016/S0968-0896(03)00493-0
Caleta I. , Kralj M. , Branimir Bertosa B. , Sanja Tomic S. , Pavlovic G. , Pavelic K. , Karminski-Zamola G. 2009 J.Med. Chem. 52 1744 -    DOI : 10.1021/jm801566q
Chung Y. , Shin Y. K. , Zhan C. G. , Lee S. , Cho H. 2004 Arch. Pharmacol. Res. 27 893 -    DOI : 10.1007/BF02975839
Yoshida M. , Hayakawa I. , Hayashi N. , Agatsuma T. , Oda Y. , Tanzawa F. , Iwasaki S. , Koyama K. , Furukawa H. , Kurakata S. 2005 Bioorg. Med. Chem. Lett. 15 3328 -    DOI : 10.1016/j.bmcl.2005.05.077
Bradshaw T. D. , Stevens M. F. G. , Westwell A. D. 2001 Curr. Med. Chem. 8 203 -    DOI : 10.2174/0929867013373714
Chua M. S. , Shi D. F. , Wrigley S. , Bradshaw T. D. , Hutchinson I. , Shaw P. N. , Barrett D. A. , Stanley L. A. , Stevens M. F. G. 1999 J. Med. Chem. 42 381 -    DOI : 10.1021/jm981076x
O#8217;Brien S. E. , Browne H. L. , Bradshaw T. D. , Westwell A. D. , Stevens M. F. G. , Laughton C. A. 2003 Org. Biomol. Chem. 1 493 -    DOI : 10.1039/b209067h
Bradshaw T. D. , Wrigley S. , Shi D. F. , Schulz R. J. , Paull K. D. , Stevens M. F. G. Br. 1998 J. Cancer 77 745 -    DOI : 10.1038/bjc.1998.122
Kashiyama E. , Hutchinson I. , Chua M. S. , Stinson S. F. , Phillips L. R. , Kaur G. , Sausville E. A. , Bradshaw T. D. , Westwell A. D. , Stevens M. F. G. 1999 J. Med. Chem. 42 4172 -    DOI : 10.1021/jm990104o
Hutchinson I. , Chua M. S. , Browne H. L. , Trapani V. , Bradshaw T. D. , Westwell A. D. , Stevens M. F. G. 2001 J. Med. Chem. 44 1446 -    DOI : 10.1021/jm001104n
Shi D. F. , Bradshaw T. D. , Wrigley S. , McCall C. J. , Lelieveld P. , Stevens M. F. G. 1996 J. Med. Chem. 39 3375 -    DOI : 10.1021/jm9600959
Lion C. J. , Matthews C. S. , Wells G. , Bradshaw T. D. , Stevens M. F. G. , Westwell A. D. 2006 Bioorg. Med. Chem. Lett. 16 5005 -    DOI : 10.1016/j.bmcl.2006.07.072
Mortimer C. S. , Wells G. , Crochard P. J. , Stone E. L. , Bradshaw T. D. , Stevens A. D. , Westwell M. F. G. 2006 J. Med. Chem. 49 179 -    DOI : 10.1021/jm050942k
Wells G. , Berry J. M. , Bradshaw T. D. , Burger A. M. , Seaton A. , Wang B. , Westwell A. D. , Stevens M. F. G. 2003 J. Med. Chem. 46 532 -    DOI : 10.1021/jm020984y
Hutchinson I. , Jennings S. A. , Vishnuvajjala B. R. , Westwell A. D. , Stevens M. F. G. 2002 J. Med. Chem. 45 744 -    DOI : 10.1021/jm011025r
Khadse B. G. , Sengupta S. R. 1993 Indian J. Chem. Sec-B 407 -
Palmer F. J. , Trigg R. B. , Warrington J. V. 1971 J. Med. Chem. 14 248 -    DOI : 10.1021/jm00285a022
Gurupadaiah B. M. , Jayachandran E. , ShivaKumar B. , Nagappa A. N. , Nargund L. V. G. 1998 Indian J. Heterocycl. Chem. 7 213 -
Gopkumar P. , Shivakumar B. , Jayachandran E. , Nagappa A. N. , Nargund L. V. G. , Gurupadaiah B. M. 2001 IndianJ. Heterocycl. Chem. 11 39 -
Burger A. , Sawhey S. N. 1968 J. Med. Chem. 11 270 -    DOI : 10.1021/jm00308a018
Jayachandran E. , Bhatia K. , Naragud L. V. G. , Roy A. 2003 Indian Drugs 40 408 -
Weekes A. A. , Westwell A. D. 2009 Curr. Med. Chem. 16 2430 -    DOI : 10.2174/092986709788682137
Henriksen G. , Hauser A. I. , Westwell A. D. , Yousefi B. H. , Schwaiger M. , Drzega A. , Wester H. J. 2007 J. Med. Chem. 50 1087 -    DOI : 10.1021/jm061466g
Mathis C. A. , Wang Y. , Holt D. P. , Haung G. F. , Debnath M. L. , Klunk W. E. 2003 J. Med. Chem. 46 2740 -    DOI : 10.1021/jm030026b
Wang X. , Sarris K. , Zhang K. , Kage D. , Brown S. P. , Kolasa T. , Surowy C. , ElKouhen O. F. , Muchmore S. W. , Brioni J. D. , Stewart A. O. 2009 J. Med. Chem. 52 170 -    DOI : 10.1021/jm801042a
Suter H. , Zutter H. 1967 Helv. Chim. Acta 50 1084 -    DOI : 10.1002/hlca.19670500415
Diaz H. M. , Molina R. V. , Andrade R. O. , Coutino D. D. , Franco L. M. , Webster S. P. , Binnie M. , Soto S. E. , Barajas M. I. , Rivera I. L. , Vazquez G. N. 2008 Bioorg. Med. Chem. Lett. 18 2871 -    DOI : 10.1016/j.bmcl.2008.03.086
Nitta A. , Fujii H. , Sakami S. , Nishimura Y. , Ohyama T. , Satoh M. , Nakaki J. , Satoh S. , Inada C. , Kozono H. , Kumagai H. , Shimamura M. , Fukazawa T. , Kawai H. 2008 Bioorg. Med. Chem. Lett. 15 5435 -    DOI : 10.1016/j.bmcl.2008.09.042
Vazquez G. N. , Paoli P. , Rivera I. L. , Molina R. V. , Franco J. L. M. , Andrade R. O. , Soto S. E. , Camici G. , Coutiño D. D. , Ortiz I. G. , Mayorga K. M. , Díaz H. M. 2009 Bioorg. Med. Chem. Lett. 17 3332 -    DOI : 10.1016/j.bmc.2009.03.042
Su X. , Vicker N. , Ganeshapillai D. , Smith A. , Purohit A. , Reed M. J. , Potter B. V. 2006 Mol. Cell Endocrinol. 248 214 -    DOI : 10.1016/j.mce.2005.10.022
Barf T. , Vallgarda J. , Emond R. , Haggstrom C. , Kurz G. , Nygren A. , Larwood V. , Mosialou E. , Axelsson K. , Olsson R. , Engblom L. , Edling N. , Ronquist-Nii Y. , Ohman B. , Alberts P. , Abrahmsen L. 2002 J. Med. Chem. 45 3813 -    DOI : 10.1021/jm025530f
Fujieda H. , Usui S. , Suzuki T. , Nakagawa H. , Ogura M. , Makishima M. , Miyata N. 2007 Bioorg. Med. Chem. Lett. 17 4351 -    DOI : 10.1016/j.bmcl.2007.05.017
Jeon R. , Kim Y. J. , Cheon Y. , Ryu J. H. 2006 Arch. Pharmacal Res. 29 394 -    DOI : 10.1007/BF02968589
Pattan S. R. , Suresh C. , Pujar V. D. , Reddy V. V. K. , Rasal V. P. , Koti B. C. 2005 Indian. J. Chem. 44B 2404 -