1890
S. A. Khanum et al. / Bioorg. Med. Chem. Lett. 19 (2009) 1887–1891
Table 2
Histopathological examination results of compounds 5a–j
Compd (100 mg/kg) p.o.
Kidney
Stomach
Gastritis
Liver
Edema
Infected cell (MNL)
Fatty change
Acute hepatitis/spotty necrosis
Cholestasis
5a
5b
5c
5d
5e
5f
5g
5h
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
++
+
ꢁ
+
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
+
++
+
++
+++
+
ꢁ
++
++
ꢁ
ꢁ
ꢁ
ꢁ
+
ꢁ
ꢁ
ꢁ
++
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
+
+
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
++
ꢁ
ꢁ
+
++
ꢁ
++
+
+
ꢁ
5i
5j
ꢁ
ꢁ
+
+
Indomethacin (10 mg/kg)
Naproxen (30 mg/kg)
Phenylbutazone (100 mg/kg)
++
+
ꢁ
++
+++
ꢁ
ꢁ
ꢁ
ꢁ
+
ꢁ
ꢁ
ꢁ
ꢁ, no; +, mild; ++, moderate; +++, severe side effects.
Corcoran, T. W.; Derian, C. K.; Eckardt, A. J.; Damiano, B. P.; Andrade-Gordon, P.;
Maryanoff, B. E. J. Biol. Chem. 2005, 280, 18001.
14. Mosnaim, A. D.; Ranade, V. V.; Wolf, M. E.; Puente, J.; Antonieta Valenzuela, M.
Am. J. Ther. 2006, 13, 261.
15. Ranise, A.; Schenone, S.; Bruno, O.; Bondavalli, F.; Filippelli, W.; Falcone, G.;
Rivaldi, B. Farmaco 2001, 56, 647.
16. Ahn, K.; Johnson, D. S.; Fitzgerald, L. R.; Liimatta, M.; Arendse, A.; Stevenson, T.;
Lund, E. T.; Nugent, R. A.; Nomanbhoy, T. K.; Alexander, J. P.; Cravatt, B. F.
in the differential diagnosis of the tubulointerstitial nephritis, but
none of our samples showed interstitial suppurative (inflammation
with polymorphonuclear leukocytes) inflammation with microab-
scesses. Therefore, the renal morphologic findings reflect the ef-
fects of the compounds. Liver tissues were also examined
thoroughly and the integrity of the basic structure, degree of lobu-
lar and portal inflammation and the presence or absence of necro-
sis, fatty change or cholestasis were evaluated. NSAIDs such as
phenylbutazone33 and naproxen34 are known to cause acute or
chronic hepatitis, confluent or spotty necrosis, cholestatic hepatitis
and/or fatty change. This shows the importance of examining the
liver tissues to better assess the safety of NSAIDs. In compounds
5b, 5c, 5h, and 5j (moderate, ++) showed macro and microvesicular
fatty change and several scattered mild (+) focal spotty necrosis.
Multiple foci of spotty necrosis (moderate ++) was seen with com-
pounds 5c and 5e. Cholestatic hepatitis was observed for com-
pounds 5c and 5j (Table 2).
Biochemistry 2007,
13019.
17. Viegas, C., Jr.; Alexandre-Moreira, M. S.; Fraga, C. A.; Barreiro, E. J.; Bolzani Vda,
S.; de Miranda, A. L. Chem. Pharm. Bull. (Tokyo) 2008, 56, 407.
18. Jiri, J.; Miroslav, P.; Josef, P.; Stanislav, W.; Csech C. S., 1991, 271, 185; Chem.
Abstr. 1992, 117, 170994d.
19. Khanum, S. A.; Shashikanth, S.; Deepak, A. V. Bioorganic Chem. 2004, 32, 211.
20. Venu, T. D.; Shashikanth, S.; Khanum, S. A.; Naveen, S.; Firdouse, A.; Sridhar, M.
A.; Shashidhara Prasad, J. Bioorg. Med. Chem. 2007, 15, 3505.
21. Compound 3a: IR (Nujol): 1725 cmꢁ1 (ester, C@O); 1H NMR (CDCl3): d 2.0 (s, 3H,
CH3), 6.9–7.3 (m, 8H, Ar-H). Anal. Calcd for C14H11BrO2 (291): C, 57.76; H, 3.81;
Br, 27.45. Found: C, 57.61; H, 3.89; Br, 27.32. Compound 3b: IR (Nujol):
1718 cmꢁ1 (ester, C@O); 1H NMR (CDCl3): d 2.1 (s, 3H, CH3), 6.5–7.3 (m, 8H, Ar-
H). Anal. Calcd for C14H11ClO2 (246.5): C, 68.16; H, 4.49; Cl, 14.37. Found: C,
68.22; H, 4.58; Cl, 14.45. Compound 3c: IR (Nujol): 1760 cmꢁ1 (ester, C@O); 1
H
NMR (CDCl3): d 2.25 (s, 6H, 2CH3), 6.9–7.4 (m, 8H, Ar-H). Anal. Calcd for
C15H14O2 (226): C, 79.62; H, 6.24. Found: C, 79.49; H, 6.15. Compound 3d: Yield
27.74 g (92%). IR (Nujol): 1770 cmꢁ1 (ester, C@O); 1H NMR (CDCl3): d 2.3 (s, 3H,
CH3), 6.95–7.45 (m, 8H, Ar-H). Anal. Calcd for C14H11FO2 (230): C, 73.03; H,
4.82; F, 8.25. Found: C, 73.13; H, 4.75; F, 8.12. Compound 3e: IR (Nujol):
1760 cmꢁ1 (ester, C@O); 1H NMR (CDCl3): d 2.2–2.5 (d, 6H, 2CH3), 6.95–7.43
(m, 8H, Ar-H). Anal. Calcd for C15H14O2 (226): C, 79.62; H, 6.24. Found: C,
79.51; H, 6.16. Compound 3f: IR (Nujol): 1735 cmꢁ1 (ester, C@O); 1H NMR
(CDCl3): d 2.15 (s, 3H, CH3), 6.9–7.5 (m, 7H, Ar-H). Anal. Calcd for C14H10Cl2O2
(281): C, 59.81; H, 3.59; Cl, 25.22. Found: C, 59.72; H, 3.66; Cl, 25.15. Compound
3g: IR (Nujol): 1750 cmꢁ1 (ester, C@O); 1H NMR (CDCl3): d 2.2 (s, 3H, CH3), 3.75
(s, 3H, OCH3), 6.8–7.65 (m, 8H, Ar-H). Anal. Calcd for C15H14O3 (242): C, 74.38;
H, 5.78. Found: C, 74.34; H, 5.75. Compound 3h: IR (Nujol): 1720 cmꢁ1 (ester,
C@O); 1H NMR (CDCl3): d 2.2–2.4 (d, 6H, 2CH3), 6.85–7.5 (m, 8H, Ar-H). Anal.
Calcd for C15H14O2 (226): C, 79.62; H, 6.24. Found: C, 79.44; H, 6.10. Compound
3i: IR (Nujol): 1710 cmꢁ1 (ester, C@O); 1H NMR (CDCl3): d 2.2 (s, 3H, CH3),
6.95–7.4 (m, 8H, Ar-H). Anal. Calcd for C14H11BrO2 (291): C, 57.76; H, 3.81; Br,
27.45. Found: C, 57.59; H, 3.81; Br, 27.29. Compound 3j: IR (Nujol): 1765 cmꢁ1
(ester, C@O); 1H NMR (CDCl3): d 2.2 (s, 3H, CH3), 6.75–7.55 (m, 9H, Ar-H). Anal.
Calcd for C14H12O2 (212): C, 79.22; H, 5.70. Found: C, 79.05; H, 5.79.
In conclusion, a new sequence of benzophenone N-ethyl piper-
idine ether analogues exhibiting anti-inflammatory activity was
synthesized. Halo compounds, with a bromo group (5a), fluoro
group (5d), and chloro group (5f), at para position showed signifi-
cant anti-inflammatory profile with low gastric ulceration inci-
dence as compared with similar toxic profiles for reference non
NSAIDs in the liver.
Acknowledgments
The authors express their sincere gratitude to the University of
Mysore, Mysore for providing laboratory facilities.
References and notes
22. Compound 4a: mp 166–168 °C; IR (Nujol): 1640 (C@O), 3515–3630 cmꢁ1 (OH);
1H NMR (CDCl3): d 2.1 (s, 3H, CH3), 6.9–7.4 (m, 7H, Ar-H), 9.0 (br s, 1H, OH); EI-
MS: m/z 290 (M+, 84), 292 (M+, 81), 289 (100), 291 (94), 135 (56), 107 (51).
Anal. Calcd for C14H11BrO2 (291): C, 57.73; H, 3.78; Br, 27.49. Found: C, 57.67;
H, 3.88; Br, 27.39. Compound 4b: mp 158–160 °C; IR (Nujol): 1660 (C@O),
3515–3625 cmꢁ1 (OH); 1H NMR (CDCl3): d 2.2 (s, 3H, CH3), 6.9–7.35 (m, 7H, Ar-
H), 9.3 (br s, 1H, OH); EI-MS: m/z 246.5 (M+, 86), 245.5 (100), 135 (57), 107
(52). Anal. Calcd for C14H11ClO2 (246.5): C, 68.15; H, 4.46; Cl, 14.40. Found: C,
68.11; H, 4.42; Cl, 14.36. Compound 4c: mp 156–158 °C; IR (Nujol): 1660
(C@O), 3520–3610 cmꢁ1 (OH); 1H NMR (CDCl3): d 2.3 (s, 6H, 2CH3), 6.95–7.65
(m, 7H, Ar-H), 9.25 (br s, 1H, OH); EI-MS: m/z 226 (M+, 87), 225 (100), 135 (56),
107 (51). Anal. Calcd for C15H14O2 (226): C, 79.62; H, 6.24. Found: C, 79.75; H,
6.38. Compound 4d: mp 130–132 °C; IR (Nujol): 1670 (C@O), 3570–3665 cmꢁ1
(OH); 1H NMR (CDCl3): d 2.0 (s, 3H, CH3), 6.8–7.55 (m, 7H, Ar-H), 9.3 (br s, 1H,
OH); EI-MS: m/z 230 (M+, 79), 229 (100), 135 (60), 107 (47). Anal. Calcd for
C14H11FO2 (230): C, 73.03; H, 4.82; F, 8.25. Found: C, 73.13; H, 4.75; F, 8.32.
Compound 4e: mp 160–162 °C; IR (Nujol): 1673 (C@O), 3550–3640 cmꢁ1
(OH);1H NMR (CDCl3): d 2.2–2.45 (d, 6H, 2CH3), 6.95–7.65 (m, 7H, Ar-H), 9.1 (br
s, 1H, OH); EI-MS: m/z 226 (M+, 88), 225 (100), 135 (55), 107 (50). Anal. Calcd
for C15H14O2 (226): C, 79.62; H, 6.24. Found: C, 79.70; H, 6.35. Compound 4f:
1. Ruedi, K. B.; Christina, F.; Paul, N.; Michael, S.; Sterner-Kock, A.; Kock, M.;
Putney, L.; Ferrick, D. A.; Hyde, D. M.; Love, R. B. Inflammation 2008, 31, 167.
2. Coussens, L. M.; Werb, Z. Nature 2002, 420, 860.
3. Smith, W. L.; Marnett, L. J. Biochim. Biophys. Acta 1991, 1083, 1.
4. Vane, J. R.; Bakhle, Y. S.; Annu, R. M. Rev. Pharmacol. Toxicol. 1998, 38, 97.
5. Smith, W. L.; DeWitt, D. L. Adv. Immunol. 1996, 62, 167.
6. Dubois, R. N.; Abramson, S. B.; Crofford, L.; Gupta, R. A.; Simon, L. S.; Van De
Putte, L. B.; Lipsky, P. E. FASEB J. 1998, 12, 1063.
7. Palomer, A.; Perez, J. J.; Navea, S.; Llorens, O.; Pascual, J.; Garcia, M. L.; Mauleon,
D. M. J. Med. Chem. 2000, 43, 2280.
8. Palomer, A.; Pascual, J.; Cabre, M.; Borras, L.; Gonzalez, G.; Aparici, M.;
Carabaza, A.; Cabre, F.; Garcia, M. L.; Mauleon, D. Bioorg. Med. Chem. Lett. 2002,
12, 533.
9. Soberman, R. J.; Christmas, P. J. Clin. Invest. 2003, 111, 1107.
10. Smith, W. L.; Garavito, R. M.; DeWitt, D. L. J. Biol. Chem. 1996, 271, 33157.
11. Taketo, M. M. J. Natl. Cancer Inst. 1998, 90, 1529.
12. Morita, I. M.; Schindler, M. K.; Regier, J. C.; Otto, T.; Hori, D. L.; DeWitt, D. L.;
Smith, W. L. J. Biol. Chem. 1995, 270, 10902.
13. De Garavilla, L.; Greco, M. N.; Sukumar, N.; Chen, Z. W.; Pineda, A. O.; Mathews,
F. S.; Di Cera, E.; Giardino, E. C.; Wells, G. I.; Haertlein, B. J.; Kauffman, J. A.;