982
S. Mittal et al. / Bioorg. Med. Chem. Lett. 14 (2004) 979–982
energy obtained through docking studies correlates with
in vitro and in vivo studies.
3. Ormrod, D.; Wellington, K.; Wagstaff, A. J. Drugs 2002,
62, 2059.
4. Dannhardt, G.; Keifer, W. Eur. J. Med. Chem. 2001, 36,
109.
A radiochemical enzyme assay was carried out for
assessing antiinflammatory activity in terms of COX-1
and COX-2 catalyzed prostaglandin biosynthesis in
vitro. S-ibuprofen and S-1b were tested for cyclooxy-
genase enzyme inhibition activity. The relative activities
of the two compounds were established by comparing
their IC50 values with those of ibuprofen in the same
model.20 The in vitro study was done on purified
enzymes, the source for COX-1 being ram seminal vesi-
cle and that for COX-2 being sheep placenta. IC50
values obtained are shown in Table 3. The results from
in vitro studies indicate that S-1b is more selective for
COX-2 enzyme (about 1.47 times more) as compared to
S-ibuprofen and is 20 times less effective on COX-1,
which indicates that it will have less adverse effects like
gastric damage as compared to S-ibuprofen. The ste-
reoisomer S-1b was evaluated for its antiinflammatory
activity in carrageenan-induced hind paw edema in a,
rat model.21 Male Sprague–Dawley rats of 8–10 weeks
age weighing 220–250 g were used in the study. The
drug was administered orally as a suspension in 1%
CMC. Acute hind paw edema was produced by inject-
ing 0.1 mL of carrageenan (prepared as 1% solution in
sterile normal saline) subcutaneously to the plantar
surface of the right hind paw of the rats half an hour
after injecting the drug. The rat paw volume up to the
ankle joint was measured using plethysmometer at 60,
120 and 180 min post carrageenan injection. ED50 of the
drugs was calculated by linear regression of the response
with various dose (0.3–100 mg/kg) at 180 min. Based on
ED50 values (Table 4), the order of potency was:
5. Wallace, J. L. Trends. Pharmacol Sci. 1999, 20, 4.
6. Agranat, I.; Caner, H.; Caldwell, J. Nature Rev. Drug.
Discov. 2002, 1, 753.
7. Anonymous Drugs of Future 1988, 13, 411.
9. Mittal, S.; Johar, P. S.; Chawla, H. P. S. Indian patent
Application no. 874/DEL/2002.
10. Roszkowski, A. P.; Rooks, W. H., II; Tomolonis, A. J.;
Miller, L. M. J. Pharmacol. Exp. Ther. 1971, 179, 114.
11. Sastry, C. V. R.; Marwah, A. K.; Marwah, P.; Rao, G. S.;
Shridhar, D. R. Synthesis 1987, 11, 1024.
12. Marwah, P.; Marwah, A. K.; Rao, G. S. Synth. Comm.
1989, 19, 2809.
13. Kumar, M. A.; Reddy, S. C. V.; Rai, S. D.GB 2,181,728,
1987; Chem. Abstr. 1988, 108 94374.
14. Sone, T.; Inoue, M.; Sato, K. Bull. Chem. Soc. Jpn. 1988,
61, 3779.
15. 1H NMR (CDCl3), IR, MS (EI), mp for representative
1
compounds: 3: H NMR (CDCl3): d 1.25 (3H, t, J=7.5),
2.66 (2H, q, J=7.5), 7.13–7.24 (4H, m), 7.42 (2H, d,
J=8.1); IR (KBr): 3100, 2965, 1501, 1425, 1008, 822, 740
cmÀ1; MS (m/z): 222 (M+); mp: 97 ꢀC. 4: 1H NMR
(CDCl3): d 1.25 (3H, t, J=7.5), 2.6 (2H, q, J=7.5), 7.21–
7.24 (2H, m), 7.37–7.40 (3H, m), 7.50–7.53 (2H, d,
J=8.0); IR (KBr): 3099, 2965, 1500, 1428, 1202, 783
cmÀ1; MS (m/z): 188 (M+); mp: 92.25 ꢀC (Lit88 mp: 96–
97 ꢀC). 5: H NMR (CDCl3): d 2.0 (3H, d, J=6.9), 5.27
1
(1H, q, J=6.9), 7.38–7.48 (5H, m), 7.56 (2H, d, J=8.1);
IR (KBr): 3097, 2982, 1428, 1372, 1174, 783 cmÀ1; MS
(m/z): 266 (MÀ1)+; mp: 88 ꢀC. 6: 1H NMR (CDCl3): d
1.67 (3H, d, J=7.3), 3.92 (1H, q, J=7.3), 7.37–7.47 (5H,
m), 7.6 (2H, d, J=8.2); IR (KBr): 3100, 2984, 2239, 1500,
837, 782 cmÀ1; MS (m/z): 213 (M+); mp: 99.5 ꢀC (Lit87
mp: 110 ꢀC). 1b: 1H NMR (CDCl3): d 1.53 (3H, d,
J=7.1), 3.76 (1H, q, J=7.1), 7.3–7.42 (5H, m), 7.55 (2H,
d, J=8.1); IR (KBr): 3101, 2936, 1691, 1408, 1223, 776
cmÀ1; MS (m/z): 232 (M+); mp: 186.12 ꢀC (Lit87 mp:
182 ꢀC).
S-naproxen > S-1b ꢁ S-naproxen > 1b ꢁ S-ibuprofen
>> RS-ibuprofen:
16. 0.5 g (2.1 mmol) and 0.42 (2.1 mmol) were dissolved in 5
mL of methanol and the solvent evaporated. The resulting
diastereomeric salt was dissolved in 10 mL of absolute
ethanol and kept for crystallization. The crystals were
dissolved in 3.5% HCl (10 mL) and extracted with di-
ethylether (2Â10 mL). The ethereal layer was dried over
Na2SO4 and evaporated to dryness to give S-1b. The ratio
of the two enantiomers of 1b was determined by (R,R)
Whelk-O 1 with 98/2/0.1 hexane/isopropyl alcohol/acetic
acid as mobile phase using UVdetector at 264 nm. The
retention time of S and R enantiomers of 1b was 13.9 min
and 14.9 min, respectively.
In conclusion, the synthesis of 4-(3-thienyl)phenyl-a-
methylacetic acid was accomplished through a more
efficient process. This racemic acid was resolved to S-4-
(3-thienyl)phenyl-a-methylacetic acid through fractional
crystallization using N-methyl-d–glucamine as a chiral
base. The S-isomer was tested for its biological activity
and was found to have better pharmacological profile as
compared to S-ibuprofen. The in vitro and in vivo
results were rationalized through docking studies on
cyclooxygenase enzymes, both COX-1 and COX-2 using
FlexX program followed by molecular dynamics.
17. (a) Sybyl6.8, Tripos Associates Inc., 1699 S Hanley Rd.,
St. Louis, MO 631444, USA. (b) Kramer, B.; Metz, G.;
Rarey, M.; Lengauer, T. Med. Chem. Res. 1999, 9, 463.
19. Fabiola, G. F.; Pattabhi, V.; Nagarajan, K. Bioorg. Med.
Chem. 1998, 6, 2337.
References and notes
20. Noreen, Y.; Ringbom, T.; Perera, P.; Danielson, H.;
Bohlin, L. J. Nat. Prod. 1998, 61, 2.
21. Hiramatsu, Y.; Akita, S.; Salamin, P. A.; Maier, R.
Arzneimittelforschung/Drug Res. 1990, 40, 1117.
1. Cashman, J. N. Drugs 1996, 52 (suppl.5), 13.
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