3068
K. V. Sashidhara et al. / Bioorg. Med. Chem. Lett. 20 (2010) 3065–3069
11. (a) Inoue, T. Atherosclerosis 2002, 160, 369; (b) Ross, R. Nature 1993, 362, 801;
(c) Aviram, M. Atherosclerosis 1993, 98, 1.
12. Graham, D. J.; Staffa, J. A.; Shatin, D.; Andrade, S. E.; Schech, S. D.; La
Grenade, L.; Gurwitz, J. H.; Chan, K. A.; Goodman, M. J.; Platt, R. JAMA 2004,
292, 2585.
13. Evans, M.; Rees, A. Curr. Opin. Lipidol. 2002, 13, 415.
14. Buccolo, G.; David, H. Clin. Chem. 1973, 19, 476.
15. Sashidhara, K. V.; Rosaiah, J. N.; Bhatia, G.; Saxena, J. K. Eur. J. Med. Chem. 2008,
43, 2592.
16. General procedure for the synthesis of compounds: Synthesis of 4-methyl-7-(1-
phenyl-ethoxy)-benzo[h]chromen-2-one (3): To a solution of compound 2 (2 g,
8.85 mmol) in dry DMF (50 mL) was added NaH (0.42 g, 17.6 mmol) at 0–5 °C
and the reaction mixture was allowed to stir for 25–30 min. 1-Bromo-ethyl-
benzene (1.63 g, 8.85 mmol) was then added to the reaction mixture and
stirring continued at room temperature for 1.5–2 h. After completion of the
reaction, excess DMF was removed under reduced pressure and the residue
was diluted with water and extracted with CHCl3 (15 mL Â 3). The organic
layer was washed with water and dried over anhydrous Na2SO4. The crude
product was purified by column chromatography over silica (230–400 mesh)
and elution with 4% ethyl acetate in hexane furnished the pure compound 3.
This was obtained in 65% yield as white solid. Mp 142–143 °C; 1H NMR (CDCl3,
300 MHz) d 8.3 (d, J = 8.8 Hz, 1H), 8.08 (d, J = 8.8 Hz, 1H), 7.61 (d, J = 9.3 Hz, 1H),
7.45–7.31 (m, 6H), 6.85 (d, J = 7.9 Hz, 1H), 6.38 (s, 1H), 5.55 (q, J = 6.1 Hz, 1H),
2.55 (s, 3H), 1.8 (d, J = 6.6 Hz, 3H); 13C NMR (CDCl3, 75 MHz) d 159.7, 152.1,
151.9, 149.0, 141.4, 127.5, 126.4, 126.0, 124.1, 123.0, 118.1, 117.3, 114.3, 113.2,
113.1, 108.5, 23.2, 17.9; ESI (m/z) 331 [M+H]+.
synthesized compounds 4 and 5 exhibited significant decrease in
superoxide ions inhibition by 40% and 28%, hydroxyl radicals inhi-
bition by 41% and 38% and microsomal lipid peroxidation inhibi-
tion by 38% and 37%, respectively. The standard drug Alloperinol,
at 20
and
l
g/mL, showed 86% inhibition in superoxide ions. Mannitol
a
-tocopherol, at the same dose, showed 48% and 45% inhibi-
tion of hydroxyl ions and microsomal lipid peroxidation, respec-
tively. The scavenging potential of the other derivatives was
modest at best. The wide variation in the free radical scavenging
potential may be due to the variation in the proton–electron trans-
fer by the derivatives due to difference in their structures and sta-
bility. As propensity of radical formation and stabilization, ability
of metal complexation, and lipophilicity are important factors for
the antioxidant activity.
In terms of SAR, the benzocoumarin derivatives (8–13) were
found to be inactive maybe due to low lipophilicity, while the simple
alkyl substituted benzocoumarins (3–5) exhibited interesting activ-
ity. The most promising was compound 4, which incorporates an un-
branched benzyl group. This compound showed good activity in
both lipid lowering and antioxidant experiments. Initial studies
indicate compound 4 to be devoid of cytotoxicity in normal cells.
Also, when evaluated for dose response activity, at a lower dose of
(25 mg/ kg) exhibited 26%, 24%, and 23% lowering in TC, PL, and
TG, respectively, and further dose optimization studies are under-
way. Further studies on 4 are in progress and will be published in
the future.
In conclusion, a series of novel alkyl substituted benzocoumarin
derivatives (3–5) have been synthesized from 7-hydroxy-4-methyl-
benzo[h]chromen-2-one (2) and the amino alcohol derivatives of
benzocoumarins (8–13) were synthesized from nucleophilic open-
ing of the oxirane moiety with different anilines. These newly
synthesized compounds were evaluated for their anti-dyslipidemic
and antioxidant activities. Compound 4 exhibited significant dual
lipid lowering and antioxidant activity and lead optimization is
underway.
Following the above procedure, compounds 4–5 have been synthesized.
7-Benzyloxy-4-methyl-benzo[h]chromen-2-one (4): This was obtained in 68%
yield as white solid. Mp 176–177 °C; 1H NMR (CDCl3, 300 MHz) d 8.24–8.17 (m,
2H), 7.61–7.39 (m, 7H), 7.09 (d, J = 7.8 Hz, 1H), 6.4 (s, 1H), 5.28 (s, 2H), 2.55 (s,
3H); 13C NMR (CDCl3, 75 MHz) d 159.6, 152.9, 152.1, 149.0, 135.2, 127.4, 126.8,
126.1, 126.0, 125.7, 123.0, 118.2, 117.2, 114.4, 113.6, 113.3, 106.8, 69.2, 17.9;
ESI (m/z) 316 [M]+.
(4-Methyl-2-oxo-2H-benzo[h]chromen-7-yloxy)-acetic acid ethyl ester (5): This
was obtained in 62% yield as white solid. Mp 148–149 °C; 1H NMR (CDCl3,
300 MHz) d 8.27–8.2 (m, 2H), 7.63 (d, J = 8.7 Hz, 1H), 7.53 (t, J = 7.8 Hz, 1H), 6.9
(d, J = 7.8 Hz, 1H), 6.41 (s, 1H), 4.84 (s, 2H), 4.33 (q, J = 7.4 Hz, 2H), 2.57 (s, 3H),
1.34 (t, J = 7.8 Hz, 3H); 13C NMR (CDCl3, 75 MHz) d 168.9, 161.3, 153.9, 153.7,
127.5, 127.3, 124.8, 120.2, 118.9, 116.2, 115.2, 115.1, 108.3, 66.1, 62.1, 19.8,
14.5; ESI (m/z) 313 [M+H]+.
Synthesis of 4-methyl-7-oxiranylmethoxy-benzo[h]chromen-2-one (6): The
compound 2 (2.0 g, 8.85 mmol) and anhydrous K2CO3 (1.83 g, 13.3 mmol)
were taken in epichlorohydrin (75 mL) and refluxed for 1 h. After completion of
the reaction, K2CO3 was filtered off and epichlorohydrin was removed in vacuo.
The residue was diluted with water and extracted with CHCl3 (75 mL Â 3). The
organic layer was washed with water, brine, and dried over anhydrous Na2SO4.
Column chromatography over silica gel (100–200 mesh) and elution with 30%
ethyl acetate in hexane furnished the epoxide 6.
Acknowledgments
Compound 7 was obtained as a side product.
This was obtained in 60% yield as white solid. Mp 142–143 °C; 1H NMR (CDCl3,
300 MHz) d 8.12–8.08 (m, 2H), 7.53–7.46 (m, 2H), 6.95 (d, J = 8.1 Hz, 1H), 6.35
(s, 1H), 4.46 (dd, J = 2.9, 11.1 Hz, 1H), 4.11 (dd, J = 5.8, 11.1 Hz, 1H), 3.53–3.48
(m, 1H), 3.0 (t, J = 4.4 Hz, 1H), 2.87–2.85 (m, 1H), 2.5 (s, 3H); 13C NMR (CDCl3,
75 MHz) d 159.6, 152.7, 152.1, 148.9, 125.9, 125.4, 122.9, 118.2, 116.9, 114.3,
113.9, 113.2, 106.4, 68.1, 48.9, 43.4, 17.8; ESI (m/z) 283 [M+H]+.
The authors are grateful to the Director, CDRI, Lucknow, India
for constant encouragement in drug development program, S.P.
Singh for technical support, SAIF for NMR, IR, and mass spectral
data. J.N.R. & A.K. thank the UGC and CSIR New Delhi, India, respec-
tively for financial support. This is CDRI publication number 7811.
7-(3-Chloro-2-hydroxy-propoxy)-4-methyl-benzo[h]chromen-2-one (7): This was
obtained in 15% yield as white solid. Mp 153–154 °C; 1H NMR (DMSO-d6,
300 MHz) d 8.15 (d, J = 8.6 Hz, 1H), 7.94 (d, J = 8.3 Hz, 1H), 7.76 (d, J = 9.1 Hz,
1H), 7.64 (t, J = 8.3 Hz, 1H), 7.24 (d, J = 7.8 Hz, 1H), 6.53 (s, 1H), 5.77 (s, 1H),
4.27 (s, 3H), 3.97–3.85 (m, 2H), 2.56 (s, 3H); 13C NMR (DMSO-d6, 75 MHz) d
160.0, 154.4, 154.3, 149.8, 128.3, 126.4, 123.7, 120.9, 118.3, 115.9, 114.5, 114.1,
108.5, 70.0, 69.0, 47.1, 19.0; ESI (m/z) 319 [M+H]+.
Supplementary data
Supplementary data associated with this article can be found, in
7-(2-Hydroxy-3-phenylamino-propoxy)-4-methyl-benzo[h]chromen-2-one
(8):
The compound 6 (0.2 g, 0.70 mmol) and aniline (0.99 g, 1.06 mmol) were
dissolved in ethanol (15 mL) and refluxed for 5 h. After completion of the
reaction excess ethanol was removed through high vacuo and the residue was
diluted with water and extracted with ethyl acetate. The organic layer was
washed with water, brine, and dried over anhydrous Na2SO4. Column
chromatography over silica gel (100–200 mesh) and elution with 50%
chloroform in hexane furnished the final product 8.
References and notes
1. Musa, M. A.; Cooperwood, J. S.; Khan, M. O. Curr. Med. Chem. 2008, 15, 2664.
2. Kulkarni, M. V.; Kulkarni, G. M.; Lin, C. H.; Sun, C. M. Curr. Med. Chem. 2006, 13,
2795.
3. Kostova, I. Mini-Rev. Med. Chem. 2006, 6, 365.
4. Fylaktakidou, K. C.; Hadjipavlou-Litina, D. J.; Litinas, K. E.; Nicolaides, D. N. Curr.
Pharm. Des. 2004, 10, 3813.
5. Kontogiorgis, C.; Hadjipavlou-Litina, D. J. Med. Chem. 2005, 48, 6400.
6. Chimenti, F.; Secci, D.; Bolasco, A.; Chimenti, P.; Bizzarri, B.; Granese, A.;
Carradori, S.; Yáñez, M.; Orallo, F.; Ortuso, F.; Alcaro, S. J. Med. Chem. 2009, 52,
1935.
7. Lin, H. C.; Tsai, S. H.; Chen, C. S.; Chang, Y. C.; Lee, C. M.; Lai, Z. Y.; Lin, C. M.
Biochem. Pharmacol. 2008, 75, 1416.
8. Yuce, B.; Danis, O.; Ogan, A.; Sener, G.; Bulut, M.; Yarat, A. Arzneim-Forsch. Drug
Res. 2009, 59, 129.
9. Madhavan, G. R.; Balraju, V.; Mallesham, B.; Chakrabarti, R.; Lohray, V. B. Bioorg.
Med. Chem. Lett. 2003, 13, 2547.
This was obtained in 75% yield as white solid. Mp 164–165 °C; IR (KBr, cmÀ1):
3427, 1714; 1H NMR (DMSO-d6, 300 MHz) d 8.17 (d, J = 9.1 Hz, 1H), 7.91 (d,
J = 8.1 Hz, 1H), 7.77 (d, J = 8.8 Hz, 1H), 7.6 (t, J = 8.4 Hz, 1H), 7.17 (d, J = 7.7 Hz,
1H), 7.06 (t, J = 7.7 Hz, 2H), 6.65 (d, J = 8.4 Hz, 2H), 6.54–6.51 (m, 2H), 5.66 (t,
J = 5.2 Hz, 1H), 5.38 (d, J = 4.4 Hz, 1H), 4.23–4.16 (m, 3H), 3.25–3.22 (m, 1H), 2.5
(s, 3H); 13C NMR (DMSO-d6, 75 MHz) d 160.1, 160.1, 154.6, 149.8, 149.2, 129.3,
128.3, 126.5, 123.7, 120.7, 118.4, 116.2, 115.9, 114.4, 113.8, 112.6, 108.5, 71.4,
68.0, 46.7, 19.1; ESI (m/z) 376 [M+H]+.
Following the above procedure, compounds 9–13 have been synthesized.
7-(2-Hydroxy-3-p-tolylamino-propoxy)-4-methyl-benzo[h]chromen-2-one
(9):
This was obtained in 78% yield as white solid. Mp 177–178 °C; IR (KBr,
cmÀ1): 3420, 1717; 1H NMR (DMSO-d6, 300 MHz) d 8.14 (d, J = 7.1 Hz, 1H), 7.88
(d, J = 6.3 Hz, 1H), 7.74 (d, J = 7.1 Hz, 1H), 7.57 (t, J = 6.3 Hz, 1H), 7.15 (d,
J = 5.5 Hz, 1H), 6.87 (d, J = 5.5 Hz, 2H), 6.55 (d, J = 6.3 Hz, 2H), 6.48 (s, 1H), 5.37–
5.31 (m, 2H), 4.21–4.14 (m, 3H), 3.18–3.16 (m, 1H), 2.51 (s, 3H), 2.14 (s, 3H);
13C NMR (CDCl3, 75 MHz) d 158.8, 153.3, 153.3, 148.6, 145.7, 128.5, 127.1,
10. Borges, F.; Roleira, F.; Milhazes, N.; Santana, L.; Uriarte, E. Curr. Med. Chem.
2005, 12, 887.