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to inhibit closely related cysteine proteases owing to
poor selectivity.9,23 Indeed, MDL 28,170 inhibited
cathepsin B and cathepsin L by nearly 100% at 0.2 lM
concentration. On the other hand, chromone derivatives
2 showed moderate inhibition on both cathepsins in a
dose-dependent manner. Compound 2i, the most potent
calpain inhibitor of this series, exhibited only 14.4% and
22.4% inhibition on the activities of cathepsin B and
cathepsin L, respectively, at the same concentration,
demonstrating high selectivity of chromone derivatives
for l-calpain.
In conclusion, chromone carboxamides as novel l-cal-
pain inhibitors were synthesized and evaluated for l-cal-
pain inhibition with a brief SAR. Among synthesized,
compound 2i derived from primary amide was the most
potent calpain inhibitor with high selectivity for l-cal-
pain over two related cysteine proteases cathepsin B
and cathepsin L. Therefore, the chromone ring can be
considered as a new scaffold in designing more selective
and potent l-calpain inhibitors for treatment of calpain-
associated diseases.
Acknowledgements
This research was supported by a grant (M1-0310-22-
0001) from Bio-challenger Program funded by Ministry
of Science and Technology, Korea.
22. Spectra data of selected compound 2i: 1H NMR
(300 MHz, DMSO-d6) d 9.41 (d, 1H, J = 9.0 Hz, –CO–
NH–), 8.20 (s, 1H, –CO–NH2), 8.05 (d, 1H, J = 7.9 Hz,
aromatic), 7.93 (s, 1H, –CO–NH2), 7.85 (t, 1H, J = 7.7 Hz,
aromatic), 7.65 (d, 1H, J = 8.4 Hz, aromatic), 7.50 (t, 1H,
J = 7.5 Hz, aromatic), 7.34–7.22 (m, 5H, aromatic), 5.47
(m, 1H, –NH–CH–CH2–Ph), 3.29 (dd, 1H, J = 3.8,
13.8 Hz, –NH–CH–CH2–Ph), 2.91 (dd, 1H, J = 13.8,
10.2 Hz, –NH–CH–CH2–Ph), 1.95 (s, 3H, –C@C–CH3);
13C NMR (75 MHz, DMSO-d6) d 201.5, 183.0, 167.9,
166.5, 160.2, 158.1, 142.8, 140.1, 134.5, 133.9, 132.2, 131.2,
130.5, 127.4, 124.1, 123.9, 61.3, 40.2, 15.0; HRFABMS
(positive-mode) m/z calcd for C12H19O5N2: 379.1294,
obsd: 379.1269.
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