4
S. Xu et al. / Bioorg. Med. Chem. Lett. xxx (2014) xxx–xxx
to possess most potent activity (0.5 lg/mL), which were 64- and
32-fold lower MICs than that of their parent compounds (7 and
9), respectively. However, when trans-cinnamic acid was intro-
duced to oxidized oridonin (11), no increase in antimicrobial activ-
ity was observed in derivative 12c. To our surprise, although parent
compound (15) was found to show good antimycobacterial activ-
ity, its 14-O-derivatives (16a–c) had no decrease in the MIC values.
Next, the compounds with potent activity against M. phlei were
further tested against M. smegmatis and M. marinum. The data
revealed that the cinnamyl-oridonin derivatives also have potent
activities against M. smegmatis and M. marinum, but they are
generally less active than the positive drug streptomycin.
In conclusion, it is the first report on the antimycobacterial
activity of natural oridonin and its semisynthetic analogues. The
preliminary results showed that these compounds may be
regarded as the interesting leads for the further design and synthe-
sis of M. tuberculosis inhibitors. Furthermore, the antimycobacterial
activity of oridonin and its derivatives could be greatly increased
by the introduction of trans-cinnamic moiety. As
a result,
cinnamyl-oridonin derivatives 2k, 8d, 10c and 10d displayed the
promising antimycobacterial activity compared to the positive
drug streptomycin. The preliminary SARs obtained suggest that
the antimycobacterial activity may be influenced by the substitu-
tions at the C-1 position of oridonin.
Based on the preliminary investigation results, our efforts are
now focused on the modification and understanding the mode of
action of these novel template molecules. It is expected that the
biological results described and the further modification studies
will expedite the development of new chemotherapeutic agents
for the clinical intervention of tubercular disease.
10. Analytical data for the representative compounds: (2k): 75% as white solid, mp
175–177 °C; 1H NMR (CDCl3, 300 MHz):
d
(ppm) 7.59, 6.20 (dd,
JA = JB = 15.9 Hz, each 1H), 7.44 (d, J = 8.7 Hz, 2H), 6.89 (d, J = 8.7 Hz, 2H), 6.21
(m, 2H), 5.93 (s, 1H), 5.49 (s, 1H), 4.42 (s, 1H), 4.09, 4.35 (dd, JA = JB = 9.6 Hz,
each 1H), 3.86 (s, 3H), 3.79 (m, 1H), 3.53 (m, 1H), 3.27 (m, 1H), 2.63 (m, 1H),
2.38 (m, 1H), 2.04 (m, 1H), 1.80 (m, 2H), 1.71 (m, 5H), 1.54 (m, 1H), 1.11 (s, 6H);
13C NMR (CDCl3, 75 MHz): d (ppm) 206.3, 165.0, 161.4, 149.4, 145.8, 129.6,
126.0, 119.7, 113.9, 113.5, 95.8, 76.1, 72.9, 62.9, 61.4, 59.4, 54.9, 54.1, 40.9,
40.8, 38.2, 33.3, 32.0, 30.0, 29.5, 21.1, 19.2; MS (ESI) m/z: 525.3 [M+H]+; HR-MS
(ESI, M+H) m/z: calcd for C30H37O8: 525.2483, found 525.2493.
Acknowledgments
This study was supported by grants from the National Natural
Science Foundation (Nos. 30973610; 81373280), the Young Teach-
ers’ Scientific Research Fund Project of Shenyang Pharmaceutical
University (QNJJ 2013501) and the Project Program of State Key
Laboratory of Natural Medicines, China Pharmaceutical University
(No. SKLNMZZCX201404).
Supplementary data
15. Wang, L.; Li, D. H.; Xu, S. T.; Cai, H.; Yao, H. Q.; Zhang, Y. H.; Jiang, J. Y.; Xu, J. Y.
Eur. J. Med. Chem. 2012, 52, 242. Analytical data for the representative
compounds: (8d): 68% as white solid, mp 148–150 °C; 1H NMR (CDCl3,
300 MHz): d (ppm) 7.60, 6.28 (dd, JA = JB = 16.2 Hz, each 1H), 7.48 (m, 2H), 7.04
(t, J = 11.4 Hz, 2H), 6.24 (s, 1H), 5.80 (s, 1H), 5.57 (s, 1H), 5.33 (d, J = 1.2 Hz, 1H),
4.60 (m, 1H), 3.96, 4.08 (dd, JA = JB = 9.6 Hz, each 1H), 3.24 (d, J = 9.3 Hz, 1H),
2.78 (m, 2H), 2.61 (m, 1H), 2.04 (m, 2H), 1.90 (s, 1H), 1.71 (m, 4H), 1.54 (m, 1H),
1.15 (s, 3H), 1.01 (s, 3H); 13C NMR (CDCl3, 75 MHz): d (ppm) 196.2, 165.6,
165.3, 147.3, 144.7, 129.8, 129.8, 119.8, 116.2, 115.6, 115.3, 101.2, 74.0, 73.6,
59.7, 53.3, 49.5, 48.0, 40.4, 36.6, 32.4, 30.5, 29.2, 22.8, 22.5, 19.3; MS (ESI) m/z:
511.3 [M+H]+; HR-MS (ESI, M+H) m/z: calcd for C29H32FO7: 511.2127, found
511.2136. (10d): 64% as white solid, mp 136–138 °C; 1H NMR (CDCl3,
Supplementary data associated with this article can be found, in
References and notes
300 MHz);
d (ppm) 7.62, 6.27 (dd, JA = JB = 16.2 Hz, each 1H), 7.47 (t,
2. World Health Organization, Tuberculosis Fact Sheet N°104, Updated October
J = 8.4 Hz, 2H), 7.07 (t, J = 8.4 Hz, 2H), 6.18 (s, 1H), 5.93 (s, 1H), 5.62 (s, 1H),
4.64 (m, 1H), 4.31, 4.02 (dd, JA = JB = 9.3 Hz, each 1H), 3.27 (d, J = 9.3 Hz, 1H),
2.60 (m, 1H), 2.06 (m, 2H), 1.93 (s, 2H), 1.74 (m, 4H), 1.52 (m, 1H), 1.26 (s, 3H),
1.22 (s, 3H); 13C NMR (CDCl3, 75 MHz): d 197.2, 189.4, 175.2, 166.0, 165.7,
162.4, 146.9, 145.4, 130.3, 130.1, 121.4, 116.2, 115.8, 74.8, 73.4, 71.3, 59.4,
50.7, 47.5, 45.9, 40.4, 36.3, 33.0, 32.2, 29.4, 23.5, 23.0, 19.1; MS (ESI) m/z: 509.2
[M+H]+, 526.2 [M+NH4]+; HR-MS (ESI, M+H) m/z: calcd for C29H30FO7:
509.1970, found 509.1966.