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DMSO) d 11.23–11.86 (br, 2H), 8.00 (t, 1H), 7.85 (s, 1H), 7.52 (s, 2H), 7.33 (t,
1H), 7.18–7.29 (m, 1H), 7.08 (dd, 2H), 3.95 (d, 2H), 3.77 (s, 3H); MS (ESI) m/z:
377.25 [MÀH]+. Anal. calcd for C16H15FN4O4S: C, 50.76; H, 3.97; F, 5.02; N,
14.81; O, 16.92; S, 8.46. Found: C, 50.66; H, 3.81; F, 5.09; N, 14.75; O, 16.84; S,
8.33. Compound 4c: White solid; mp: 258–261 °C; 1H NMR (300 MHz, DMSO) d
11.51–11.71 (br, 2H), 7.99 (t, 1H), 7.84 (s, 1H), 7.53 (s, 2H), 7.25 (dd, 2H), 7.07
(t, 2H), 3.90 (d, 2H), 3.77 (s, 3H); MS(ESI) m/z: 377.55 [MÀH]+. Anal. calcd for
C
16H15FN4O4S: C,50.72; H, 3.96; F, 5.02; N, 14.79; O, 16.91; S, 8.45. Found: C,
50.65; H, 3.88; F, 5.01; N, 14.63; O, 16.82; S, 8.33. Compound 4d: White solid;
mp: 251–253 °C; 1H NMR (300 MHz, DMSO) d 11.50–12.30 (br, 2H), 8.04 (t,
1H), 7.87 (s, 1H), 7.54 (s, 2H), 7.39 (dd, 2H), 7.26 (pd, 2H), 4.00 (d, 2H), 3.77 (s,
3H); MS (ESI) m/z: 440.03 [M+H]+. Anal. calcd for C16H15BrN4O4S: C, 48.12; H,
3.59; Br, 20.03; N, 14.04; O, 16.04; S, 8.02. Found: C, 48.05; H, 3.42; Br, 20.11;
N, 14.01; O, 16.02; S, 8.12. Compound 4e: White solid; mp: 262–264 °C; 1H
NMR (300 MHz, DMSO) d 11.50–11.69 (br, 2H), 8.02 (t, 1H), 7.83 (s, 1H), 7.53
(d, 2H), 7.39–7.48 (m, 2H), 7.18 (d, 2H), 3.89 (d, 2H), 3.77 (s, 3H).MS (ESI) m/z:
393.42[MÀH]+. Anal. calcd for C16H15N4O4SCl: C, 48.68; H, 3.80; Cl, 9.0; N,
14.20; O, 16.23; S, 8.11. Found: C, 48.59; H, 3.66; Cl, 8.94; N, 14.12; O, 16.10; S,
8.01. Compound 4f: White solid; mp: 260–262 °C; 1H NMR (300 MHz, DMSO) d
10.93–12.58 (br, 2H), 8.04 (t, 1H), 7.83 (s, 1H), 7.53 (d, 2H), 7.30 (dd, 2H), 7.23
(dd, 2H), 3.91 (d, 2H), 3.80 (s, 3H).MS (ESI) m/z: 393.31 [MÀH]+. Anal. calcd for
C
16H15N4O4SCl: C, 48.69; H, 3.80; Cl, 9.0; N, 14.20; O, 16.23; S, 8.11. Found: C,
48.50; H, 3.62; Cl, 8.85; N, 14.14; O, 16.13; S, 8.02. Compound 4g: White solid;
mp: 247–249 °C; 1H NMR (300 MHz, DMSO) d 11.27–12.88 (br, 2H), 8.07 (t,
1H), 7.84 (s, 1H), 7.53 (s, 2H), 7.50 (d, 1H), 7.42 (d, 1H), 7.34 (dd, 1H), 3.99 (d,
2H), 3.77 (s, 3H).MS (ESI) m/z: 429.72 [M+H]+. Anal. calcd for C16H14N4O4SCl2:
C, 44.78; H, 3.27; Cl, 16.56; N, 13.06; O, 14.93; S, 7.46. Found: C, 44.64; H, 3.18;
Cl, 16.46; N, 13.01; O, 14.73; S, 7.31. Compound 4h: White solid; mp: 243–
245 °C; 1H NMR (300 MHz, DMSO) d 11.58–12.18 (br, 2H), 8.08 (s, 1H), 7.80 (s,
1H), 7.50 (s, 2H), 7.48 (s, 1H), 7.39 (d, 1H), 7.21 (dd, 1H), 3.95 (d, 2H), 3.77 (s,
3H); MS (ESI) m/z: 429.36 [M+H]+. Anal. calcd for C16H14N4O4SCl2: C, 44.82; H,
3.27; Cl, 16.57; N, 13.07; O, 14.94; S, 7.47. Found: C, 44.71; H, 3.15; Cl, 16.43; N,
13.02; O, 14.82; S, 7.33. Compound 4i: White solid; mp: 217–220 °C; 1H NMR
(300 MHz, DMSO) d 11.92–12.17 (br, 2H), 7.84 (s, 1H), 7.52 (s, 2H), 7.12 (d, 2H),
6.80 (d, 2H), 3.83 (d, 2H), 3.77 (s, 3H), 3.68 (s, 3H); MS (ESI) m/z: 389.33
[MÀH]+. Anal. calcd for C17H18N4O5S: C, 52.26; H, 4.61; N, 14.35; O, 20.50; S,
8.20. Found: C, 52.12; H, 4.48; N, 14.14; O, 20.42; S, 8.17. Compound 4j: White
solid; mp: 255–259 °C; 1H NMR (300 MHz, DMSO) d 11.23–12.67 (br, 2H), 7.91
(s, 1H), 7.85 (s, 1H), 7.52 (s, 2H), 7.08–7.18 (m, 1H), 6.99 (d, 3H), 3.87 (d, 2H),
3.77 (s, 3H), 2.16 (s, 3H); MS (ESI) m/z: 375.38 [M+H]+. Anal. calcd for
Figure 6. TLCK in the active site of acrosin.
In summary,
a series of novel methyl 5-substituted 1H-
benzo[d]imidazol-2-ylcarbamates were designed, synthesized
and their acrosin inhibitory activities were evaluated in vitro.
The results of acrosin inhibitory activity showed that all title com-
pounds were more potent than that of the control TLCK. Compound
4w displayed the most potent acrosin inhibitory activity among all
the compounds, with IC50 of 6.3 Â 10À5 M, making it worth further
study. The results identify a new structural class for the further
development of novel acrosin inhibitory agents.
C
17H18N4O4S: C, 54.49; H, 4.80; N, 14.96; O, 17.09; S, 8.55. Found: C, 54.32; H,
4.65; N, 14.75; O, 17.01; S, 8.50. Compound 4k: White solid; mp: 242–243 °C;
1H NMR (300 MHz, DMSO) d 11.32–12.46 (br, 2H), 7.89 (s, 1H), 7.84 (s, 1H),
7.53 (s, 2H), 7.09 (d, 2H), 7.05 (d, 2H), 3.86 (d, 2H), 3.77 (s, 3H), 2.22 (s, 3H); MS
(ESI) m/z: 375.10 [M+H]+. Anal. calcd for C17H18N4O4S: C, 54.53; H, 4.81; N,
14.97; O, 17.11; S, 8.55. Found: C, 54.44; H, 4.68; N, 14.75; O, 17.07; S, 8.47.
Compound 4l: White solid; mp: 253–256 °C; 1H NMR (300 MHz, DMSO) d
11.28–12.58 (br, 2H), 7.97 (t, 1H), 7.86 (s, 1H), 7.54 (s, 2H), 7.17–7.30 (m, 5H),
3.91 (d, 2H), 3.77 (s, 3H); MS (ESI) m/z: 359.24 [MÀH]+. Anal. calcd for
Acknowledgment
Financial support from the Science and Technology Support
Program, Jiang Su 2010, BE2010682.
C
16H15N4O4S: C, 53.30; H, 4.16; N, 15.55; O, 17.77; S, 8.88. Found: C, 53.12; H,
4.07; N, 15.42; O, 17.65; S, 8.77. Compound 4m: White solid; mp: 265–268 °C;
1H NMR (300 MHz, DMSO) d 11.35–12.56 (br, 2H), 8.12 (t, 1H), 7.82 (s, 1H),
7.58 (d, 2H), 7.52 (s, 2H), 7.46 (d, 2H), 4.02 (d, 2H), 3.78 (s, 3H); MS (ESI) m/z:
428.82 [MÀH]+. Anal. calcd for C17H15F3N4O4S: C, 47.46; H, 3.49; N, 13.03; O,
14.89; S, 7.44, F, 13.26. Found: C, 47.33; H, 3.31; N, 13.01; O, 14.76; S, 7.41, F,
13.10. Compound 4n: White solid; mp: 246–249 °C; 1H NMR (300 MHz, DMSO)
d 11.33–12.41 (br, 2H), 8.00 (t, 1H), 7.83 (s, 1H), 7.51 (s, 2H), 7.35 (dd, 1H),
7.16–7.05 (m, 1H), 6.98 (dd, 1H), 3.93 (d, 2H), 3.77 (s, 3H); MS (ESI) m/z: 395.04
[MÀH]+. Anal. calcd for C16H14F2N4O4S: C, 48.48; H, 3.53; N, 14.14; O, 16.16; S,
8.08; F, 9.60. Found: C, 48.23; H, 3.35; N, 14.01; O, 16.02; S, 8.05, F, 9.47.
Compound 4o: White solid; mp: 249–252 °C; 1H NMR (300 MHz, DMSO) d
11.36–12.55 (br, 2H), 8.08 (t, 1H), 7.79 (d, 1H), 7.52 (s, 2H), 7.12–7.41 (m, 2H),
7.07 (s, 1H), 3.93 (d, 2H), 3.80 (s, 3H); MS (ESI) m/z: 395.57 [MÀH]+. Anal. calcd
for C16H14F2N4O4S: C, 48.42; H, 3.53; N, 14.12; O, 16.14; S, 8.07, F, 9.58. Found:
C, 48.31; H, 3.24; N, 14.05; O, 16.24; S, 8.01, F, 9.42. Compound 4p: White solid;
mp: 263–264°C; 1H NMR (300 MHz, DMSO) d 11.24–12.61(br, 2H), 8.04 (t, 1H),
7.85 (s, 1H), 7.53 (s, 2H), 7.29 (dd, 1H), 6.90–7.15 (m, 3H), 3.96 (d, 2H), 3.78 (s,
3H); MS (ESI) m/z: 377.57 [MÀH]+. Anal. calcd for C16H15FN4O4S: C, 50.72; H,
3.96; N, 14.79; O, 16.91; S, 8.45;F, 5.02. Found: C, 50.62; H, 3.73; N, 14.62; O,
16.86; S, 8.32, F, 5.12. Compound 4q: White solid; mp: 224–225°C; 1H NMR
(300 MHz, DMSO) d 11.38–12.49 (br, 2H), 7.85 (s, 1H), 7.79 (t, 1H), 7.53 (s, 2H),
7.10–7.31 (m, 2H), 6.86 (t, 2H), 3.86 (d, 2H), 3.77 (s, 3H), 3.67 (s, 3H); MS (ESI)
m/z: 389.57 [MÀH]+. Anal. calcd for C17H18N4O5S: C, 52.23; H, 4.61; N, 14.34; O,
20.48; S, 8.19. Found: C, 52.13; H, 4.55; N, 14.25; O, 20.32; S, 8.07. Compound
4r: White solid; mp: 217–219 °C; 1H NMR (300 MHz, DMSO) d 11.28–12.48 (br,
2H), 7.96 (t, 1H), 7.85 (s, 1H), 7.53 (s, 2H), 7.11–7.32 (m, 1H), 6.77 (dd, 3H), 3.89
(d, 2H), 3.77 (s, 3H), 3.65 (s, 3H); MS (ESI) m/z: 389.24 [MÀH]+. Anal. calcd for
References and notes
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19. Stuctural data for compounds 4a–4x: Compound 4a: White solid; mp: 277–
279 °C; 1H NMR (300 MHz, DMSO) d 11.30-11.72 (br, 2H), 9.30 (s, 1H), 7.67 (s,
1H), 7.47 (d, 1H), 7.36 (dd, 1H), 6.93 (d, 1H), 6.85 (d, 2H), 3.76 (s, 3H), 2.13 (s,
3H), 1.80 (s, 3H); MS (ESI) m/z: 373.19 [MÀH]+. Anal. calcd for C17H18N4O4S: C,
54.52; H, 4.81; N, 14.97; O, 17.10; S, 8.55. Found: C, 54.47; H, 4.77; N, 14.89; O,
17.05; S, 8.41. Compound 4b: White solid; mp: 257–259 °C; 1H NMR (300 MHz,
C
17H18N4O5S: C, 52.28; H, 4.61; N, 14.35; O, 20.50; S, 8.20. Found: C, 52.14; H,
4.54; N, 14.22; O, 20.32; S, 8.11. Compound 4s: White solid; mp: 248–249 °C;
1H NMR (300 MHz, DMSO) d 10.89–12.50 (br, 2H), 7.85 (s, 2H), 7.51 (s, 2H),
6.79 (d, 1H), 6.71 (d, 2H), 3.86 (d, 2H), 3.78 (s, 3H), 3.67 (s, 3H), 3.60 (s, 3H); MS
(ESI) m/z: 419.30 [MÀH]+. Anal. calcd for C18H20N4O6S: C, 51.39; H, 4.76; N,
13.32; O, 22.84; S, 7.61. Found: C, 51.14; H, 4.55; N, 13.25; O, 22.74; S, 7.52.
Compound 4t: White solid; mp: 201–203 °C; 1H NMR (300 MHz, DMSO) d
11.26–12.57 (br, 2H), 7.86 (d, 1H), 7.54 (d, 2H), 7.42 (t, 1H), 3.77 (s, 3H), 3.03-
3.22 (m, 1H), 0.90 (t, 6H); MS (ESI) m/z: 311.23[MÀH]+. Anal. calcd for