7276
H. Xu, Y.-Y. Wang / Bioorg. Med. Chem. Lett. 20 (2010) 7274–7277
NH
NH
tion for Young Talents (No. 121032). We also thank to Prof. H.L.
Zhang for the NMR experiments.
Me, Et > H, n-pentyl
H N
2
N
3
R
Supplementary data
Me, H > CN
1
R
Supplementary data associated with this article can be found, in
N
SO
2
Me, H > NO
2
2
References and notes
R
1. Gadad, A. K.; Mahajanshetti, C. S.; Nimbalkar, S.; Raichurkar, A. Euro. J. Med.
Chem. 2000, 35, 853.
Figure 2. The preliminary graphical depiction of the SAR for compounds 5a–r.
2. (a) Buchheit, K. H.; Klein, F.; Klöppner, E.; Pfannkuche, H. J.; Mattes, H. Bioorg.
Med. Chem. Lett. 1995, 5, 2495; (b) Wei, R. G.; Arnaiz, D. O.; Chou, Y. L.; Davey,
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1997, 40, 3484.
4. Cai, T. W.; Xian, M.; Wang, P. G. Bioorg. Med. Chem. Lett. 2002, 12, 1507.
5. Khownium, K.; Wood, S. J.; Miller, K. A.; Balakrishna, R.; Nguyen, T. B.; Kimbrell,
M. R.; Georg, G. I.; David, S. A. Bioorg. Med. Chem. Lett. 2006, 16, 1305.
6. Ran, J. Q.; Huang, N.; Xu, H.; Yang, L. M.; Lv, M.; Zheng, Y. T. Bioorg. Med. Chem.
Lett. 2010, 20, 3534.
7. (a) Xu, H.; Zeng, X. W. Bioorg. Med. Chem. Lett. 2010, 20, 4193; (b) Xu, H.; Xiao,
X. Bioorg. Med. Chem. Lett. 2009, 19, 5415; (c) Xu, H.; Wang, J. J.; Sun, H. J.; Lv,
M.; Tian, X.; Yao, X. J.; Zhang, X. J. Agric. Food. Chem. 2009, 57, 7919; (d) Xu, H.;
Wang, J. J. Bioorg. Med. Chem. Lett. 2010, 20, 2500.
57.8%/56.7%, 61.45%/65.26%, 38.84%/34.86%, 46.34%/44.15%,
66.51%/66.05%, and 33.70%/36.54%, respectively. However, when
the cyano group was introduced at 5-position on the indolyl ring
of 5a or 5b to afford 5f or 5g, respectively, the inhibition rates of 5f
and 5g against F. oxysporum f. sp. vasinfectum, P. oryzae, A. alternata,
A. brassicae, F. graminearum, B. sorokinianum, and F. oxysporum f. sp.
cucumarinum were 14.07%/13.04%, 20.14%/16.27%, 23.4%/15.16%,
9.09%/10.43%, 25.98%/13.34%, 13.84%/16.98%, and 11.06%/6.55%,
respectively, and vice versa. (2) In general, when R2 was introduced
as the electron-withdrawing group, the corresponding compound
exhibited less potent activities than that possessing electron-donat-
ing one (5c versus 5b). For example, the inhibition rates of 5c (R2 =
3-NO2) and 5b (R2 = 4-Me) against F. oxysporum f. sp. vasinfectum,
P. oryzae, A. alternata, A. brassicae, F. graminearum, B. sorokinianum,
and F. oxysporum f. sp. cucumarinum were 28.57%/51.77%, 42.31%/
56.7%, 51.06%/65.26%, 29.98%/34.86%, 31.36%/44.15%, 36.89%/
66.05%, and 28.01%/36.54%, respectively. (3) The proper length of
substituent R3 of 5a–r were usually very important for their anti-
fungal activities. For example, the inhibition rates of 5a (R3 = H)
against F. oxysporum f. sp.vasinfectum, P.oryzae, A.alternata, A.brass-
icae, F. graminearum, B. sorokinianum, and F. oxysporum f. sp. cucum-
arinum were 47.83%, 57.8%, 61.45%, 38.84%, 46.34%, 66.51%, and
33.7%, respectively; the inhibition rates of 5j (R3 = Me) and 5l
(R2 = Et) against F. oxysporum f. sp.vasinfectum, P.oryzae, A.alternata,
A. brassicae, F. graminearum, B. sorokinianum, and F. oxysporum f. sp.
cucumarinum were 60.04%/56.71%, 74.29%/75.57%, 73.49%/73.83%,
40.24%/43.33%, 37.8%/50.47%, 75.29%/69.17%, and 49.67%/48.4%,
respectively; while the inhibition rates of 5m (R3 = n-pentyl) against
F. oxysporum f. sp. vasinfectum, P. oryzae, A. alternata, A. brassicae,
F.graminearum, B. sorokinianum, and F. oxysporum f. sp. cucumarinum
were 30.74%, 52.04%, 60.64%, 29.98%, 39.43%, 50.24%, and 38.57%,
respectively. The same results were also found between 5d and
5n, and between 5e and 5o.
8. (a) Cole, D. C.; Kelly, M. G.; Nunn, D. S.; Greenblatt, L. P. US Patent 20040002527
A1, 2004.; (b) Cole, D. C.; Stock, J. R.; Lennox, W. J.; Bernotas, R. C.; Ellingboe, J.
W.; Boikess, S.; Coupet, J.; Smith, D. L.; Leung, L.; Zhang, G.; Feng, X.; Kelly, M.
F.; Galante, R.; Huang, P.; Dawson, L. A.; Marquis, K.; Rosenzweig-Lipson, S.;
Beyer, C. E.; Schechter, L. E. J. Med. Chem. 2007, 50, 5535.
9. Takatori, K.; Lee, M.; Kajiwara, M. Curr. Radiopharm. 2008, 1, 122.
10. Ketcha, D. M.; Gribble, G. M. J. Org. Chem. 1985, 50, 5451.
11. Spectra data for 5a: White solid, mp 186–188 °C; 1H NMR (400 MHz, DMSO-d6)
d: 8.49 (s, 1H), 8.36–8.40 (m, 2H), 8.03 (d, J = 8 Hz, 2H), 7.96 (d, J = 8 Hz, 1H),
7.71 (t, J = 7.6 Hz, 1H), 7.61 (t, J = 7.6 Hz, 2H), 7.43 (t, J = 7.6 Hz, 1H), 7.33 (t,
J = 7.6 Hz, 1H); ESI-MS m/z 342 ([M+H]+, 100); HRMS-ESI: Calcd for
C
16H16N5O2S [M+H]+: 342.1019. Found: 342.1010. 5b: White solid, mp 138-
140 °C (lit. 8a not reported); 1H NMR (400 MHz, DMSO-d6) d: 8.34–8.38 (m, 3H),
7.89–7.96 (m, 3H), 7.40–7.45 (m, 3H), 7.32 (t, J = 7.6 Hz, 1H), 2.32 (s, 3H, CH3);
ESI-MS m/z 356 ([M+H]+, 100). 5c: Yellow solid, mp 148–150 °C; 1H NMR
(400 MHz, DMSO-d6) d: 8.68 (s, 1H), 8.58 (s, 1H), 8.50–8.54 (m, 2H), 8.37–8.39
(m, 2H), 8.02 (d, J = 8 Hz, 1H), 7.91 (t, J = 8 Hz, 1H), 7.47 (t, J = 7.6 Hz, 1H), 7.36–
7.40 (m, 1H); ESI-MS m/z 387 ([M+H]+, 100); HRMS-ESI: Calcd for C16H15N6O4S
[M+H]+: 387.0870. Found: 387.0864. 5d: White solid, mp 136–138 °C; 1H NMR
(400 MHz, DMSO-d6) d: 8.58–8.60 (m, 2H), 8.01 (d, J = 7.6 Hz, 2H), 7.82 (d,
J = 8.4 Hz, 1H), 7.71–7.73 (m, 1H), 7.61 (t, J = 7.6 Hz, 2H), 7.25 (t, J = 7.6 Hz, 1H),
7.09 (d, J = 7.2 Hz, 1H), 2.57 (s, 3H, CH3); ESI-MS m/z 356 ([M+H]+, 100); HRMS-
ESI: Calcd for C17H18N5O2S [M+H]+: 356.1176. Found: 356.1170. 5e: White
solid, mp 154–155 °C; 1H NMR (400 MHz, DMSO-d6) d: 8.63–8.67 (m, 2H), 7.89
(d, J = 8 Hz, 2H), 7.80 (d, J = 8.4 Hz, 1H), 7.41 (d, J = 8.4 Hz, 2H), 7.25 (t,
J = 7.6 Hz, 1H), 7.09 (d, J = 7.2 Hz, 1H), 2.57 (s, 3H, CH3), 2.32 (s, 3H, CH3); ESI-
MS m/z 370 ([M+H]+, 100); HRMS-ESI: Calcd for C18H20N5O2S [M+H]+:
370.1332. Found: 370.1339. 5f: White solid, mp 165–166 °C; 1H NMR
(400 MHz, DMSO-d6) d: 8.81 (s, 1H), 8.51 (s, 1H), 8.30 (s, 1H), 8.12 (d,
J = 9.2 Hz, 1H), 8.06 (d, J = 8 Hz, 2H), 7.82–7.84 (m, 1H), 7.76–7.81 (m, 1H), 7.62
(t, J = 7.6 Hz, 2H); ESI-MS m/z 367 ([M+H]+, 100); HRMS-ESI: Calcd for
17H15N6O2S [M+H]+: 367.0972. Found: 367.0966. 5g: White solid, mp 164–
Finally, according to the above SAR study, the preliminary
graphical depiction of the SAR for the antifungal activities of
5a–r was summarized in Figure 2.
In conclusion, 18 aminoguanidine derivatives of N-arylsulfonyl-
3-acylindoles (including 16 new compounds) were prepared and
bioevaluated in vitro as antifungal agents against seven phytopath-
ogenic fungi. Especially compounds 5n and 5o showed more
potent antifungal activities than or comparable to hymexazol, a
C
166 °C; 1H NMR (400 MHz, DMSO-d6) d: 8.81 (s, 1H), 8.48 (s, 1H), 8.31 (s, 1H),
8.11 (d, J = 8.8 Hz, 1H), 7.94 (d, J = 8 Hz, 2H), 7.81 (d, J = 9.2 Hz, 1H), 7.43 (d,
J = 8 Hz, 2H), 2.34 (s, 3H, CH3); ESI-MS m/z 381 ([M+H]+, 100); HRMS-ESI: Calcd
for C18H17N6O2S [M+H]+: 381.1128. Found: 381.1137. 5h: White solid, mp
190–192 °C; 1H NMR (500 MHz, DMSO-d6) d: 8.37 (s, 1H), 8.35 (s, 1H), 8.21 (d,
J = 8 Hz, 1H), 8.03 (d, J = 7.5 Hz, 2H), 7.78 (s, 1H), 7.72 (t, J = 7.5 Hz, 1H), 7.62 (t,
J = 7.5 Hz, 2H), 7.17 (d, J = 8.5 Hz, 1H), 2.47 (s, 3H, CH3); ESI-MS m/z 356
([M+H]+, 100); HRMS-ESI: Calcd for C17H18N5O2S [M+H]+: 356.1176. Found:
356.1181. 5i: White solid, mp 159–161 °C; 1H NMR (400 MHz, DMSO-d6) d:
8.29–8.31 (m, 2H), 8.20 (d, J = 8 Hz, 1H), 7.90 (d, J = 8.4 Hz, 2H), 7.76 (s, 1H),
7.40 (d, J = 8 Hz, 2H), 7.15 (d, J = 8.4 Hz, 1H), 2.46 (s, 3H, CH3), 2.32 (s, 3H, CH3);
commercially available agricultural fungicide at 100 lg/mL. Preli-
minary SAR study indicated that introduction of electron-donating
substituents R1 and R2, and the proper length of substituent R3
were very usually important for their antifungal activities.
ESI-MS m/z 370 ([M+H]+, 100); HRMS-ESI: Calcd for C18H20N5O2S [M+H]+:
370.1332. Found: 370.1337. 5j: White solid, mp 148–150 °C (lit.
8a,8b
not
reported); 1H NMR (400 MHz, DMSO-d6) d: 8.42 (s, 1H), 8.27 (d, J = 7.6 Hz, 1H),
8.07 (d, J = 7.6 Hz, 2H), 7.96 (d, J = 8 Hz, 1H), 7.70–7.74 (m, 1H), 7.60 (t,
J = 7.6 Hz, 2H), 7.40–7.44 (m, 1H), 7.31 (t, J = 7.6 Hz, 1H), 2.45 (s, 3H, CH3); ESI-
MS m/z 356 ([M+H]+, 100). 5k: White solid, mp 188–190 °C; 1H NMR (400 MHz,
DMSO-d6) d: 8.40 (s, 1H), 8.27 (d, J = 7.6 Hz, 1H), 7.95–7.97 (m, 3H), 7.74 (s, 1H,
NH), 7.40–7.43 (m, 3H), 7.30–7.34 (m, 1H), 2.46 (s, 3H, CH3), 2.32 (s, 3H, CH3);
ESI-MS m/z 370 ([M+H]+, 100); HRMS-ESI: Calcd for C18H20N5O2S [M+H]+:
370.1332. Found: 370.1324. 5l: White solid, mp 122–124 °C; 1H NMR
(400 MHz, DMSO-d6) d: 8.39 (s, 1H), 8.23 (d, J = 7.6 Hz, 1H), 8.07 (d, J = 8 Hz,
2H), 7.97 (d, J = 8.4 Hz, 1H), 7.69 (t, J = 7.6 Hz, 1H), 7.59 (t, J = 7.6 Hz, 2H), 7.40
(t, J = 7.6 Hz, 1H), 7.30–7.34 (m, 1H), 2.91–2.94 (m, 2H, CH2), 1.11 (t, J = 7.6 Hz,
Acknowledgments
This work was financially in part supported by the Program for
New Century Excellent University Talents, State Education Minis-
try of China (NCET-06-0868), National Natural Science Foundation
of China (No. 31071737), and the Fok Ying Tong Education Founda-