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In summary, the novel tetrahydroisoquinolines based on
lanosterol 14a-demethylase of fungi were discovered by
coupling structure-based de novo design with chemical
synthesis, and their antifungal activities in vitro were
evaluated. The mode of action of the lead molecules
was represented, which was different from that of azoles
(Fig. 4). The lead compounds exhibited potent anti-
fungal activities in vitro. Because the affinity of the lead
molecules for CYP51 was mainly attributed to their
non-bonding interaction with the apoprotein, the studies
presented here afford the opportunity to develop novel
antifungal agents that specifically interact with the resi-
dues in the active site and avoid the serious toxicity aris-
ing from coordination binding with the heme of
mammalian P450s.
Acknowledgment
19. Bohm, H.-J. J. Comput.-Aided Mol. Des. 1994, 8, 243.
20. Bohm, H.-J. J. Comput.-Aided Mol. Des. 1998, 12, 309.
21. Mp 252–253 °C (lit.22 251–252 °C); 1HNMR (DMSO,
300 MHz): 3.04 (t, 2H, J = 6.2 Hz), 3.49 (t, 2H,
J = 6.3 Hz), 3.81 (s, 3H), 3.82 (s, 3H), 4.28 (s, 2H), 6.81
(s, 1H), 6.87 (s, 1H).
The work was supported by the National Natural
Science Foundation of China (Grant No. 30572257).
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1
24. Compound 4ÆHBr, HNMR (DMSO, 500 MHz): 0.85 (t,
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3.23 (m, 2H), 3.29–3.35 (t, 2H), 4.11–4.4 (dd,
JA = 133 Hz, JB = 15.1 Hz, 2H), 6.68 (s, 1H), 6.75 (s,
1H), 9.61 (s, 1H); compound 6ÆHBr (DMSO, 300 MHz)
0.86 (t, J = 6.7 Hz, 3H), 1.26 (m, 14H), 1.73 (s, 2H),
2.73–2.83 (m, 2H), 2.96–3.58 (m, 4H), 4.02–4.33 (dd,
JA = 75.2 Hz, JB = 13.6 Hz, 2H), 6.55 (d, J = 9.4 Hz,
2H), 9.05 (d, J = 13.2 Hz, 2H), 10.05 (s, 1H); compound
7ÆHBr (DMSO, 500 MHz) 0.86 (t, J = 6.8 Hz, 3H), 1.25–
1.73 (m, 20H), 2.80 (m, 2H), 2.96 (m, 2H), 3.15–3.65 (m,
2H), 4.09–4.36 (dd, JA = 117.8 Hz, JB = 14.6 Hz, 2H),
6.57 (d, J = 13.6 Hz, 2H), 9.04 (d, J = 16.5 Hz, 2H), 9.78
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