L. Meerpoel et al. / Bioorg. Med. Chem. Lett. 15 (2005) 3453–3458
3457
Table 2. Structure–activity relationship of 6-(4-ethylphenyl)-6H-pyrrolo[1,2-a][1,4]benzodiazepines 2a–c
Compound ID R1 R3 A. fumigatusa C. parapsilosis Cr. Neoformans M. canis S. schenkii T. mentagrophytes T. rubrum
B42928
B66126
B66663
B68128
B64284
B70554
B68183
1c (ꢀ) R
Cl
Cl
H
H
H
Cl
H
1
0.32
0.32
1
100
100
1
0.32
0.03
0.32
0.32
100
100
6.6
10
0.01
0.03
0.1
0.03
0.01
2a
2b
2c
0.32
0.32
1
0.065
0.065
H
3.2
100
0.32
a MIC in lM: microdilution test method in dilute casein hydrolysate-yeast extract-glucose medium (CYG), evaluation by OD measurement.15,16
Reduction of test growth to <35% of control growth is interpreted as an indicator of inhibitory activity.
Chem. 1987, 31, 1365; Fromtling, R. Drugs Today 1992,
28, 501.
low plasma concentrations after oral administration,
and a rapid decrease of the plasma concentration in
both cases. This poor bio-availability (<5%) might ex-
plain the lack of in vivo activity in guinea pigs.
9. McNeely, W.; Spencer, C. M. Drugs 1998, 55, 405.
10. Cheeseman, G. W. H.; Rafiq, M. J. Chem. Soc. (C) 1971,
2732; Raines, S.; Chai, S. Y.; Palopoli, F. P. J. Heterocycl.
Chem. 1976, 13, 711; Cheeseman, G. W. H.; Greenberg, S.
G. J. Heterocycl. Chem. 1979, 16, 241; Vomero, S.;
Giuliano, R.; Artico, M.; Stefancich, G. Farmacol. Ed. Sci.
1980, 35, 110; Corelli, F.; Pantaleoni, G. C.; Palumbo, G.;
Fanini, D. Farmacol. Ed. Sci. 1984, 39, 707; Cheeseman,
G. W. H.; Eccieshali, S. A. J. Heterocycl. Chem. 1986, 23,
65; Trinka, P.; Slegel, P.; Reiter, J. J. Prakt. Chem./Chem.-
Ztg. 1996, 338, 675.
In conclusion, compounds 1a, 1c and 2a have been
identified as a new class of pyrrolo[1,2-a][1,4]benzodi-
azepine anti-fungal agents with an anti-dermatophyte
spectrum similar to that of terbinafine. Biochemical
assessment of the mode of action of 1a pointed to
squalene epoxidase inhibition, a clinically validated tar-
get with the fungicidal potential. Overall, the potency
gap between this new class and terbinafine is rather
small.
11. Klaubert, D. H.; Sellstedt, J. H.; Guinosso, C. J.;
Capetola, R. J.; Bell, S. C. J. Med. Chem. 1981, 24, 742;
Nickson, T. E.; Roche-Dolson, C. A. Synthesis 1985, 669;
Harris, N. V.; Smith, C.; Bowden, K. J. Med. Chem. 1990,
33, 434.
12. Chiral separation of 1a on a ChiralpakTM AD HPLC
column with 100% ethanol as eluent gave optical pure 1b
as the first fraction and 1c as the second fraction.
Acknowledgments
We gratefully acknowledge Mr. Jef Verboven and Mr.
Alex De Groot for technical assistance in HPLC purifi-
cation and NMR analysis, Mr. Tom Kuppens from
Gent University for VCD calculations on compound
1b and 1c, and Mrs. Mireille Vanderhallen for editorial
assistance.
Compound
1c:
mp
250–252 °C
(i-PrOH/HCl);
20
½aꢁD ꢀ 196.05 (c 0.516 in MeOH); 1H NMR (360
MHz, DMSO-d6) d ppm 1.21 (t, J = 7.6 Hz, 3H) 2.66
(q, J = 7.5 Hz, 2H) 3.84 (d, J = 13.9 Hz, 1H) 4.53 (d,
J = 13.9 Hz, 1H) 5.17 (s, 1H) 5.84 (ddd, J = 3.6, 1.6,
0.8 Hz, 1H) 6.28 (dd, J = 3.6, 2.9 Hz, 1H) 7.32 (d,
J = 8.2 Hz, 2H) 7.40 (dd, J = 2.9, 1.6 Hz, 1H) 7.63 (m,
2H) 7.69 (m, 1H) 7.72 (d, J = 8.4 Hz, 2H) 10.61 (br s,
2H).
References and notes
13. IR and VCD spectra were recorded at 6 cmꢀ1 resolution
on an FTIR Equinox spectrometer equipped with the
VCD module PMA 37 (Bruker, Germany). A low-pass
filter (<1800 cmꢀ1), BaF2 polarizer, ZnSe modulator
(Hinds instruments) oscillating at a frequency of 50 Hz
and MCT (InfraRed Associates) detector were used.
Samples were dissolved in CD2Cl2 and placed in a
demountable KBr cell with a 0.09 mm Teflon spacer (1 h
collection time). OPUS software (Bruker, Germany) was
used for spectral processing. A thorough conformational
search is performed at the molecular mechanics level. A
MM3 stochastic search is performed in combination with
a systematic MMFF search with a dihedral grid of 30°.
The located minima were optimized using Gaussian03RB5
at the B3LYP/6-31G* level. All conformations within
5 kcal/mol interval were used to simulate VCD and IR
spectrum. Dipole and rotational strengths were calculated
at the same B3LYP/6-31G* level, using the standard
Gaussian (75,302)p grid.
1. Marichal, P. Curr. Opin. Anti-Infect. Invest. Drugs 1999, 1,
318; Canuto, M. M.; Rodero, F. G. Lancet Infect. Dis.
2002, 2, 550.
2. Monk, B. C.; Cannon, R. D. Curr. Drug Targets: Infect.
Disord. 2002, 2, 309; Groll, A. H.; Walsh, T. J. Swiss Med.
Wkly 2002, 132, 303.
3. Heeres, J.; Backx, L. J. J.; Mostmans, J. H.; Van Cutsem,
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4. Heeres, J.; Backx, L. J. J.; Van Cutsem, J. J. Med. Chem.
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5. Richardson, K.; Cooper, K.; Marriott, M. S.; Tarbit, M.
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6. Barrett-Bee, K. J.; Lane, A. C.; Turner, R. W. J. Med.
Vet. Mycol. 1986, 24, 155; Ryder, N. S.; Frank, I.;
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Antimicrob. Agents Chemother. 1981, 19, 386; Paltauf, F.;
Daum, G.; Zuder, G.; Ho¨genauer, G.; Schulz, G.; Seidl,
1
14. Compound 2a: H NMR (360 MHz, CDCl3) d ppm 1.23
(t, J = 7.6 Hz, 3H) 2.66 (q, J = 7.6 Hz, 2H) 4.15 (br s, 1H)
5.48 (br s, 1H) 6.43 (dd, J = 3.8, 2.84 Hz, 1H) 6.51 (dd,
J = 3.8, 1.7 Hz, 1H) 7.18 (d, J = 8.2 Hz, 2H) 7.27 (m, 2H)
7.32 (dd, J = 2.9, 1.7 Hz, 1H) 7.37 (dd, J = 6.8, 2.5 Hz,
1H) 7.63 (d, J = 8.2 Hz, 2H).
G. Biochim. Biophys. Acta 1982, 712, 268; Stutz, A.;
¨
Georgopoulos, A.; Granitzer, W.; Petranyi, G.; Berney, D.
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8. Petranyi, G.; Ryder, M. S.; Stutz, A. Science 1984, 224,
¨
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15. Odds, F. C. J. Clin. Microbiol. 1991, 29, 2735.