Arch. Pharm. Chem. Life Sci. 2009, 342, 541–545
3-Imidazolyl Flavans as Potential Antifungal Agents
545
1H, H-7), 7.88 (d, J = 7.26 and 1.02 Hz, 1H, H-5); 13C-NMR
(125 MHz, DMSO-d6) d: 55.96, 64.04, 82.26, 114.61, 118.87,
120.65, 123.00, 127.91, 128.53. 129.99, 137.82, 160.60, 161.66,
189.86. Anal. Calcd for C19H16N2O3: C, 71.24; H, 5.03; N, 8.74.
Found: C, 71.23; H, 5.00; N, 8.69.
zole H-4), 6.81 (m, 2H, H-59 and H-6), 7.09–7.21 (m, 4H, H-49, H-69,
H-8 and imidazole H-2), 7.43 (dt, J = 7.75 and 1.5 Hz, 1H, H-7), 7.93
(dd, J = 8.00 and 1.0 Hz, 1H, H-5), 11.94 (s, 1H, oxime); 13C-NMR
(125 MHz, DMSO-d6) d: 50.81, 54.93, 78.56, 111.14, 113.89,
117.91, 118.13, 122.68, 123.51, 129.19, 131.27, 137.22, 145.40,
154.98, 158.96. Anal. Calcd for C19H17N3O3: C, 68.05; H, 5.11; N,
12.53. Found: C, 68.22; H, 5.09; N, 12.71.
(l)-trans-2,3-Dihydro-3-(1H-imidazol-1-yl)-2-(3-
methoxyphenyl)-4H-1-benzopyran-4-one 5c
Antifungal activity
Yield: 81%; m.p.: 168–1698C;1H-NMR (500 MHz, DMSO-d6) d: 3.72
(s, 3H, OCH3), 6.07 (d, J = 12.46 Hz, 1H, H-2), 6.17 (d, J = 12.45 Hz,
1H, H-3), 6.85 (br s, 1H, imidazole H-5), 6.90 (d, J = 8.10 Hz, 1H, H-
49), 6.98 (d, J = 7.35 Hz, 1H, H-69), 7.02 (s, 1H, H-29), 7.08–7.30 (m,
4H, H-6, H-8, H-59 and imidazole H-4), 7.48 (br s, 1H, imidazole H-
2), 7.71 (t, J = 7.72 Hz, 1H, H-7), 7.90 (d, J = 7.72 Hz, 1H, H-5); 13C-
NMR (125 MHz, DMSO-d6) d: 55.98, 64.11, 82.43, 113.92, 115.54,
118.89, 120.64, 120.72, 123.12, 127.92, 130.39, 137.88, 137.99,
159.95, 161.53, 189.63. Anal. Calcd for C19H16N2O3: C, 71.24; H,
5.03; N, 8.74. Found: C, 71.36; H, 4.91; N, 8.74.
The minimum inhibitory concentrations (MICs) were deter-
mined by the agar dilution method against the pathogenic fungi
Candida albicans, Saccharomyces cerevisiae, Aspergillus niger, and
Microsporum gypseum [16]. Sabouraud dextrose agar (SDA) was
employed for fungal growth. Stock solutions of tested com-
pounds were prepared in dimethyl sulfoxide (DMSO). Inocula
containing approximately 105 CFUs/mL of fungi were prepared
from broth cultures in log-phase growth. Fungal plates were
made in triplicate and incubated at 308C about 24 to 48 h for
yeast, about 72 h for moulds, and about 168 h for dermato-
phytes. The MIC value was defined as the lowest concentration
of the antifungal agent, at which no growth on the plate was
visible; all experiments were repeated at least three times. To
ensure that the solvent had no effect on fungal growth, a control
test was performed with test medium supplemented with DMSO
at the same dilutions as used in the experiment.
General procedure for the synthesis of trans-3-(imidazol-
1-yl)flavan-4-one (Z)-oximes 6a–c
A mixture of trans-3-imidazolylflavanone 5a–c (1.0 mmol),
hydroxylamine hydrochloride (3 mmol) and K2CO3 (1.0 mmol) in
methanol (4 mL) was stirred at room temperature for three to
six days. The reaction mixture was poured into water, and the
precipitate was filtered, washed with water, and crystallized
from methanol to afford pure (Z)-isomer of 6a–c.
References
(l)-(Z)-trans-2,3-Dihydro-3-(1H-imidazol-1-yl)-2-(4-
[1] D. Sanglard, F. C. Odds, Lancet Infect. Dis. 2002, 2, 73–78.
methylphenyl)-4H-1-benzopyran-4-one oxime 6a
Yield: 69%; m.p.: 204–2058C;1H-NMR (500 MHz, DMSO-d6) d: 2.27
(s, 3H, CH3), 5.55 (d, J = 2.30 Hz, 1H, H-2), 5.95 (d, J = 2.39 Hz, 1H,
H-3), 6.65 (s, 1H, imidazole H-5), 6.72 (s, 1H, imidazole H-4), 7.05-
7.19 (m, 7H, H-29, H-39, H-59, H-69, H-6, H-8 and imidazole H-2), 7.43
(t, J = 7.08 Hz, 1H, H-7), 7.94 (dd, J = 7.86 and 1.24 Hz, 1H, H-5),
11.92 (s, 1H, oxime);13C-NMR (125 MHz, DMSO-d6) d: 21.59, 51.57,
79.53, 118.74, 118.94, 119.35, 123.47, 124.40, 126.64, 128.85,
129.54, 132.12, 133.65, 138.11, 138.41, 146.42, 155.97. Anal.
Calcd for C19H17N3O2: C, 71.46; H, 5.37; N, 13.16. Found: C, 71.79;
H, 5.39; N, 13.15.
[2] D. Peres-Bota, H. Rodriguez-Villalobos, G. Dimopoulos, C.
Melot, J.-L. Vincent, Clin. Microbiol. Infect. 2004, 10, 550–
555.
[3] J. A. Maertens, Clin. Microbiol. Infect. 2004, 10 (Suppl. 1), 1–
10.
[4] W. J. Watkins, T. E. Renau in Annual Reports in Medicinal
Chemistry (Ed.: A. M. Doherty), Academic Press, New York,
1999, Vol. 35, pp 157–166.
[5] D. J. Sheehan, C. A. Hitchcock, C. M. Silbey, Clin. Microbiol.
Rev. 1999, 12, 501–517.
[6] B. J. Spellberg, S. G. Filler, J. E. Edwards, Jr., Clin. Pract.
2006, 42, 244–251.
(l)-(Z)-trans-2,3-Dihydro-3-(1H-imidazol-1-yl)-2-(4-
[7] P. Kale, L. B. Johnson, Drugs Today 2005, 41, 91–105.
[8] K. de Beule, J. van Gestel, Drugs 2001, 61, 27–37.
methoxyphenyl)-4H-1-benzopyran-4-one oxime 6b
Yield: 87%; m.p.: 184–1868C;1H-NMR (500 MHz, DMSO-d6) d: 3.70
(s, 3H, OCH3), 5.53 (br s, 1H, H-2), 5.92 (br s, 1H, H-3), 6.66 (br s,
1H, imidazole H-5), 6.72 (br s, 1H, imidazole H-4), 6.81 (d, J =
7.50 Hz, 2H, H-39 and H-59), 7.04–7.37 (m, 5H, H-29, H-69, H-6, H-8
and imidazole H-2), 7.42 (t, J = 7.50 Hz, 1H, H-7), 7.92 (d, J =
7.50 Hz, 1H, H-5), 11.92 (s, 1H, oxime); 13C-NMR (125 MHz, DMSO-
d6) d: 54.99, 78.43, 113.46, 114.16, 117.83, 118.06, 122.58, 123.50,
127.20, 127.62, 127.81, 131.22, 145.54, 155.15, 158.96. Anal.
Calcd for C19H17N3O3: C, 68.05; H, 5.11; N, 12.53. Found: C, 67.92;
H, 5.19; N, 12.52.
[9] T. J. Walsh, M. A. Viviani, E. Arathoon, Med. Mycol. 2000, 38,
335–347.
[10] S. Emami, A. Shafiee, Heterocycles 2001, 55, 2059–2074.
[11] S. Emami, M. Falahati, A. Banifatemi, K. Moshiri, A. Sha-
fiee, Arch. Pharm. 2002, 335, 318–324.
[12] S. Emami, M. Falahati, A. Banifatemi, M. Amanlou, A. Sha-
fiee, Bioorg. Med. Chem. 2004, 12, 3971–3976.
[13] S. Emami, A. Foroumadi, M. Falahati, E. Lotfali, et al., Bio-
org. Med. Chem. Lett. 2008, 18, 141–146.
[14] D. N. Dhar The Chemistry of Chalcone and Related Compounds,
Cambridge University Press, London, 1973.
(l)-(Z)-trans-2,3-Dihydro-3-(1H-imidazol-1-yl)-2-(3-
methoxyphenyl)-4H-1-benzopyran-4-one oxime 6c
Yield: 67%; m.p.: 229–2308C;1H-NMR (500 MHz, DMSO-d6) d: 3.64
(s, 3H, OCH3), 5.54 (d, J = 1.20 Hz, 1H, H-2), 5.96 (d, J = 1.18 Hz, 1H,
H-3), 6.65 (br s, 1H, imidazole H-5), 6.70 (br s, 2H, H-29 and imida-
[15] A. Foroumadi, N. Mohammadhosseini, S. Emami, B. Leta-
fat, et al., Arch. Pharm. 2007, 340, 47–52.
[16] S. Arikan, Med. Mycol. 2007, 45, 569–587.
i 2009 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim