1-[(3-Aryloxy-3-aryl)propyl]-1H-imidazoles, new imidazoles with potent activity against Candida albicans and dermatophytes. Synthesis, structure-activity relationship, and molecular modeling studies

Article abstract of DOI:10.1021/jm800009r

New 1-[(3-aryloxy-3-aryl)propyl]-1H-imidazoles were synthesized and evaluated against Candida albicans and dermatophytes in order to develop structure-activity relationships (SARs). Against C. albicans the new imidazoles showed minimal inhibitory concentrations (MICs) comparable to those of ketoconazole, miconazole, and econazole, and were more potent than fluconazole. Several derivatives (10, 12, 14, 18-20, 24, 28, 29, 30, and 34) turned out to be potent inhibitors of C. albicans strains resistant to fluconazole, with MIC values less than 10 μg/mL. Against dermatophytes strains, compounds 20, 25, and 33 (MIC ≤ 5 μg/mL) were equipotent to ketoconazole, econazole, and miconazole. SARs of imidazoles 10-44 were rationalized with reasonable accuracy by a previously developed quantitative pharmacophore for antifungal agents.

Full text of DOI:10.1021/jm800009r

Supporting Information
1-(3-Aryloxy-3-arylpropyl)-1H-imidazoles, New Imidazoles with Potent Activity
against Candida albicans and dermatophytes. Synthesis, Structure-Activity
Relationship and Molecular Modeling Studies
Giuseppe La Regina, Felicia Diodata D’Auria, Andrea Tafi, Francesco Piscitelli,
Stefania Olla, Fabiana Caporuscio, Lucia Nencioni, Roberto Cirilli, Francesco La
Torre, Nadja Rodrigues De Melo, Steven L. Kelly, David C. Lamb, Marino Artico,
Maurizio Botta, Anna Teresa Palamara, and Romano Silvestri
TOC Graphic
Cl
B
D
C
N
O
N
D
*
A
B
R1
R2
N
X
n
Cl
C N
A
O
Cl
11, 15-28, 30-37, 39-50
10
R1 = H, 4-Cl, 4-F, 4-Me, 4-Me, 2,4-Cl2; R2 = H, 2-Cl, 4-Cl, 4-Me, 4-Et,
4-i-Pr, 4-t-Bu, 2,4-Cl2, 2,6-Cl2, 3.5-Cl2, 2,4-Me2; n = 1-4; X = CH, N.
Contents
Computational Investigations – Additional Information
Figure 1S. Superposition of MOD3 with (A) 49 and 44, and (B) with 49 and 50.
Figure 2S. Superposition of MOD3 with (A) 52 and 4, and (B) with 55 and 54.
Figure 3S. Difference spectra and determination of binding constants of compounds 5,
10 and 33.
Table 1S. Elemental analyses of compounds 11, 15-28, 30-37, 39-52 and 56.
S1

Computational Investigations – Additional Information
The spread of the MIC values among derivatives 48, 49 and 50, about one
order of magnitude, roughly corresponded to the acceptable prediction uncertainty by
MOD3.15 At the same time, the measured antifungal values pointed to 50 as the less
active derivative within this series and to 49 as the very most potent compound.
MOD3 did not reproduced the trend of the measured MIC values of these compounds,
even if it correctly predicted their antifungal activities within the measured order of
magnitude. Figure 1S shows that the chain connecting the imidazole to the chiral
carbon atom of 50 does not superimpose the corresponding shorter chain of 49. This
event might be consistent with the steric clashes of the former derivative within the
catalytic cavity of the enzyme. Loosing torsional entropy (further to binding) might
magnify this hypothetical effect determining the lower activity of 50 with respect to
49.
Compound 52, even sharing structural similarity with 4 (Figure 2A), was 20-
fold less potent than 4 (see Table 7). According to MOD3, this result was caused by
the prolonged chain connecting ring C to ring B. The first mapping (corresponding to
a predicted MIC = 0.11 µM) proposed an orientation of the imidazole ring which was
inconsistent with those adopted by the whole set of compounds (Figure 2A). Such an
orientation, that was automatically selected by Catalyst to counterbalance the
exceeding distance between the rings, would prevent the coordination bond with the
heme moiety of the cytochrome (results not shown). Conversely, the second mapping
(Figure 2SA) showed an apparently appropriate alignment of 52, corresponding to an
higher MIC value (0.89 µM) due to a slightly worse mapping of the pharmacophoric
features onto the corresponding structural functions.
The trend of antifungal activities shown by compounds 53-56 was reproduced
fairly well by MOD3 (Table 7). Figure 2SB displays the superposition of MOD3 with
compounds 54 (white) and 55 (yellow). The different antifungal activity of these
compounds is determined by the common structural scaffold, showing two phenyl
rings too close each other. As a consequence, mapping of MOD3 is variable,
depending on the substitution pattern of the two rings. The case of 53 has been
already discussed as due to the impossibility of this derivative to match three
pharmacophoric features.
S2

Figure 1S. (A) Superposition of MOD3 with 49 (yellow) and 44 (white). The fourth mapping of 44 is shown
in the figure. (B) Superposition of MOD3 with 49 (yellow) and 50 (white).
Figure 2S. (A) Superposition of MOD3 with 52 (yellow) and 4 (white). The second mapping of 52 is shown
in the figure. (B) Superposition of MOD3 with 55 (yellow) and 54 (white).
On the contrary, in addition to UNA, 54 could partially map HY1 with the
unsubstituted phenyl ring and HY2 with the para-chloro of the other ring (Figure
2SB). Compound 55 might map both HY1 and HY2 with two para-chlorine atoms.
The MIC values estimated by Catalyst for 54 (2.6) and 55 (0.4) highlighted their
different behaviour. Finally, the software was actually unable to rationalize the
complete inactivity of 56.
S3

Figure 3S. Difference Spectra and Determination of Binding Constants of Compounds 5, 10 and 33.
S4

Table 1S. Elemental Analyses of Compounds 11, 15-28, 30-37, 39-52 and 56.
Compd
Calcd
Found
11
15
16
17
18
19
20
21
22
23
24
25
26
27
28
30
31
32
33
34
35
36
37
39
40
41
42
43
44
45
46
47
48
49
50
51
52
56
C, 77.67; H, 6.52; N, 10.06.
C, 77.52; H, 6.49; N, 9.94.
C, 62.26; H, 4.64; Cl, 20.42; N, 8.07.
C, 62.26; H, 4.64; Cl, 20.42; N, 8.07.
C, 69.12; H, 5.48; Cl, 11.33; N, 8.96.
C, 62.26; H, 4.64; Cl, 20.42; N, 8.07.
C, 62.26; H, 4.64; Cl, 20.42; N, 8.07.
C, 69.83; H, 5.86; Cl, 10.85; N, 8.57.
C, 70.48; H, 6.21; Cl, 10.40; N, 8.22.
C, 71.07; H, 6.53; Cl, 9.99; N, 7.89.
C, 71.63; H, 6.83; Cl, 9.61; N, 7.59.
C, 56.64; H, 3.96; Cl, 27.87; N, 7.34.
C, 56.64; H, 3.96; Cl, 27.87; N, 7.34.
C, 70.48; H, 6.21; Cl, 10.40; N, 8.22.
C, 72.95; H, 5.78; F, 6.41; N, 9.45.
C, 73.53; H, 6.17; F, 6.12; N, 9.03.
C, 59.19; H, 4.14; Cl, 19.41; F, 5.20; N, 7.67. C, 58.92; H, 4.07; Cl, 19.24; F, 5.04; N, 7.41.
C, 59.19; H, 4.14; Cl, 19.41; F, 5.20; N, 7.67. C, 59.01; H, 4.11; Cl, 19.36; F, 5.12; N, 7.52.
C, 78.05; H, 6.89; N, 9.58.
C, 69.83; H, 5.86; Cl, 10.85; N, 8.57.
C, 78.40; H, 7.24; N, 9.14.
C, 78.71; H, 7.55; N, 8.74.
C, 62.07; H, 4.51; Cl, 20.22; N, 7.84.
C, 62.12; H, 4.55; Cl, 20.30; N, 7.97.
C, 68.91; H, 5.35; Cl, 11.12; N, 8.74.
C, 61.97; H, 4.49; Cl, 20.08; N, 7.79.
C, 62.04; H, 4.52; Cl, 20.27; N, 7.95.
C, 69.72; H, 5.80; Cl, 10.62; N, 8.48.
C, 70.27; H, 6.18; Cl, 10.28; N, 8.09.
C, 70.92; H, 6.44; Cl, 9.86; N, 7.71.
C, 71.51; H, 6.79; Cl, 9.45; N, 7.40.
C, 56.45; H, 3.86; Cl, 27.72; N, 7.16.
C, 56.55; H, 3.90; Cl, 27.75; N, 7.18.
C, 70.32; H, 6.08; Cl, 10.28; N, 8.10.
C, 72.77; H, 5.71; F, 6.32; N, 9.28.
C, 73.38; H, 6.13; F, 5.96; N, 8.87.
C, 77.88; H, 6.78; N, 9.32.
C, 69.70; H, 5.78; Cl, 10.71; N, 8.39.
C, 78.28; H, 7.18; N, 9.02.
C, 78.53; H, 7.48; N, 8.55.
C, 78.84; H, 7.78; N, 8.12.
C, 79.00; H, 7.84; N, 8.38.
C, 79.27; H, 8.10; N, 8.04.
C, 79.08; H, 8.02; N, 7.91.
C, 63.17; H, 5.02; Cl, 19.63; N, 7.75
C, 63.17; H, 5.02; Cl, 19.63; N, 7.75
C, 70.48; H, 6.21; Cl, 10.40; N, 8.22.
C, 70.48; H, 6.21; Cl, 10.40; N, 8.22.
C, 78.71; H, 7.55; N, 8.74.
C, 51.95; H, 3.39; Cl, 34.08; N, 6.73.
C, 58.63; H, 4.34; Cl, 20.36; N, 12.07.
C, 53.36; H, 3.69; Cl, 27.79; N, 10.98.
C, 59.68; H, 4.73; Cl, 19.57; N, 11.60.
C, 69.12; H, 5.48; Cl, 11.33; N, 8.96.
C, 70.48; H, 6.21; Cl. 10.40; N, 8.22.
C, 71.07; H, 6.53; Cl, 9.99; N, 7.89.
C, 77.67; H, 6.52; N, 10.06.
C, 63.05; H, 4.96; Cl, 19.45; N, 7.59
C, 62.65; H, 4.91; Cl, 19.38; N, 7.38
C, 70.36; H, 6.16; Cl, 10.28; N, 8.08.
C, 70.29; H, 6.10; Cl, 10.18; N, 7.92.
C, 78.66; H, 7.48; N, 8.61.
C, 51.82; H, 3.31; Cl, 33.74; N, 6.52.
C, 58.48; H, 4.30; Cl, 20.13; N, 11.84.
C, 53.21; H, 3.61; Cl, 27.62; N, 10.84.
C, 59.44; H, 4.65; Cl, 19.31; N, 11.48.
C, 68.95; H, 5.44; Cl, 11.24; N, 8.80.
C, 70.26; H, 6.13; Cl. 10.28; N, 8.09.
C, 70.87; H, 6.41; Cl, 9.74; N, 7.70.
C, 77.52; H, 6.46; N, 9.90
C, 57.67; H, 4.33; Cl, 26.88; N, 7.08.
C, 51.95; H, 3.39; Cl, 34.08; N, 6.73.
C, 57.44; H, 4.26; Cl, 26.55; N, 6.85.
C, 51.82; H, 3.30; Cl, 33.87; N, 6.62.
S5