Imidazolylchromanones containing alkyl side chain as lanosterol 14α-demethylase inhibitors: Synthesis, antifungal activity and docking study

Article abstract of DOI:10.3109/14756366.2013.776554

Previously, 2-alkylchromans have been introduced as non-azole inhibitors of 14α-demethylase. Accordingly, we incorporated imidazole ring on the 3-position of 2-alkylchromanones to design new inhibitors of 14α-demethylase and potential antifungal agents. T

Full text of DOI:10.3109/14756366.2013.776554

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ISSN: 1475-6366 (print), 1475-6374 (electronic)
J Enzyme Inhib Med Chem, Early Online: 1–9
2013 Informa UK Ltd. DOI: 10.3109/14756366.2013.776554
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ORIGINAL ARTICLE
Imidazolylchromanones containing alkyl side chain as lanosterol
4a-demethylase inhibitors: synthesis, antifungal activity and docking
study
1
1
1
1
2
3
Saeed Emami , Touba Banipoulad , Hamid Irannejad , Alireza Foroumadi , Mehraban Falahati ,
3
Mahtab Ashrafi-Khozani , and Somaye Sharifynia
3
1
Department of Medicinal Chemistry and Pharmaceutical Sciences Research Center, Faculty of Pharmacy, Mazandaran University of Medical
2
Sciences, Sari, Iran, Department of Medicinal Chemistry, Faculty of Pharmacy and Drug Design and Development Research Center, and
3
Department of Parasitology, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran
Abstract
Previously, 2-alkylchromans have been introduced as non-azole inhibitors of 14a-demethylase. Antifungal activity, azole antifungals,
Keywords
Accordingly, we incorporated imidazole ring on the 3-position of 2-alkylchromanones to design
new inhibitors of 14a-demethylase and potential antifungal agents. Thus, a series of 2-alkyl-3-
imidazolylchromanones were synthesized starting from 2-hydroxyphenacyl bromide. The trans-
configuration of compounds was confirmed by NMR-spectroscopy. The antifungal activity
of title compounds were evaluated against different fungi in comparison with fluconazole
and miconazole. trans-2-(1-Pentyl)-3-imidazolylchroman-4-one (4d) showed the most potent
chroman-4-one, docking study, imidazole,
lanosterol 14a-demethylase
History
Received 27 December 2012
Revised 7 February 2013
Accepted 7 February 2013
Published online 14 March 2013
1
activity against yeasts comparable to fluconazole. The experimental data based on H NMR
spectroscopy revealed that 2-alkyl side chain and 3-imidazolyl moiety in compound 4d exist
predominantly in the di-equatorial conformation. While docking study with 14a-demethylase
demonstrated that the di-axial form of compound 4d can be considered as active
conformation.
Introduction
azole antifungal agents, such as luliconazole, voriconazole,
pramiconazole, posaconazole, albaconazole and isavuconazole
In the recent decades, the risk of fungal infections such as
candidiasis and aspergillosis has increased greatly because of the
rising number of patients who are severely immunocompromised.
Thus, invasive fungal infections have become a significant cause
of morbidity and mortality in immunocompromised patients
suffering from tuberculosis, diabetes, cancer, AIDS and patients
4,5
are marketed or currently in the late stages of clinical trials
.
However, the extensive use of azoles has led to the development
of fungal resistance which significantly reduced their efficacy.
Therefore, there is a need to an ongoing search for novel
antifungal azoles.
1
,2
Azole antifungals act by blocking the active site of lanosterol
4a-demethylase (CYP51), a key enzyme in the fungal ergos-
who have undergone organ or bone marrow transplant
.
Moreover, the development of severe resistance is becoming a
1
6
3
major problem in the field of antifungal chemotherapy . On the
terol biosynthesis . The affinity of azole antifungals to the
lanosterol 14a-demethylase is not only determined by the
coordination binding of the nitrogen of azole ring to the heme
iron, but also by the affinity of N-l substituent for the apoprotein
other hand, there are only a few chemotherapeutic agents that can
be used for life-threatening fungal infections. Natural products
such as polyenes and echinocandins, and synthetic chemicals
including flucytosine and azoles are currently available classes of
7
part of the enzyme . The remaining part of the azole antifungal
fits in the similar way like lanosterol in the hydrophobic
4
antifungal agents . Among the different classes of antifungal
8
groove of lanosterol 14a-demethylase . Previously, Ji et al.
designed 2-alkylchromanone and their oximes (Figure 1, structure
agents that have been discovered, azoles are first-line drugs for the
treatment of invasive fungal infections, because of their high
therapeutic index. The azoles are chemically either an imidazole
or a triazole ring attached to a functionalized phenethyl moiety
as their pharmacophore (Figure 1, structure A). Several new
9
B) as non-azole inhibitors of 14a-demethylase . Moreover, we
have reported 3-imidazolyl chromanone oxime ethers as anti-
10
fungal agents . In this study, we incorporated imidazole ring on
the 3-position of 2-alkylchromanones to design new inhibitors
of 14a-demethylase and potential antifungal agents (Figure 1,
structure C). It is speculated that the chroman ring having the
2
-alkyl side chain in compounds C might be a mimetic of B
and C rings or D ring and 17-alkyl side chain of the lanosterol
Figure 2), and that the 3-imidazolyl residue of C fills the position
of the 14-methyl group of lanosterol for coordination binding
to the heme of lanosterol 14a-demethylase. Thus, we describe
Address for correspondence: Dr Saeed Emami, Department of Medicinal
Chemistry, Faculty of Pharmacy, Mazandaran University of Medical
Sciences, Sari, Iran. Tel: 0098-151-3543082. Fax: 0098-151-3543084.
E-mail: sd_emami@yahoo.com
(

2
S. Emami et al.
J Enzyme Inhib Med Chem, Early Online: 1–9
standard. The spin multiplicities are reported as s (singlet), br s
(broad singlet), d (doublet), t (triplet), q (quartet) and m
X
R2
N
R1
(multiplet). Coupling constants (J) are reported in Hertz (Hz).
N
A
The IR spectra were obtained on a PerkinElmer (Norwalk, CT)
FT-IR spectrophotometer (potassium bromide disks). Elemental
analyses were carried out on a CHN-O rapid elemental analyzer
CH3
O
n
A
B
(Heraeus GmbH, Hanau, Germany) for C, H and N, and the
A= CH, N
X = O, NOH
n = 0-6
results are within ꢀ0.4% of the theoretical values.
1
2
R = R, OR, Ar ; R = H
1
2
R = R = 1,3-spirodioxolane ring
1
2
General procedure for the synthesis of trans-2,3-dihydro-3-
(1H-imidazol-1-yl)-2-alkyl-4H-1-benzopyran-4-one nitrate (4b–g)
R = R = N-OR
A solution of compound 2 (404 mg, 2.0 mmol) and appropri-
ate aliphatic aldehyde (2.4 mmol) in 2-propanol (4 mL) containing
piperidine (0.67 mmol) was heated under reflux for 2–4 h. The
reaction was concentrated under reduced pressure and mixed
with water (20 mL). The mixture was left in the fridge overnight
until viscose oil was separated. The aqueous phase was decanted
and the oily residue was dissolved in diethyl ether, and treated
with 65% HNO (0.2 mL). The mixture was cooled at a freezer to
3
complete the precipitation of the nitrate salts 4b–g, which were
collected by filtration and washed with diethyl ether.
N
X
N
n
CH3
O
C
X = O, NOH
n = 0-6
trans-2,3-Dihydro-3-(1H-imidazol-1-yl)-2-(1-propyl)-4H-1-
benzopyran-4-one nitrate (4b)
Figure 1. The common structure of azole antifungals (structure A),
previously described 2-alkylchromans as non-azole inhibitors for 14a-
demethylase of fungi (structure B) , and 2-alkyl-3-imidazolylchroma-
ꢁ
ꢁ
ꢂ1
Yield 25%; m.p. 111 C–112 C; IR (KBr, cm ) ꢀmax: 1715
9
1
(
C¼O). H NMR (500 MHz, DMSO-d ) ꢁ: 0.86 (t, J ¼ 7.25 Hz,
3 2 2
6
nones designed as new inhibitors of 14a-demethylase and potential
antifungal agents (structure C).
3
H, CH ), 1.22–1.46 (m, 2H, CH ), 1.51–1.77 (m, 2H, CH ), 5.13
(
m, 1H, H-2), 6.00 (d, J ¼ 12.35 Hz, 1H, H-3), 7.19 (d, J ¼ 8.1 Hz,
1
7
9
2
H, H-8), 7.20 (t, J ¼ 7.8 Hz, 1H, H-6), 7.71 (t, J ¼ 7.3 Hz, 1H, H-
), 7.78–7.91 (m, 2H, imidazole), 7.84 (d, J ¼ 6.75 Hz, 1H, H-5),
C
D
þ
.22 (br s, 1H, imidazole). MS (m/z, %): 256 (M , 60), 255 (77),
13 (34), 188 (35), 173 (20), 150 (32), 136 (47), 121 (85), 120
A
B
(
(
100), 109 (68), 107 (53), 92 (68), 80 (26), 71 (47), 69 (96), 53
39). Anal. Calcd for C H N O (%): C, 56.42; H, 5.37;
1
5 17 3 5
Lanosterol skeleton
N, 13.16. Found (%): C, 56.70; H, 5.59; N, 13.12.
CH3
trans-2,3-Dihydro-3-(1H-imidazol-1-yl)-2-(1-butyl)-4H-1-
benzopyran-4-one nitrate (4c)
CH3
CH3
13
CH3
1
7
ꢁ
ꢁ
ꢂ1) ꢀmax
Yield 52%; m.p. 108 C–109 C; IR (KBr, cm : 1714
1
HO
H C
1
4
CH3
(C¼O). H NMR (500 MHz, DMSO-d ) ꢁ: 0.84 (t, J ¼ 7.2 Hz,
6
3
3
1
H, CH ), 1.19–1.42 (m, 4H, CH CH ), 1.48–1.61 (m, 1H, HCH ),
3 2 2 a
Lanosterol
.62–1.74 (m, 1H, HCHb), 5.13 (m, 1H, H-2), 6.00
Figure 2. The structure of lanosterol; natural substrate of lanosterol (d, J ¼ 12.35 Hz, 1H, H-3), 7.19 (d, J ¼ 8.0 Hz, 1H, H-8),
1
4a-demethylase.
7
H-7), 7.84 (m, 3H, two imidazole-H and H-5), 9.22
.20 (t, J ¼ 6.7 Hz, 1H, H-6), 7.71 (dt, J ¼ 7.78 and 1.55 Hz, 1H,
þ
(s, 1H, imidazole). MS (m/z, %): 270 (M , 15), 269 (55),
here, synthesis, antifungal activity and docking studies of 2-alkyl-
-imidazolylchromanone derivatives.
2
9
13 (23), 189 (35), 176 (55), 150 (100), 121 (96), 107 (19),
2 (57), 85 (45), 68 (45), 57 (51). Anal. Calcd for C H N O (%):
3
1
6 19 3 5
C, 57.65; H, 5.75; N, 12.61. Found (%): C, 57.58; H, 5.87; N, 12.33.
Experimental
Chemistry
trans-2,3-Dihydro-3-(1H-imidazol-1-yl)-2-(1-pentyl)-4H-1-
benzopyran-4-one nitrate (4d)
The 1-(2-hydroxyphenyl)-2-(1H-imidazol-1-yl)ethanone (2)
ꢁ ꢁ
ꢂ1
trans-2,3-dihydro-3-(1H-imidazol-1-yl)-2-methyl-4H-1- Yield 35%; m.p. 124 C–125 C; IR (KBr, cm ) ꢀmax: 1715
and
benzopyran-4-one (4a) were prepared according to the literature (C¼O). H NMR (500 MHz, DMSO-d ) ꢁ: 0.85 (t, J ¼ 6.2 Hz, 3H,
1
6
1
1,12
methods
compounds were checked by a thin-layer chromatography using HCH ), 1.64–1.75 (m, 1H, HCH ), 5.13 (m, 1H, H-2), 6.00
. The progress of reactions and the purity of CH ), 1.14–1.42 (m, 6H, CH CH CH ), 1.50–1.62 (m, 1H,
3 2 2 2
a
b
Merck silica gel 60 F254 plates (Darmstadt, Germany), and (d, J ¼ 12.3 Hz, 1H, H-3), 7.19 (d, J ¼ 8.35 Hz, 1H, H-8), 7.21
visualization was achieved with UV light (254 nm). Yields are (t, J ¼ 8.0 Hz, 1H, H-6), 7.71 (t, J ¼ 7.5 Hz, 1H, H-7), 7.78–7.91
based on purified material and were not optimized. Melting points (m, 2H, imidazole), 7.84 (d, J ¼ 8.15 Hz, 1H, H-5), 9.22 (s, 1H,
þ
were determined in open glass capillaries using the Bibby Stuart imidazole). MS (m/z, %): 284 (M , 18), 283 (45), 232 (15), 213
Scientific SMP3 apparatus (Stuart Scientific, Stone, UK) and are (23), 203 (22), 189 (29), 176 (77), 150 (90), 121 (100), 105
1
uncorrected. The H NMR spectra were recorded using a Bruker (26), 99 (54), 92 (27), 69 (61), 55 (28). Anal. Calcd for
4
00 or 500 spectrometers (Rheinstatten, Germany), and chemical C H N O (%): C, 58.78; H, 6.09; N, 12.10. Found (%):
17 21 3 5
shifts are expressed as d (ppm) with tetramethylsilane as internal C, 59.01; H, 5.88; N, 11.97.

DOI: 10.3109/14756366.2013.776554
Imidazolylchromanones containing alkyl side chain as lanosterol 14ꢂ-demethylase inhibitors
3
trans-2,3-Dihydro-3-(1H-imidazol-1-yl)-2-(1-hexyl)-4H-1-
benzopyran-4-one nitrate (4e)
(t, J ¼ 7.4 Hz, 3H, CH ), 1.17–1.29 (m, 1H, HCH ), 1.41–1.52
b
3
a
(m, 1H, HCH ), 4.19 (m, 1H, H-2), 5.83 (d, J ¼ 1.1 Hz, H-3), 6.85
ꢂ1
(
br s, 2H, H-4 and H-5 imidazole), 7.04 (d, J ¼ 8.35 Hz, 1H, H-8),
ꢁ
ꢁ
Yield 44%; m.p. 112 C–113 C; IR (KBr, cm ) ꢀmax: 1708
1
7.06 (t, J ¼ 7.85 Hz, 1H, H-6), 7.37 (dt, J ¼ 7.75 and 1.5 Hz, 1H,
(
C¼O). H NMR (400 MHz, DMSO-d ) ꢁ: 0.86 (t, J ¼ 6.8 Hz, 3H,
6
H-7), 7.61 (br s, 1H, imidazole H), 7.84 (dd, J ¼ 7.85 and 1.5 Hz,
CH ), 1.10–1.78 (m, 10H, CH CH CH CH CH ), 5.12 (m, 1H,
3 2 2 2 2 2
þ
1
H, H-5), 11.82 (s, 1H, OH). MS (m/z, %): 257 (M , 100), 240
H-2), 5.98 (d, J ¼ 12 Hz, 1H, H-3), 6.82 (br s, 1H, imidazole),
(
1
18), 213 (18), 189 (48), 173 (32), 146 (30), 132 (25), 121 (53),
02 (19), 91 (26), 69 (34), 53 (26). Anal. Calcd for C H N O
4 15 3 2
7
1
1
.17 (d, J ¼ 8.0 Hz, 1H, H-8), 7.20 (dt, J ¼ 7.60 and 0.8 Hz,
1
H, H-6), 7.35 (br s, 1H, imidazole), 7.71 (dt, J ¼ 8.6 and 1.6 Hz,
(%): C, 65.35; H, 5.88; N, 16.33. Found (%): C, 65.33; H, 6.02;
N, 16.40.
H, H-7), 7.84 (dd, J ¼ 7.8 and 1.6 Hz, 1H, H-5), 9.23 (s, 1H,
þ
imidazole). MS (m/z, %): 298 (M , 25), 297 (70), 213 (42), 189
(
(
18), 176 (37), 150 (76), 121 (100), 113 (57), 107 (25), 92 (31), 85
26), 68 (55), 55 (25). Anal. Calcd for C H N O (%): C, 59.82;
(Z)-trans-2,3-Dihydro-3-(1H-imidazol-1-yl)-2-(1-propyl)-4H-1-
benzopyran-4-one oxime (5b)
1
8 23 3 5
H, 6.41; N, 11.63. Found (%): C, 59.77; H, 6.48; N, 11.84.
ꢁ
ꢁ
ꢂ1
Yield 40%; m.p. 184 C–185 C; IR (KBr, cm ) ꢀmax: 3450
1
(
(
(
O–H), 1635 (C¼NOH). H NMR (500 MHz, DMSO-d ) ꢁ: 0.87
trans-2,3-Dihydro-3-(1H-imidazol-1-yl)-2-(1-heptyl)-4H-1-
benzopyran-4-one nitrate (4f)
6
t, J ¼ 6.8 Hz, 3H, CH ), 1.10–1.65 (m, 4H, CH CH ), 4.23–4.30
3
2
2
m, 1H, H-2), 5.80 (d, J ¼ 1.2 Hz, 1H, H-3), 6.81 (br s, 1H,
ꢁ
ꢁ
ꢂ1
Yield 28%; m.p. 95 C–96 C; IR (KBr, cm ) ꢀmax: 1715 (C¼O).
imidazole), 6.83 (br s, 1H, imidazole), 7.03 (d, J ¼ 8.1 Hz, 1H,
H-8), 7.06 (t, J ¼ 7.6 Hz, 1H, H-6), 7.37 (t, J ¼ 7.7 Hz, 1H, H-7),
1
H NMR (500 MHz, DMSO-d ) ꢁ: 0.85 (t, J ¼ 6.88 Hz, 3H, CH ),
6
3
1
HCH ), 1.63–1.78 (m, 1H, HCH ), 5.13 (m, 1H, H-2), 5.99
(
(
7
imidazole). MS (m/z, %): 312 (M , 25), 311 (64), 297 (27), 213
(
.15–1.40 (m, 10H, CH CH CH CH CH ), 1.48–1.62 (m, 1H,
2 2 2 2 2
7
(
.56 (br s, 1H, imidazole), 7.84 (d, J ¼ 7.75 Hz, 1H, H-5), 11.80
þ
a
b
s, 1H, OH). MS (m/z, %): 271 (M , 100), 254 (76), 227 (20),
d, J ¼ 12.35 Hz, 1H, H-3), 7.19 (d, J ¼ 8.4 Hz, 1H, H-8), 7.20
2
(
03 (38), 186 (21), 174 (19), 159 (19), 146 (35), 131 (20), 120
28), 91 (18), 69 (28), 53 (20). Anal. Calcd for C H N O (%):
t, J ¼ 7.53 Hz, 1H, H-6), 7.71 (dt, J ¼ 7.8 and 1.60 Hz, 1H, H-7),
1
5 17 3 2
.77–7.85 (m, 1H, H-5 and 2H, imidazole), 9.20 (s, 1H,
C, 66.40; H, 6.32; N, 15.49. Found (%): C, 66.34; H, 6.39;
N, 15.80.
þ
42), 189 (15), 176 (29), 150 (30), 127 (53), 121 (63), 107 (18),
2 (25), 69 (96), 57 (100). Anal. Calcd for C H N O (%):
9
1
9 25 3 5
(Z)-2,3-Dihydro-3-(1H-imidazol-1-yl)-2-(1-butyl)-4H-1-
benzopyran-4-one oxime (5c)
C, 60.79; H, 6.71; N, 11.19. Found (%): C, 60.88; H, 6.49;
N, 10.89.
ꢁ
ꢁ
ꢂ1
Yield 44 %; m.p. 142 C–144 C; IR (KBr, cm ) ꢀmax: 3450
1
(
(
(
O–H), 1606 (C¼NOH). H NMR (500 MHz, DMSO-d ) ꢁ: 0.85
6
trans-2,3-Dihydro-3-(1H-imidazol-1-yl)-2-(1-isobutyl)-4H-1-
benzopyran-4-one nitrate (4g)
t, J ¼ 7.5 Hz, 3H, CH ), 1.12–1.60 (m, 6H, CH CH CH ), 4.24
3
2
2
2
m, 1H, H-2), 5.81 (d, J ¼ 1.2 Hz, H-3), 6.83 (br s, 1H, imidazole),
ꢁ
ꢁ
ꢂ1
Yield 40%; m.p. 100 C–101 C; IR (KBr, cm ) ꢀmax: 1705 6.85 (br s, 1H, imidazole), 7.03 (d, J ¼ 7.5 Hz, H-8), 7.05
1
(
C¼O). H NMR (500 MHz, DMSO-d ) ꢁ: 0.83 (d, J ¼ 6.5 Hz, 3H, (dt, J ¼ 7.5 and 1.0 Hz, H-6), 7.62 (br s, 1H, imidazole), 7.84
6
CH ), 0.85–0.95 (m, 1H, CH(Me) ), 0.89 (d, J ¼ 6.6 Hz, 3H, CH ),
3
2
3
(dd, J ¼ 8.0 and 1.5 Hz, H-5), 11.83 (s, 1H, OH). MS (m/z, %):
þ
1
1
1
2
1
2
5
1
.78–1.96 (m, 2H, CH ), 5.21 (m, 1H, H-2), 5.97 (d, J ¼ 12.2 Hz, 285 (M , 100), 268 (87), 241 (19), 228 (20), 217 (38), 200 (22),
2
H, H-3), 7.19 (d, J ¼ 8.3 Hz, 1H, H-8), 7.20 (t, J ¼ 7.4 and 1.0 Hz, 174 (28), 159 (30), 146 (32), 131 (23), 120 (32), 107 (24), 91 (26),
H, H-6), 7.71 (dt, J ¼ 7.78 and 1.7 Hz, 1H, H-7), 7.76–7.88 (m,
81 (24), 69 (49), 53 (28). Anal. Calcd for C H N O (%):
16 19 3 2
C, 67.35; H, 6.71; N, 14.73. Found (%): C, 67.66; H, 6.53;
H, imidazole), 7.84 (dd, J ¼ 7.8 and 1.5 Hz, 1H, H-5), 9.17 (br s,
þ
H, imidazole). MS (m/z, %): 270 (M , 35), 269 (100), 213 (67), N, 14.64.
02 (27), 187 (32), 150 (35), 121 (62), 107 (53), 92 (36), 69 (46),
7 (50). Anal. Calcd for C H N O (%): C, 57.65; H, 5.75; N,
1
6
19
3
5
(Z)-trans-2,3-Dihydro-3-(1H-imidazol-1-yl)-2-(1-pentyl)-4H-1-
benzopyran-4-one oxime (5d)
2.61. Found (%): C, 57.37; H, 5.81; N, 12.73.
ꢁ
ꢁ
ꢂ1
Yield 86%; m.p. 150 C–152 C; IR (KBr, cm ) ꢀmax: 3450
General procedure for the synthesis of (Z)-trans-2,3-dihydro-
-(1H-imidazol-1-yl)-2-alkyl-4H-1-benzopyran-4-one
oximes (5a–g)
1
(
O–H), 1605 (C¼NOH). H NMR (400 MHz, DMSO-d ) ꢁ: 0.85
6
3
(
t, J ¼ 7.0 Hz, 3H, CH ), 0.98–1.62 (m, 8H, CH CH CH CH ),
3
2
2
2
2
4
.22 (m, 1H, H-2), 5.81 (m, 1H, H-3), 6.82 (br s, 2H, H-4 and H-5
A solution of compound 2 (404 mg, 2.0 mmol) and appropriate imidazole), 7.03 (d, J ¼ 8.4 Hz, 1H, H-8), 7.05 (t, J ¼ 7.6 Hz,
aliphatic aldehyde (2.4 mmol) in 2-propanol (4 mL) containing 1H, H-6), 7.37 (dt, J ¼ 7.2 and 1.2 Hz, 1H, H-7), 7.57 (m, 1H,
piperidine (0.67 mmol) was heated under reflux for 2–4 h. The imidazole), 7.84 (d, J ¼ 8.0 Hz, 1H, H-5), 11.80 (s, 1H, OH). MS
þ
reaction was concentrated under reduced pressure and mixed with (m/z, %): 299 (M , 89), 282 (100), 255 (24), 231 (29), 212 (24),
water (20 mL). The mixture was left in the fridge overnight until 188 (20), 174 (26), 159 (29), 146 (30), 131 (23), 120 (35), 107
viscose oil was separated. The aqueous phase was decanted (24), 91 (18), 81 (23), 69 (45), 55 (27). Anal. Calcd for
and the oily residue was dissolved in methanol (3 mL). After an C H N O (%): C, 68.20; H, 7.07; N, 14.04. Found (%):
1
7 21 3 2
addition of hydroxylamine hydrochloride (417 mg, 6 mmol) and C, 68.11; H, 7.20; N, 14.02.
K CO (276 mg, 2.0 mmol), the mixture was stirred at room
2
3
temperature for 2–6 d. Then, the reaction mixture was poured into (Z)-trans-2,3-Dihydro-3-(1H-imidazol-1-yl)-2-(1-hexyl)-4H-1-
water, and the precipitate was filtered, washed with water to give benzopyran-4-one oxime (5e)
oxime derivative 5.
ꢁ
ꢁ
ꢂ1
Yield 87%; m.p. 158 C–159 C; IR (KBr, cm ) ꢀmax: 3450
(
1
O–H), 1622 (C¼NOH). H NMR (500 MHz, DMSO-d6)
0.86 (t, J ¼ 6.8 Hz, 3H, CH3), 1.17–1.57 (m, 10H,
CH CH CH CH CH ), 4.25 (m, 1H, H-2), 5.81 (d, J ¼ 2.15 Hz,
(Z)-trans-2,3-Dihydro-3-(1H-imidazol-1-yl)-2-ethyl-4H-1-
benzopyran-4-one oxime (5a)
ꢁ
:
2
2
2
2
2
ꢁ
ꢂ1
Yield 58%; m.p. 160–162 C; IR (KBr, cm ) ꢀmax: 3450 (O–H), 1H, H-3), 6.82 (br s, 1H, imidazole), 6.84 (br s, 1H, imidazole),
1
1
605 (C¼NOH). H NMR (500 MHz, DMSO-d ) ꢁ: 0.98 7.04 (d, J ¼ 8.15 Hz, 1H, H-8), 7.07 (t, J ¼ 7.2 Hz, 1H, H-6), 7.38
6

4
S. Emami et al.
J Enzyme Inhib Med Chem, Early Online: 1–9
Scheme 1. Synthesis of chromanone
derivatives (4a–f) and chromanone (Z)-oxime
(5a–f).
Scheme 2. Synthesis of compounds 4g and 5g.
(
7
dt, J ¼ 7.75 and 1.60 Hz, 1H, H-7), 7.57 (br s, 1H, imidazole),
(Z)-trans-2,3-Dihydro-3-(1H-imidazol-1-yl)-2-(1-heptyl)-4H-1-
benzopyran-4-one oxime (5f)
.85 (dd, J ¼ 7.9 and 1.45 Hz, 1H, H-5), 11.82 (s, 1H, OH). MS
þ
(
2
m/z, %): 313 (M , 64), 296 (100), 269 (21), 245 (22), 228 (32),
12 (30), 188 (19), 174 (21), 159 (31), 146 (32), 131 (32), 121 Yield 63%; m.p. 147 C–148 C; IR (KBr, cm ) ꢀmax: 3460
ꢁ
ꢁ
ꢂ1
1
(
41), 107 (31), 91 (30), 81 (26), 69 (58), 55 (42). Anal. Calcd (O–H), 1604 (C¼NOH). H NMR (400 MHz, DMSO-d ) ꢁ:
18 23 3 2 a 2 2 2 2 2 3
6
for C H N O (%): C, 68.98; H, 7.40; N, 13.41. Found (%): 0.62–1.40 (m, 14H, HCH CH CH CH CH CH CH ), 1.80–1.97
C, 69.07; H, 7.22; N, 13.47.
(m, 1H, HCH ), 4.31–4.47 (m, 1H, H-2), 5.75–5.94 (m, 1H, H-3),
b

DOI: 10.3109/14756366.2013.776554
Imidazolylchromanones containing alkyl side chain as lanosterol 14ꢂ-demethylase inhibitors
5
Table 1. The chemical shifts of compounds 4 and 5.
OH
2
'
.HNO3
2'
O
N
N
N
5
5
N
R
N
R
6
4
4'
6
4
4'
3
2
3
2
5
'
5'
1
O
1
O
7
8
7
8
4
a-g
5a-g
0
0
0
Compound
H-2
H-3
H-5
H-6
H-7
7.71
7.35–7.38
H-8
H-2
H-4 & H-5
4a–g
a–g
5.12–5.21
4.18–4.47
5.97–6.00
5.75–5.97
7.77–7.85
7.80–7.85
7.20–7.21
7.05–7.35
7.17–7.19
7.03–7.05
9.17–9.23
7.56–7.62
6.82–7.91
6.80–6.85
5
Table 2. Antifungal activity (MICs, mg/mL) of compounds 4a–g and 5a–g in comparison with standard antifungal drugs.
N
.HNO3
OH
N
O
N
N
R
N
O
O
R
4a-g
5a-g
Compound
R
C. albicans
S. cerevisiae
M. gypseum
A. niger
4
4
4
4
4
4
4
5
5
5
5
5
5
5
a
b
c
d
e
f
g
a
b
c
d
e
f
CH
CH
3
2
464
464
464
8
32
16
464
464
464
32
464
464
32
8
16
464
464
464
32
32
16
464
32
464
32
32
32
464
32
464
4
464
464
464
464
32
CH
2
CH
3
CH
CH
CH
CH
2
2
2
2
(CH
(CH
(CH
(CH
2
)
)
)
)
2
CH
3
CH
4
CH
5
CH
3
3
3
3
2
2
2
8
32
CH
CH
CH CH
2
CH(CH
CH
CH
3
)
2
464
464
464
32
464
464
464
464
464
32
464
464
464
8
2
3
2
2
3
CH
CH
CH
CH
2
2
2
2
(CH
(CH
(CH
(CH
2
)
)
)
)
2
CH
3
CH
4
CH
5
CH
3
3
3
3
2
2
2
32
32
464
464
464
16
464
464
464
8
g
2 3 2
CH CH(CH )
Fluconazole
Miconazole
a
a
nt
nt
a
Not tested.
6
.85 (br s, 2H, H-4 and H-5 imidazole), 7.03 (d, J ¼ 8.8 Hz, 1H, Antifungal activity assay
H-8), 7.06 (t, J ¼ 7.6 Hz, 1H, H-6), 7.37 (t, J ¼ 7.6 Hz, 1H, H-7),
The minimum inhibitory concentrations (MICs) of compounds
against Candida albicans ATCC 10231, Saccharomyces
cerevisiae PTCC 5177, Aspergillus niger PTCC 5011 and
Microsporum gypseum PTCC 5070 were determined by micro-
7
.61 (br s, 1H, imidazole), 7.85 (d, J ¼ 8.0 Hz, 1H, H-5), 11.82
þ
(s, 1H, OH). MS (m/z, %): 327 (M , 44), 310 (61), 283 (15), 259
(34), 228 (19), 212 (61), 188 (20), 173 (24), 160 (22), 145 (36),
127 (43), 121 (54), 107 (29), 92 (27), 82 (36), 69 (100), 55 (46).
Anal. Calcd for C H N O (%): C, 69.70; H, 7.70; N, 12.83.
Found (%): C, 69.72; H, 7.59; N, 12.97.
13
dilution method . A stock solution (128 mg/mL) of compounds
1
9 25 3 2
was prepared in a Sabouraud dextrose broth (SDB) by using 10%
v/v DMSO. The stock solution of compounds was transferred into
the plates with 96 U-shaped wells and serially diluted with SDB
in subsequent wells. Then, fungal suspension was added to each
(Z)-trans-2,3-Dihydro-3-(1H-imidazol-1-yl)-2-(1-isobutyl)-4H-1-
benzopyran-4-one oxime (5g)
3
well to reach the final inoculum size of 0.5 ꢃ 10 CFU/mL. The
ꢂ1
final concentrations of tested compounds in the medium were 64,
32, 16, 8, 4, 2, 1 and 0.5 mg/mL. Fungal plates were made in
triplicate and incubated at 35 C about 24–48 h for C. albicans
ꢁ
ꢁ
Yield 50%; m.p. 169 C–171 C; IR (KBr, cm ) ꢀmax: 3460
1
(
1
O–H), 1606 (C¼NOH). H NMR (400 MHz, DMSO-d ) ꢁ: 0.62–
6
ꢁ
.80 (m, 9H, CH CH(CH ) ), 4.18–4.28 (m, 1H, H-2), 5.76–5.84
2 3 2
and S. cerevisiae, about 72 h for A. niger and about 96 h for
M. gypseum. The MIC value was defined as lowest concentration
of the antifungal agent at which there were no visible growth
shown.
(m, 1H, H-3), 6.80 (br s, 1H, imidazole), 6.82 (br s, 1H,
imidazole), 7.02 (d, J ¼ 8.0 Hz, 1H, H-8), 7.05 (t, J ¼ 7.6 Hz, 1H,
H-6), 7.37 (t, J ¼ 7.4 Hz, 1H, H-7), 7.56 (br s, 1H, imidazole),
7
2
1
.84 (d, J ¼ 7.6 Hz, 1H, H-5), 11.82 (s, 1H, OH). MS (m/z, %):
þ
85 (M , 62), 268 (100), 228 (16), 217 (20), 212 (25), 200 (17),
84 (17), 174 (24), 161 (25), 146 (34), 131 (22), 120 (21), 107
Computational method
(13), 91 (18), 81 (15), 69 (43), 53 (18). Anal. Calcd for Crystal structure of cytochrome P450 14a-sterol demethylase
C H N O (%): C, 67.35; H, 6.71; N, 14.73. Found (%): (CYP51) from Mycobacterium tuberculosis in complex with
C, 67.51; H, 6.70; N, 14.44.
1
6 19 3 2
fluconazole with ID 1EA1 was retrieved from the Brookhaven

6
S. Emami et al.
J Enzyme Inhib Med Chem, Early Online: 1–9
Figure 3. Docking pose view (2D map) for the enantiomers of compounds 4d and 5d. Only important amino acids for interactions are shown.
Protein Data Bank (http://www.rcsb.org). The FlexX program General and specific aspects of compounds’ structures were
1
interfaced with LeadIT 2.0.2 (BioSolveIT GmbH, Sankt Augustin, elucidated by H NMR spectroscopy. Table 1 represents the
Germany) was used for docking. The binding site was defined chemical shifts of the core structure based on the protons of
˚
to any residues 8 A distant from the co-crystallized fluconazole chroman and imidazole rings. Since the N-3 atom of imidazole
in the complex crystal structure of the enzyme. For an evaluation ring is protonated in the nitrate salts of compounds 4, the
of the ligands affinity towards active site, the HYDE assessment chemical shift of proton at the C-2 position of imidazole ring is
module of LeadIT software was used to report the free energy of deshielded. The large vicinal coupling constant (J2,3 ¼ 12.0–12.35
1
4,15
binding (DG) and ligand efficiency of the best scored pose
.
Hz) between H-2 and H-3 of chroman ring indicates that the
orientation of the 2-alkyl group and the 3-imidazole ring is trans.
1
In the H NMR spectra of oxime derivatives 5, only a set of
Results and discussion
signals were appeared which confirmed the exclusive formation
of one stereoisomer during the oximation reaction. The (E)- or
The designed 2-alkyl-3-imidazolylchromanones were synthesized (Z)-geometry was readily identified by H NMR, based on the
starting from 2-hydroxyphenacyl bromide (1) as outlined in deshielding effect of the oxime oxygen. According to the previous
Scheme 1. Compound 1 was reacted with excess imidazole in studies, when the (E)-isomer is produced in the oximation reaction,
Chemistry
1
1
1
DMF to give N-(2-hydroxyphenacyl)imidazole derivative 2 . the H-5 proton of chroman ring is significantly deshielded
1
0,16
Cyclization of compound 2 with linear aliphatic aldehydes (ꢁ48.5 ppm) with respect to the parent ketone (ꢁ58 ppm)
.
occurred in refluxing 2-propanol, in the presence of piperidine As seen in Table 1, the chemical shifts of oxime derivatives (5)
as a catalyst. The oily crude product (3) was trans-stereoisomer, are virtually the same as those of ketones (4) and no signal
which underwent nitrate salt formation by using nitric acid in was detected around 8.5 ppm. Thus, the (E)-configuration was
diethyl ether. The 2-alkyl-3-imidazolylchromanone nitrate (4) was consequently ruled out and the orientation of the oxime moiety
obtained as a pure crystalline product. For preparation of oxime of compound 5 was assigned to be of (Z)-geometry.
derivatives 5, the crude product (3) was treated with excess
It should be noted that all designed compounds 4 and 5 possess
hydroxylamine hydrochloride in methanol at room temperature. two chiral centers in their chroman core structure at the C-2 and
In this reaction, the addition of K CO assisted to the reaction C-3 positions. These compounds are actually as racemates but for
completion. The oxime product (5) was assigned as (Z)-trans- more clarity, only one enantiomer was presented. Similarly, many
2
3
stereoisomer. As shown in Scheme 2, the isobutyl derivative of marketed azole antifungals such as miconazole, bifonazole,
(3g) was prepared by the reaction of intermediate 2 and sertaconazole, ketoconazole, itraconazole and terconazole are
1
-methylbutanal. Further reaction steps were the same as racemic mixtures. In the H NMR spectra of compounds 4 and 5,
3
described for compounds 4a–f and 5a–f. the signals of methylene group which connected to the chroman

DOI: 10.3109/14756366.2013.776554
Imidazolylchromanones containing alkyl side chain as lanosterol 14ꢂ-demethylase inhibitors
7
Figure 4. (a) (SS)-enantiomer of compound
4
d in the active site of enzyme. Note that
carbonyl group of compound 4d orients
towards Phe255 carbonyl group; (b) (RR)-
enantiomer of compound 4d in the active site
of enzyme. Note that carbonyl group of
compound 4d orients toward the guanidine
group of Arg96. For the sake of clarity only
˚
amino acids within 7 A distant from the
docked ligand are shown.
ring indicated the diastereotopic nature of the methylene Its growth inhibitory activity against yeasts was comparable to
group protons because of the presence of C-2 stereocenter in fluconazole. Also, compound 4f showed good inhibitory activity
chroman ring.
(MICs ¼ 8–16 mg/mL) against yeasts comparable to fluconazole.
Furthermore, compounds 4c, 4e, 5c and 5d were active against
yeasts with MIC values of 16–64 mg/mL. Although, fluconazole
was inactive against M. gypseum and A. niger (MICs464 mg/mL),
Antifungal activity
The antifungal activity of designed 2-alkyl-3-imidazolylchroman but compounds 4d–f, 5a, 5c–e and 5g exhibited mild activity
derivatives 4a–g and 5a–g were evaluated by determining against these fungi. A survey of MIC values in Table 2 revealed
their MICs against C. albicans (yeast), S. cerevisiae (yeast), that the imidazolylchromanones (4a–c and 4g) containing small
M. gypseum (dermatophyte) and A. niger (mould). The MICs side chain (1C–4C) were inactive. While chromanones bearing
of compounds were determined by the micro-dilution method longer 2-alkyl group (44C) showed better antifungal activity
in comparison with fluconazole and miconazole as standard azole against all fungi strains tested. The comparison of ketone
antifungal agents. The results were summarized in Table 2.
compounds (4) with related oxime derivatives (5) demonstrated
The MIC values of title compounds in comparison with that oximation had negative effect and diminished the antifungal
those of fluconazole and miconazole were presented in Table 2. activity. Also, compounds 4g and 5g with a branched alkyl group
In the case of C. albicans and S. cerevisiae, compound 4d (isobutyl) showed no activity against C. albicans, S. cerevisiae
was the most potent compound with MIC values of 8 mg/mL. and A. niger.

8
S. Emami et al.
J Enzyme Inhib Med Chem, Early Online: 1–9
Figure 5. (RR)- and (SS)-enantiomers of
compound 5d in the active site of enzyme.
Note that oxime groups have been oriented in
the opposite directions. The oxime group of
(
RR)-enantiomer orients toward the guanidine
group of Arg96, while the oxime group of
SS)-enantiomer orients towards the Phe255
(
carbonyl group. For both enantiomers, phenyl
ring, pentyl side chain and imidazole ring
occupy the same place in the active site. For
the sake of clarity only amino acids within
˚
7
A distant from the docked ligand are shown.
Table 3. HYDE scoring reported affinities of ligands
toward cytochrome P450 14a-sterol demethylase.
Docking study
With the aim of rationalizing the antifungal activity data obtained,
docking study was performed for the selected derivatives 4d
Compound
RR)-enantiomer of compound 4d
(SS)-enantiomer of compound 4d
(RR)-enantiomer of compound 5d
(SS)-enantiomer of compound 5d
Fluconazole
DGbinding (kJ/mol)
(keto-compound) and its oxime analog 5d, in order to investigate
(
ꢂ47
ꢂ39
ꢂ45
ꢂ42
ꢂ19
the possible interactions with Cytochrome P450 14a-sterol
demethylase. Since no experimental data were available for the
target enzyme Candida P450 DM in the Protein Data Bank,
the crystallographic structure of the complex between
Cytochrome P450 14a-sterol demethylase from M. tuberculosis
(Mycobacterium P450 DM) and fluconazole with the ID 1EA1
was used for the docking study.
For evaluation of the ligands affinity towards active site, the
As depicted in Figure 3, both (SS)- and (RR)-enantiomers HYDE assessment module of LeadIT software was used to report
of compounds 4d and 5d were included for docking studies. the free energy of binding (DG) and ligand efficiency of the best
The aromatic part of chroman ring in both compounds 4d and 5d is scored pose (Table 3). HYDE is an empirical scoring function,
situated in a lipophilic region and interacts with Phe255, which assesses protein–ligand complex by considering hydrogen
Met79, Tyr76, Val434, Leu321 and Phe78. The pentyl side bond interactions and also hydrophobic and desolvation effects and
1
4,15
chain is in close contact with Phe83, Leu100 and Ala256. provides estimation for the binding affinity
. For the (SS)-
Furthermore, the imidazole ring of both compounds is pos- enantiomeric form of 5d (with DGbinding ¼ ꢂ42 kJ/mol), hydrogen
itioned above the porphyrine plane, in which the N-3 atom of bonding seems to be more possible between the oxime hydrogen
˚
imidazole ring is coordinated to the heme iron. Distance between atom and carbonyl oxygen atom of Phe255 (3 A). In the (RR)-
˚
the nitrogen atom and heme iron is 2.2 A in both compounds, which enantiomer (with DGbinding ¼ ꢂ45 kJ/mol), stronger hydrogen
is in good agreement with that found in the crystal structure of bonding is possible between the oxime group and the guanidine
˚
˚
Mycobacterium P450 DM complexed with fluconazole (2.3 A) group of Arg96 due to a very close proximity (2 A) of the
Figure 3). By investigating the binding mode of compound two groups (Figure 5). In both compounds 4d and 5d, (RR)-
d enantiomers (Figure 4), it is revealed that the orientation enantiomers have better interactions in the active site of the enzyme
(
4
of pyran ring is different in the two enantiomers. On the other with the lower energy of binding compared to the (SS)-enantiomers.
hand, in both enantiomers the aromatic part of chroman ring, pentyl Investigating the binding mode shows that Arg96 plays a key role
side chain and imidazole ring occupy the same place in the active for hydrogen bonding to the carbonyl or the oxime group of the RR-
site, but carbonyl groups in both the enantiomers of compound 4d enantiomer of both compounds 4d and 5d.
are facing in the opposite directions. However, hydrogen bonding is
As discussed in the ‘‘Chemistry’’ section, the large vicinal
not disturbed by oppositely oriented carbonyl groups, because coupling constant between H-2 and H-3 of chroman ring in
Arg96 and His259 are in close vicinity to the respective carbonyl the compound 4d prototype indicates that the orientation of the 2-
groups for hydrogen bonding in both the RR and SS enantiomeric alkyl group and the 3-imidazole ring is trans. Theoretically, the
˚
˚
forms (3.1 A and 4.8 A, respectively).
fused six-membered hetero-ring of chroman moiety can exist
As shown in Figure 5, the binding mode of the oxime in the form of two energetically different half-chairs in which
derivative (compound 5d) is highly similar to compound 4d 2-alkyl side chain and 3-imidazolyl moiety occupy di-axial or
because the same place in the active site has been occupied by the di-equatorial positions (Figure 6). The relatively large J2,3 value
phenyl ring, pentyl side chain and imidazole ring of compound in compound 4d prototype confirms the preferred di-axial
1
5
5
d. Moreover, the oxime group has been superimposed on the conformation of H-2 and H-3 . Thus, it is believed that 2-alkyl
carbonyl group of the parent compound 4d but hydrogen bonding side chain and 3-imidazolyl moiety in compound 4d exist
is different.
predominantly in the di-equatorial conformation. FlexX is an

DOI: 10.3109/14756366.2013.776554
Imidazolylchromanones containing alkyl side chain as lanosterol 14ꢂ-demethylase inhibitors
9
This work was supported by a grant from the Research Council of
Mazandaran University of Medical Sciences, Sari, Iran.
O
H
H
O
N
H
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O
N
O
1
2
3
.
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2
-alkylchromanones to design new inhibitors of 14a-demethylase
and potential azole antifungal agents. The designed 2-alkyl-3-
imidazolylchromanones were synthesized selectively and assig-
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of 2-alkyl-3-imidazolylchromanones were prepared exclusively
(
1
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1
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results of antifungal evaluation against different strains of fungi
demonstrated that the length of alkyl side chain had a significant
impact on antifungal activity. In general, chromanones bearing
longer 2-alkyl group (44C) showed better antifungal activity
against all fungi tested. Among the chroman-4-ones, 2-(1-pentyl)
derivative (4d) showed the most potent activity against yeasts
comparable to fluconazole. Docking study of selected compounds
4
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0. Emami S, Falahati M, Banifatemi A, et al. Stereoselective synthesis
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manone oxime ethers. Arch Pharm (Weinheim) 2002;335:318–24.
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4
d and 5d with cytochrome P450 14a-sterol demethylase revealed 12. Emami S, Falahati M, Banifatemi A, Shafiee A. Stereoselective
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highly similar to parent ketone (compound 4d) because the same
place in the active site has been occupied by the phenyl ring,
pentyl side chain and imidazole ring of compound 5d.
1
3. National Committee for Clinical Laboratory Standards. Reference
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Declaration of interest
The authors have declared no conflict of interest.