Synthesis and anti-candida potential of certain novel 1-[(3-substituted-3- phenyl)propyl]-1H-imidazoles

Article abstract of DOI:10.1002/ardp.201000224

The synthesis and anti-Candida activity of 1-[(3-aroyloxy-3-phenyl)propyl]- 1H-imidazoles 5a-f and 1-[(3-alkyl/aralkyl/phenyl-3-phenyl)propan-3-ol]-1H- imidazoles 5g-j are reported. The influence of the ester formation and different substitutions on the anti-Candida activity of the alcohol 4 was investigated. Among the newly developed bioactive chemical entities, compounds 5b and 5c displayed minimum inhibitory concentrations (MICs) against Candida albicans and Candida pseudotropicales comparable to that of tioconazole and more potent than miconazole. The target compounds 1-[(3-aroyloxy-3-phenyl)propyl]-1H-imidazoles 5a-f were obtained in four steps starting from acetophenone 1 whereas 1-[(3-alkyl/aralkyl/phenyl-3-phenyl)propan-3-ol]-1H-imidazoles 5g-j were synthesized in three steps. Compounds 5b and 5c showed anti-Candida activity comparable to tioconazole and were more potent than miconazole. Copyright

Full text of DOI:10.1002/ardp.201000224

794
Arch. Pharm. Chem. Life Sci. 2011, 344, 794–801
Full Paper
Synthesis and Anti-Candida Potential of Certain Novel
1-[(3-Substituted-3-phenyl)propyl]-1H-imidazoles
Mohamed Nabil Aboul-Enein1, Aida Abd El-Sattar El-Azzouny1, Mohamed Ibrahim Attia1,2
Ola Ahmed Saleh1, and Amany Lotfy Kansoh3
,
1 Medicinal and Pharmaceutical Chemistry Department, Pharmaceutical and Drug Industries Research
Division, National Research Centre, Giza, Egypt
2 Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh,
Saudi Arabia
3 Microbial Chemistry Department, Genetic Engineering and Biotechnology Division,
National Research Centre, Giza, Egypt
The synthesis and anti-Candida activity of 1-[(3-aroyloxy-3-phenyl)propyl]-1H-imidazoles 5a–f and 1-[(3-
alkyl/aralkyl/phenyl-3-phenyl)propan-3-ol]-1H-imidazoles 5g–j are reported. The influence of the ester
formation and different substitutions on the anti-Candida activity of the alcohol 4 was investigated.
Among the newly developed bioactive chemical entities, compounds 5b and 5c displayed minimum
inhibitory concentrations (MICs) against Candida albicans and Candida pseudotropicales comparable to
that of tioconazole and more potent than miconazole.
Keywords: Anti-Candida / Grignard reaction / Imidazoles / Mannich reaction
Received: July 31, 2010; Revised: September 28, 2010; Accepted: October 8, 2010
DOI 10.1002/ardp.201000224
Introduction
keted drugs containing the azole moiety, e.g. ketoconazole,
itraconazole, econazole, miconazole, tioconazole, and fluco-
nazole are used as antifungal drugs [5]. Also, the imidazole
fluxetine analogue I [6] has been found to possess anti-Candida
activity and the imidazole derivatives II–IV (Fig. 1) exhibited
potent antifungal activity against Candida albicans and der-
matophytes [5]. On the other hand, the therapeutic use of
many antifungal drugs is often accompanied by some draw-
backs like drug resistance specially in chronic patients [2, 3]
as well as unwanted side effects and limited bioavailability
[7, 8]. Accordingly, the need for new antifungal drugs has
prompted intensive research worldwide.
A significant increase in fungal infections has been observed
over the past two decades. Many reports of invasive topical
and systemic infections caused by the opportunistic
pathogen Candida species are always associated with the
use of broad-spectrum antibiotics, immunosuppressive
agents, anticancer and anti-AIDS drugs [1]. One of the major
problems in the treatment of Candida infections is the spread
of antifungal drug resistance mainly in patients chronically
subjected to antimycotic therapy such as HIV-infected
patients [2, 3].
Antifungal drugs are mainly classified into five major
classes: Azoles, polyenes, allylamines, thiocarbamates, and
fluoropyrimidines [4]. Azole class is commonly used as anti-
fungal agent specially for Candida infections as many mar-
In a previous work [9], it was reported that the alcohol 4
exhibited antifungal activity against human and animal
pathogens. Therefore, compound 4 would serve as prototypic
molecule for subsequent molecular modifications.
Based upon the aforementioned premises, we became
interested toward the development of novel bioactive drug-
like candidates namely, the esters 1-[(3-aroyloxy-3-phenyl)-
propyl]-1-H-imidazoles 5a–f, and the tertiary alcohols 1-[(3-
alkyl/aralkyl/phenyl-3-phenyl)propan-3-ol]-1-H-imidazoles
5g–j to be screened as anti-Candida agents (Fig. 2). The influ-
ence of the lipophilic nature of the ester functionality in
Correspondence: Prof. Dr. Mohamed Nabil Aboul-Enein, Medicinal and
Pharmaceutical Chemistry Department, Pharmaceutical and Drug
Industries Research Division, National Research Centre, 12622, Dokki,
Giza, Egypt
E-mail: mnaboulenein@yahoo.com
Fax: þ2 027601877
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Arch. Pharm. Chem. Life Sci. 2011, 344, 794–801
Anti-Candida Potential of 1-[(3-Substituted-3-phenyl)propyl]-1H-imidazoles
795
Cl
Cl
Cl
Cl
Cl
Cl
O
O
O
N
N
N
N
N
N
Cl
Cl
III
I
II
(Miconazole)
S
Cl
Cl
O
N
N
Cl
IV
(Tioconazole)
Figure 1. Imidazoles as antifungal agents.
OH
OR
OH
N
N
N
N
N
N
R
5a-f
5g-j
4
Figure 2. The prototype imidazole alcohol 4, the corresponding esters 5a–f and tertiary alcohols 5g–j.
compounds 5a–f as well as alkyl, phenyl, or aralkyl substi-
tutions in alcohols 5g–j on the anti-Candida activity of the
alcohol 4 was investigated.
alcohol 4 was esterified using the appropriate acid chloride
and triethylamine in benzene to furnish the respective esters
5a–e in moderate yields. The nitro ester 5e was hydrogenated
under normal pressure in the presence of PtO2 at room
temperature to yield the respective amino derivative 5f
(Scheme 2).
Results and discussion
Synthesis
Furthermore, Grignard reaction was employed on the
ketone 3 and the proper Grignard reagent in diethyl ether
to give the corresponding tertiary alcohols 5g–j in 32–71%
yields (Scheme 2).
Synthetic pathways for the synthesis of the target compounds
5a–j have been illustrated in Schemes 1 and 2. Thus, the
Mannich base hydrochloride 2 was prepared according to
the reported procedure [10] using acetophenone, paraformal-
dehyde, and dimethylamine hydrochloride in the presence of
2 mL conc. HCl/mmol acetophenone in small amount of
ethanol. Subsequently, compound 2 was subjected to nucle-
ophilic substitution with imidazole in water to afford the
ketone 3 [9] in 77% yield (Scheme 1).
Biological evaluation
Table 1 displays the anti-Candida activity of the tested com-
pounds 4 and 5a–j, and of miconazole and tioconazole,
taken as reference drugs, on Candida albicans and Candida
pseudotropicales, which are important human pathogenic
fungi, measured as minimum inhibitory concentration
(MIC, mg/mL).
Ketone 3 was elaborated to the alcohol 4 by adopting
sodium borohydride reduction in methanol [9]. The produced
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M. N. Aboul-Enein et al.
Arch. Pharm. Chem. Life Sci. 2011, 344, 794–801
O
O
O
N(CH3)2 .HCl
CH3
N
N
i
ii
2
3
1
Reagents: (i) HN(CH3)2 · HCl, (CH2O)n, conc. HCl, ethanol, reflux, 2 h. (ii) Imidazole, water, reflux, 5 h.
Scheme 1. Synthesis scheme for 3.
OH
O
OR
N
N
N
ii
i
N
N
N
4
3
5a-e
5a: R = C6H5CO
5b: R = 4-Cl-C6H4CO
5c: R = 2,4-Cl2-C6H3CO
5d: R = 4-OCH3-C6H4CO
5e: R = 4-NO2-C6H4CO
5f: R = 4-NH2-C6H4CO
iv
iii
OH
N
N
R
5g-j
5g: R = CH3
5h: R = C6H5
5i: R = C6H5CH2
5j: R = C6H5 (CH2)2
Reagents: (i) NaBH4, methanol, reflux, 3 h. (ii) Aroyl chloride, triethylamine, benzene, reflux, 18 h. (iii) H2/PtO2, THF, rt, 2 h. (iv) Mg,
alkyl/aryl or aralkyl halide, diethyl ether, reflux, 18 h.
Scheme 2. Synthesis scheme for 5a–f and 5g–j.
Walker and Hills [9] documented the antifungal activity of
the alcohol 4. Accordingly, we focused our attention on the
synthesis of the lipophilic 3-(1H-imidazol-1-yl)-1-phenyl-
propyl-4-benzoates 5a–f to verify the effect of esterification
of the free OH group of 4 on the anti-Candida activity.
Compound 5a showed anti-Candida activity (MIC ¼ 1.5 mg/mL)
which is nearly seven-fold greater than that of the alcohol 4
(MIC ¼ 10 mg/mL) thus suggesting the lipophilic nature of
this ester functionality to be responsible for the increase of
anti-Candida activity. Nonetheless, the inhibitory potency of
5a differs significantly from those of miconazole (MIC ¼
0.5 mg/mL) and tioconazole (MIC ¼ 0.3 mg/mL). We therefore
attempted to improve the anti-Candida potential of 5a by
substituting the phenyl moiety of the ester functionality
of 5a with substituents endowed with different electronic
and steric properties. These substituents may be able to favor
interaction with the structures of the target enzyme, the
fungal cytochrome P450 14a-lanosterol demethylase
(P45014DM), leading to inhibition of the ergosterol formation
in the fungal cell membrane [11]. In addition, these substitu-
ents could improve the bioavailability and the in vivo anti-
Candida activity of the newly synthesized bioactive chemical
entities which had been already observed in the class of
antifungal azoles [12].
Halogen substitution, like chlorine in compounds 5b and
5c, is very useful to modulate the electronic effects on phenyl
ring and may also influence the steric characteristics and the
hydrophilic–hydrophobic balance of the molecules. Thus, the
chlorinated esters 5b and 5c showed the best anti-Candida
profile of the whole synthesized series exhibiting
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Arch. Pharm. Chem. Life Sci. 2011, 344, 794–801
Anti-Candida Potential of 1-[(3-Substituted-3-phenyl)propyl]-1H-imidazoles
797
Table 1. The antifungal activities of the tested compounds 4 and 5a–j against Candida albicans and Candida pseudotropicales.
Compound No.
MICꢀ
Candida albicans
Candida pseudotropicales
(mg/mL)
Mean ꢁ SDꢀꢀ
LSDꢀꢀꢀ
Mean ꢁ SDꢀꢀ
LSDꢀꢀꢀ
4
5a
5b
5c
5d
5e
5f
5g
10.0
1.5§
0.3
0.3
0.4
75.0
5.0
20.0
7.5
7.5
5.0
0.5
0.3
13.7 ꢁ 1.53
13.0 ꢁ 1.00
16.2 ꢁ 1.76
17.2 ꢁ 1.04
14.2 ꢁ 1.76
12.7 ꢁ 1.53
13.7 ꢁ 1.53
12.0 ꢁ 1.00
12.7 ꢁ 1.53
13.0 ꢁ 1.00
13.8 ꢁ 1.26
13.3 ꢁ 1.53
13.8 ꢁ 1.26
5b, 5c
5b, 5c
4, 5a, 5e-j, III & IV
4, 5a, 5e-j, III & IV
5c
14.0 ꢁ 1.00
14.7 ꢁ 1.53
17.2 ꢁ 1.76
18.2 ꢁ 1.76
15.2 ꢁ 1.76
13.3 ꢁ 1.53
14.5 ꢁ 1.50
13.0 ꢁ 1.00
13.0 ꢁ 1.00
13.3 ꢁ 1.53
14.3 ꢁ 0.76
14.0 ꢁ 1.00
14.5 ꢁ 0.50
5b, 5c
5b, 5c
4, 5a, 5e-j, III & IV
4, 5a, 5e-j, III & IV
5c
5b, 5c
5b, 5c
5b, 5c
5b, 5c
5b, 5c
5b, 5c
5b, 5c
5b, 5c
5b, 5c
5b, 5c
5b, 5c
5b, 5c
5b, 5c
5b, 5c
5b, 5c
5b, 5c
5h
5i
5j
Miconazole (III)
Tioconazole (IV)
For Candida albicans F-ratio ¼ 3.178, P ¼ 0.005 and for Candida pseudotropicales F-ratio ¼ 4.033, P < 0.0001.ꢀThe lowest concentration of
the compound that produced complete microbial growth inhibition (mg/mL) against Candida albicans and Candida pseudotropicales. ꢀꢀThe
§
arithmetic mean of the inhibition zone diameters in mean ꢁ standard deviation. ꢀꢀꢀLeast significant differences (LSD). MIC of 5a was
1.0 mg/mL for Candida pseudotropicales.
MIC ¼ 0.3 mg/mL which is nearly 33 fold greater than that of
the alcohol 4 and were equipotent with the reference com-
pound tioconazole (MIC ¼ 0.3 mg/mL) while they were more
potent than miconazole (MIC ¼ 0.5 mg/mL). Moreover, the
mean of the inhibition zones of compounds 5b and 5c against
Candida albicans and Candida pseudotropicales was significantly
larger than that of all other compounds whereas there was no
significant difference between the activity of compounds 5b
and 5c against both organisms (Table 1).
analogue 5e and two times more potent than the alcohol 4 as
anti-Candida.
The tertiary alcohols 5g–j exhibited anti-Candida potential
in the following descending order: 5j > 5h ¼ 5i > 5g indi-
cating that the lipophilic phenethyl moiety in the alcohol 5j
seems to be the favorable substituent for exerting the anti-
Candida activity of the alcohols 5g–j. Alcohol 5j (MIC ¼ 5 mg/mL)
is two-fold more potent than the alcohol 4 and equipotent
with the ester 5f as anti-Candida. However, replacing the
phenyl/aralkyl moieties of 5h–j with methyl group to afford
the alcohol 5g (MIC ¼ 20 mg/mL) led to four-fold decrease in
the anti-Candida activity as compared to the alcohol 5j.
On the other hand, incorporation of hydrogen-bonding
acceptor endowed with positive mesomeric effect on phenyl
rings, such as methoxy group in compound 5d, may be able
to improve the inhibitory potency by increasing the affinity
toward the enzyme-recognizing sites. Thus, the para-methoxy Conclusion
derivative 5d displayed MIC ¼ 0.4 mg/mL which is 25 fold
more potent than the alcohol 4 as anti-Candida. On the con-
trary, substitution of the phenyl ring of the ester function-
ality with a strong electron withdrawing group endowed
with negative mesomeric effect as hydrogen-bonding
acceptor, such as nitro group in 5e, does not seem to be
practically favorable, causing a dramatic decrease in the
anti-Candida activity with MIC ¼ 75 mg/mL. However,
reduction of the nitro group in 5e to afford the respective
amino derivative 5f improves the anti-Candida properties of
5e suggesting that the enzyme-recognizing sites contains
hydrogen-bonding acceptor residues in the region corre-
sponding to the position containing NO2/NH2 groups of
the tested compounds. Compound 5f displayed
MIC ¼ 5 mg/mL which is 15 times more potent than the nitro
This study was undertaken to evaluate the effects on the anti-
Candida activity of the esterification of the OH group of the
previously reported antifungal alcohol 4. The obtained data
revealed that the anti-Candida activity of the alcohol 4 was
increased substantially through lipophilic esterification
especially with chlorinated benzoic acids to give the esters
5b and 5c which are equipotent with the reference antifungal
tioconazole and more potent than miconazole. There was no
significant difference between compounds 5b and 5c against
Candida albicans and Candida pseudotropicales. Also, the newly
synthesized esters 5a–f could be considered as prodrugs
which may improve the pharmacokinetics and hence the
bioavailability of the alcohol 4 leading to enhancement of
its in vivo anti-Candida activity. In addition, the phenethyl
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798
M. N. Aboul-Enein et al.
Arch. Pharm. Chem. Life Sci. 2011, 344, 794–801
derivative 5j of the alcohol 4 displayed a two-fold increase in
the anti-Candida activity as compared to the alcohol 4.
dry benzene (15 mL) was added the appropriate acid chloride
(6.0 mmol) in dry benzene (5 mL) dropwise. The reaction
mixture was refluxed for 18 h then cooled, filtered and
evaporated under reduced pressure. The residue was dis-
solved in ethyl acetate and washed with water and 10%
sodium bicarbonate solution. The organic layer was dried
(Na2SO4) and evaporated under reduced pressure to afford
the aroyl esters 5a–d as oils which were purified by column
chromatography using chloroform/methanol (9.5:0.5) and
the ester 5e as a yellow solid which was recrystallized from
ethyl acetate.
Experimental section
General
All melting points were determined using Electrothermal
Capillary melting point apparatus and are uncorrected.
Infrared (IR) spectra were recorded as thin film (for oils) in
NaCl discs or as KBr pellets (for solids) with JASCO FT/IR-6100
spectrometer and values are represented in cmꢂ1 1H-NMR
.
and 13C-NMR spectra were carried out on Jeol ECA 500 MHz
spectrophotometer using TMS as internal standard and
chemical shift values were recorded in ppm on d scale.
The 1H-NMR data were represented as follows: Chemical
shifts, multiplicity (s, singlet; d, doublet; t, triplet; m, mul-
tiplet; br, broad), and number of protons. The 13C-NMR data
were represented as chemical shifts and type of carbon. EI
mass spectra were determined on a Finnigan Mat SSQ-7000
spectrophotometer and Jeol JMS-AX 500. Elemental analyses
were carried out at the Microanalytical Centre, Cairo
University, Egypt. Silica gel TLC (thin layer chromatography)
cards from Merck (silica gel precoated aluminum cards with
fluorescent indicator at 245 nm) were used for thin layer
chromatography. Visualization was performed by illumina-
tion with UV light source (254 nm). Column chromatography
was carried out on silica gel 60 (0.063–0.200 mm) obtained
from Merck.
3-(1H-Imidazol-1-yl)-1-phenylpropyl-4-benzoate 5a
Yield 60%; pale yellow viscous oil; IR (KBr): n (cmꢂ1) 3109,
1
3064, 1717 (C O), 1506, 1270, 710; H-NMR (CDCl ): d 2.38–
–
–
3
2.39 (m, 1H, –CH2–CH2–N), 2.56–2.57 (m, 1H, –CH2–CH2–N),
4.03–4.04 (m, 2H, –CH2–CH2–N), 5.97–5.99 (m, 1H,
–
–
–
C H –CH–O–), 6.91 (s, 1H, –N–CH CH–N ), 7.05 (s, 1H,
–
6
5
–
–
–
–N–CH CH–N ), 7.36–7.45 (m, 9H, –N–CH N–, Har.), 8.05
–
–
–
(d, J ¼ 8.1 Hz, 2H,
H
ar.); 13C-NMR (CDCl3):
d
37.9
(–CH2–CH2–N), 43.5 (–CH2–CH2–N), 73.7 (C6H5–C–O–), 118.8
–
–
–
(–N–CH CH–N ), 126.4, 128.6, 128.9, 129.7, 129.8, 129.9
–
–
–
–
–
133.5 (–N–CH CH–N , CHar., Car.), 137.1 (–N–CH N–), 139.3
–
–
þ
–
(Car.), 165.7 (C O); MS m/z (%): 306 (M , 21), 201 (100), 105 (50),
–
77 (33); Anal. calcd. for C19H18N2O2: C, 74.49; H, 5.92; N, 9.14.
Found: C, 74.38; H, 5.90; N, 9.21.
3-(1H-Imidazol-1-yl)-1-phenylpropyl-4-chlorobenzoate 5b
Yield 60%; pale yellow viscous oil; IR (KBr): n (cmꢂ1) 3108,
1
2947, 1717 (C O), 1501, 1271, 755; H-NMR (CDCl ): d 2.35–
–
–
Preparation of 3-(dimethylamino)-1-phenylpropan-1-one
hydrochloride 2
3
2.37 (m, 1H, –CH2–CH2–N), 2.53–2.56 (m, 1H, –CH2–CH2–N),
3.99–4.00 (m, 2H, –CH2–CH2–N), 5.93–5.95 (m, 1H,
Compound 2 was synthesized according to [10], mp 152–
1548C ([10] 1538C), and its spectral data were consistent with
those previously published [10].
–
–
–
C H –CH–O–), 6.89 (s, 1H, –N–CH CH–N ), 7.03 (s, 1H,
–
6
5
–
–
–
–
–N–CH CH–N ), 7.29–7.46 (m, 6H, –N–CH N–, Har.), 7.38,
–
–
(d, J ¼ 8.4 Hz, 2H, Har.).7.93 (d, J ¼ 8.4 Hz, 2H, Har.); 13C-
Preparation of 3-(1H-imidazol-1-yl)-1-phenylpropan-1-
one 3
NMR (CDCl3): d 37.7 (–CH2–CH2–N), 43.5 (–CH2–CH2–N), 74.1
–
–
–
(C H –C–O–), 118.9 (–N–CH CH–N ), 126.4, 128.8, 128.9,
–
6
5
–
–
–
A solution of 2 (21.4 g, 100 mmol) and imidazole (13.6 g,
200 mmol) in water (100 ml) was heated at 1008C for 5 h.
The cooled reaction mixture was filtered and the collected
solid was dried to furnish 3 (15.4 g, 77%) as a white solid, mp
95–978C ([9] 96–99.58C), and it was pure enough to be used in
the next step without any purification.
129.0, 129.5, 131.1 (–N–CH CH–N , CHar.
,
Car.), 137.1
–
–
–
–
–
(–N–CH N–), 139.0, 139.9 (C ), 164.8 (C O); MS m/z (%):
ar.
341 (Mþ, 61), 201 (100); Anal. calcd. for C19H17ClN2O2: C,
66.96; H, 5.03; N, 8.22. Found: C, 66.86; H, 5.10; N, 8.34.
3-(1H-Imidazol-1-yl)-1-phenylpropyl-2,4-dichlorobenzoate
5c
Preparation of 3-(1H-imidazol-1-yl)-1-phenylpropan-1-ol 4
Compound 4 was synthesized according to [9], mp 107–1098C
([9] 106.5–1088C).
Yield 43%; pale yellow viscous oil; IR (KBr): n (cmꢂ1) 3103,
1
2942, 1726 (C O), 1506, 1278, 761; H-NMR (CDCl ): d 2.31–
–
–
3
2.35 (m, 1H, –CH2–CH2–N), 2.51–2.56 (m, 1H, –CH2–CH2–N),
3.98–4.04 (m, 2H, –CH2–CH2–N), 5.92–5.93 (m, 1H,
–
C H –CH–O–), 6.88 (s, 1H, –N–CH CH–N ), 7.02 (s, 1H,
–
6 5
–
General procedure for the preparation of the substituted
aroyl esters 5a–e
–
–
–
–
–
–N–CH CH–N ), 7.25–7.44 (m, 8H, –N–CH N–, Har.), 7.72,
–
–
To an ice-cold mixture of the imidazole alcohol 4 (1.01 g,
5.0 mmol) and triethylamine (0.55 mL, 0.6 g, 6.0 mmol) in
(dd, J ¼ 8.6, 2.3 Hz, 1H, Har.); 13C-NMR (CDCl3): d 37.6
(–CH2–CH2–N), 43.4 (–CH2–CH2–N), 74.9 (C6H5–C–O–), 118.8
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Arch. Pharm. Chem. Life Sci. 2011, 344, 794–801
Anti-Candida Potential of 1-[(3-Substituted-3-phenyl)propyl]-1H-imidazoles
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–
–
–
(–N–CH CH–N ), 126.6, 127.3, 128.0, 128.8, 128.9, 129.8,
(D2O): d 2.49–2.50 (m, 1H, –CH2–CH2–N), 2.65–2.67 (m, 1H,
–CH2–CH2–N), 4.65–4.67 (m, 2H, –CH2–CH2–N), 5.90–5.92 (m,
1H, C6H5–CH–O–), 7.20–7.34 (m, 9H, Har), 7.90 (d, J ¼ 7.05 Hz,
–
–
–
–
131.2, 132.8, 134.9 (–N–CH CH–N , CHar.
, Car.), 137.1
–
–
(–N–CH N–), 138.6, 138.8 (Car.), 164.0 (C ¼ O); MS m/z (%):
–
377 (Mþþ2, 0.6), 375 (Mþ, 1), 201 (100), 105 (24), 81 (37);
Anal. calcd. for C19H16Cl2N2O2: C, 60.81; H, 4.30; N, 7.47.
Found: C, 60.73; H, 4.32; N, 7.51.
2H, –N–CH CH–N ), 8.51 (s, 1H, –N–CH N–); 13C-NMR (D2O):
–
–
–
–
–
–
d 35.1 (–CH2–CH2–N), 46.2 (–CH2–CH2–N), 75.3 (C6H5–C–O–),
–
–
–
119.9 (–N–CH CH–N ), 120.9, 121.8, 126.1, 126.2, 128.9,
–
–
–
–
129.1, 131.5, 134.5 (–N–CH CH–N , CHar.
,
Car.), 138.8
–
–
–
–
3-(1H-Imidazol-1-yl)-1-phenylpropyl-4-methoxybenzoate 5d
Yield 40%; pale yellow viscous oil; IR (KBr): n (cmꢂ1) 3114,
(–N–CH N–), 140.4, 165.3 (C ), 166.7 (C O); MS m/z (%):
–
ar.
321 (MþꢂHCl, 100), 201 (68), 185 (24), 120 (55); Anal. calcd.
for C19H20ClN3O2: C, 63.77; H, 5.63; N, 11.74. Found: C, 63.68;
H, 5.71; N, 11.69.
1
2944, 1709 (C O), 1508, 1263, 763; H-NMR (CDCl ): d 2.30–
–
–
3
2.31 (m, 1H, –CH2–CH2–N), 2.49–2.50 (m, 1H, –CH2–CH2–N),
3.79 (s, 3H, OCH3), 3.97–3.98 (m, 2H, –CH2–CH2–N), 5.89–5.92
–
–
–
(m, 1H, C H –CH–O–), 6.86–7.42 (m, 10H, –N–CH CH–N ,
General procedure for the preparation of the alcohols 5g–j
A 250-mL three necked flask was charged with magnesium
turnings (0.45 g, 18.5 mmol), diethyl ether (15 mL), and nearly
one tenth of the appropriate alkyl, phenyl, or aralkyl halide
(15.2 mmol) in diethyl ether (25 mL). The resulting suspension
was warmed under stirring prior to initiation of Grignard
reaction (few crystals of iodine may be added for initiation).
A positive reaction start was detected by initiation of reflux
and the remaining alkyl, aryl, or aralkyl halide was then added
to the reaction mixture dropwise. Upon completion of the
addition, reflux was maintained by heating for 1 h. The ketone
3 (1.0 g, 5.0 mmol) in dry THF (10 mL) was added dropwise to
the stirred reaction mixture under reflux. After complete
addition of 3, reflux was continued for 18 h. The reaction
mixture was then cooled (0–58C) and quenched by a slow
addition of saturated ammonium chloride solution. The
organic phase was separated and the aqueous phase was
extracted with ethyl acetate (2 ꢃ 30 mL). The organic layers
were combined, dried (Na2SO4) and evaporated under reduced
pressure. The residue was purified by column chromatography
using chloroform/methanol (9:1) for compound 5g or recrys-
tallized from ethyl acetate for compounds 5h–j.
–
6
5
–
–
–
–
–
–
–N–CH CH–N , –N–CH N–, Har.), 7.95–8.02 (m, 2H, Har.);
13C-NMR (CDCl3): d 37.9 (–CH2–CH2–N), 43.5 (–CH2–CH2–N),
–
–
–
–
55.6 (OCH3), 73.3 (C6H5–C–O–), 113.9 (CHar.), 118.9 (–N–CH
–
CH–N ), 122.2, 126.3, 128.5, 128.9, 129.5, 131.8, (–N–CH
–
–
–
–
–
CH–N , CHar., Car.), 137.1 (–N–CH N–), 139.6, 163.8 (Car.),
þ
–
–
165.4 (C O); MS m/z (%): 336 (M , 13), 201 (88), 135 (100),
105 (19), 81 (46); Anal. calcd. for C20H20N2O3: C, 71.41; H, 5.99;
N, 8.33. Found: C, 71.60; H, 6.01; N, 8.38.
3-(1H-Imidazol-1-yl)-1-phenylpropyl-4-nitrobenzoate 5e
Yellowish white solid, yield 70%; mp 138–1408C; IR (KBr): n
(cmꢂ1) 3112, 2960, 1716 (C O), 1510, 1271, 708; 1H-NMR
–
–
(CDCl3): d 2.42–2.43 (m, 1H, –CH2–CH2–N), 2.62–2.63 (m,
1H, –CH2–CH2–N), 4.02–4.03 (m, 2H, –CH2–CH2–N), 5.97–
–
–
–
5.98 (m, 1H, C H –CH–O–), 6.91 (s, 1H, –N–CH CH–N ),
–
6
5
–
–
–
–
–
–
7.04 (s, 1H, –N–CH CH–N ), 7.35–7.44 (m, 6H, –N–CH N–,
H
ar.), 8.16, (d, J ¼ 9.2 Hz, 2H, Har.), 8.26 (d, J ¼ 9.2 Hz,
2H, Har.); 13C-NMR (CDCl3): d 37.4 (–CH2–CH2–N), 43.5
–
–
–
(–CH –CH –N), 75.1 (C H –C–O–), 118.8 (–N–CH CH–N ),
–
2
2
6 5
123.7, 126.5, 129.0, 129.1, 129.9, 130.9, 135.2, 137.2
–
–
–
–
(–N–CH CH–N , CHar.
–
,
Car.), 137.2 (–N–CH N–), 138.5,
þ
–
150.8 (Car.), 163.9 (C O); MS m/z (%): 351 (M , 15), 183 (15),
–
–
150 (68) 81 (100); Anal. calcd. for C19H17N3O4: C, 64.95; H,
4.88; N, 11.96. Found: C, 65.08; H, 4.79; N, 12.07.
4-(1H-Imidazol-1-yl)-2-phenylbutan-2-ol 5g
Yield 71%; pale yellow viscous oil; Anal. IR (KBr): n (cmꢂ1) 3390
1
(OH), 2971, 1958, 1674, 1511, 1079, 701; H-NMR (CDCl3): d
Synthesis of 3-(1H-imidazol-1-yl)-1-phenylpropyl-4-
aminobenzoate hydrochloride 5f
1.55 (s, 3H, CH3), 2.18–2.22 (m, 2H, –CH2–CH2–N), 3.64–3.66
(m, 1H, CH2–N), 4.02–4.03 (m, 1H, CH2–N), 5.75 (brs., 1H, OH),
–
–
A solution of 1.0 g (2.8 mmol) of 4-nitro benzoate ester 5e in
THF (20 mL) was hydrogenated at room temperature and
normal pressure for 2 h using platinum(IV) oxide 0.06 g
(0.28 mmol). The catalyst was filtered off and ethanol was
evaporated under reduced pressure to give the corresponding
amino derivative as yellow viscous oil which was dissolved in
ethyl acetate (5 mL) then acidified with methanolic HCl
solution. The acidic mixture was evaporated under reduced
pressure to afford the hydrochloride salt 5f which was recrys-
tallized from ethyl acetate/methanol to afford 0.80 g (80%) of
5f as a yellowish white crystals, mp 198–2028C; IR (KBr): n
6.73 (s, 1H, –N–CH CH–N–), 6.83 (s, 1H, –N–CH CH–N–),
–
–
7.31–7.46 (m, 6H, –N–CH N–,
–
H
ar.); 13C-NMR (CDCl3):
–
d 31.1 (CH3), 43.1 (–CH2–CH2–N), 45.4 (–CH2–CH2–N), 72.9
–
–
–
–
(CH –C–OH), 119.2, (–N–CH CH–N ), 124.8, 126.9, 128.4,
3
–
–
–
–
–
–
128.6, (–N–CH CH–N , CH ), 137.4 (–N–CH N–), 147.2
ar.
(Car.); MS m/z (%): 217 (Mþþ1, 100), 216 (Mþ, 52), 158 (8), 68
(40); Anal. calcd. for C13H16N2O: C, 72.19; H, 7.46; N, 12.95.
Found: C, 72.31; H, 7.52; N, 12.86.
4-(1H-Imidazol-1-yl)-1,1-diphenylpropan-1-ol 5h
White solid, yield 61%; mp 182–1848C ([5] 165–1688C from
ethanol); IR (KBr): n (cmꢂ1) 3569 (OH), 3112, 1594, 1502, 1450,
(cmꢂ1) 3416, 2926, 1720 (C O), 1502, 1270, 764; 1H-NMR
–
–
ß 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

800
M. N. Aboul-Enein et al.
Arch. Pharm. Chem. Life Sci. 2011, 344, 794–801
1
753; H-NMR (CDCl3): d 1.80 (brs., 1H, OH), 2.72–2.75 (m, 2H,
–CH2–CH2–N), 3.89–3.93 (m, 2H, –CH2–CH2–N), 6.75 (s, 1H,
antimicrobial activities by agar diffusion technique [13].
Sterile nutrient and malt extract agar media will be inocu-
lated, separately, with 100-mL cell suspension of the chosen
yeasts and poured into Petri-dishes (20 cm diameter).
The minimum inhibitory concentrations (MICs) of the
tested compounds were determined using serial dilutions
technique [14]. For each compound, different concentrations
ranging from 0.2 to 100.0 mg/mL chloroform were prepared
from stock solution (0.1 mg/mL chloroform). Each concen-
tration was placed on filter paper disc (1 cm diameter) in
portions (in a successive manner after the preceding portion
evaporated). Solvent was allowed to evaporate and the discs
were deposited on the surface of inoculated agar plates and
kept at low temperature (48C) for 12 h, before incubation
which favors diffusion over microbial growth to detect the
inhibition zone clearly.
–
–
–
–
–
–
–
–
–N–CH CH–N ), 6.85 (s, 1H, –N–CH CH–N ), 7.26–7.41
(m, 11H, –N–CH N–, Har.); 13C-NMR (DMSO-d6): d 42.9
–
–
(–CH2–CH2–N), 43.2 (–CH2–CH2–N), 76.2 (C6H5–C–OH), 118.9
–
–
–
–
–
–
–
–
(–N–CH CH–N ), 126.1, 126.9, 128.5, 128.9, (–N–CH CH–N ,
CHar.), 137.6 (–N–CH N–), 148.0 (Car.); MS m/z (%): 278 (Mþ, 22),
–
–
183 (53), 105 (100), 67 (74); Anal. calcd. for C18H18N2O: C,
77.67; H, 6.52; N, 10.06. Found: C, 77.59; H, 6.61; N, 10.12.
4-(1H-Imidazol-1-yl)-1,2-diphenylbutan-2-ol 5i
White solid, yield 68%; mp 172–1748C; IR (KBr): n (cmꢂ1) 3177
1
(OH), 2920, 1594, 1501, 1445, 699; H-NMR (CDCl3): d 2.28–
2.30 (m, 1H, –CH2–CH2–N), 2.39–2.41 (m, 1H, –CH2–CH2–N),
2.69 (brs., 1H, OH), 3.12 (d, J ¼ 13.4 Hz, 1H, –CH2–C6H5), 3.19
(d, J ¼ 13.4 Hz, 1H, –CH2–C6H5), 3.57–3.59 (m, 1H,
–CH2–CH2–N), 3.97–3.99 (m, 1H, –CH2–CH2–N), 6.75 (s, 1H,
The plates were incubated at 308C. Experiments were per-
formed in duplicate and diameters of inhibition zones were
measured after 24 h. MIC was expressed as the lowest concen-
tration of the compound that produced complete microbial
growth inhibition. Miconazole and tioconazole were used as
positive controls. The anti-Candida activity was expressed as the
diameter of the growth inhibition zone in mm.
–
–
–
–
–
–N–CH CH–N ), 6.89–6.92 (m, 2H, H ), 6.94 (s, 1H, –N–CH
–
ar.
CH–N ), 7.18–7.37 (m, 9H, –N–CH N–, Har.); 13C-NMR (CDCl3):
–
–
–
–
d 42.7 (–CH2–CH2–N), 43.6 (–CH2–CH2–N), 50.3 (CH2–C6H5),
–
–
–
–
76.9 (CH2–C–OH), 118.9 (–N–CH CH–N ), 125.3, 127.2,
–
–
–
–
128.5, 128.6, 129.3, 130.7 (–N–CH CH–N , CHar.), 135.3
þ
–
–
(–N–CH N–), 137.0, 144.3 (C ); MS m/z (%): 293 (M þ 1,
ar
28), 292 (Mþ, 4), 201 (100), 105 (58); Anal. calcd.
for C19H20N2O: C, 78.05; H, 6.89; N, 9.58. Found: C, 78.19;
H, 6.93; N, 9.67.
Statistical analysis
All antimicrobial results were statistically analyzed using
SPSS software, version 14.0. Comparisons between the results
of the different compounds were done through analysis of
variance (ANOVA) and the post-hoc test, least significant
differences (LSD). The significance level was considered at
P-value < 0.05.
1-(1H-Imidazol-1-yl)-3,5-diphenylpentan-3-ol 5j
White solid, yield 32%; mp 154–1568C; IR (KBr): n (cmꢂ1) 3226
1
(OH), 2930, 1590, 1498, 1447, 698; H-NMR (CDCl3): d 2.17–
2.64 (m, 6H, –CH2–CH2–N, C6H5–CH2–CH2–), 3.62–3.64
(m, 1H, –CH2–CH2–N), 4.02–4.04 (m, 1H, –CH2–CH2–N), 6.77
–
–
–
–
–
(s, 1H, –N–CH CH–N ), 7.07 (s, 1H, –N–CH CH–N ),
The authors have declared no conflict of interests.
–
–
–
7.23–7.46 (m, 11H, –N–CH N–, Har.); 13C-NMR (CDCl3):
–
–
29.9 (C6H5–CH2–CH2–), 42.7 (C6H5–CH2–CH2–), 44.7
d
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–
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–
–
–
–
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www.archpharm.com