A novel antifungal agent with broad spectrum: 1-(4-Biphenylyl)-3-(1H- imidazol-1-yl)-1-propanone

Article abstract of DOI:10.1002/ardp.201200287

A series of (1-substituted aryl)-3-(1H-imidazol-1-yl)-1-propanones was synthesized through the N-alkylation of imidazole with 3-dimethylamino-1- (substituted aryl)-1-propanone hydrochlorides (ketonic Mannich bases). A second series of N¹-substituted imidazoles was obtained by the reduction of the carbonyl function of the imidazole-ketones in the previous series by means of NaBH₄. All of the compounds were evaluated for antifungal activity against 16 strains of Candida, and 3-(1H-imidazol-1-yl)-1-(4-biphenylyl)-1- propanone emerged as a broad-spectrum antifungal agent. Several 3-(1H-imidazol-1-yl)-1-(2′-(substituted benzyl)oxyphenyl)-1-propanones were also active towards Candida kefyr. Copyright

Full text of DOI:10.1002/ardp.201200287

110
Arch. Pharm. Chem. Life Sci. 2013, 346, 110–118
Full Paper
A Novel Antifungal Agent with Broad Spectrum:
1-(4-Biphenylyl)-3-(1H-imidazol-1-yl)-1-propanone
1
Gheorghe Roman , Mihai Mares¸ , and Valentin Nastasa
2
2
˘
˘
1 Petru Poni Institute of Macromolecular Chemistry, Ias¸i, Romania
2 Ion Ionescu de la Brad University, Laboratory of Antimicrobial Chemotherapy, Ias¸i, Romania
A series of (1-substituted aryl)-3-(1H-imidazol-1-yl)-1-propanones was synthesized through the
N-alkylation of imidazole with 3-dimethylamino-1-(substituted aryl)-1-propanone hydrochlorides
(ketonic Mannich bases). A second series of N1-substituted imidazoles was obtained by the
reduction of the carbonyl function of the imidazole–ketones in the previous series by means of
NaBH4. All of the compounds were evaluated for antifungal activity against 16 strains of Candida,
and 3-(1H-imidazol-1-yl)-1-(4-biphenylyl)-1-propanone emerged as a broad-spectrum antifungal agent.
Several 3-(1H-imidazol-1-yl)-1-(20-(substituted benzyl)oxyphenyl)-1-propanones were also active towards
Candida kefyr.
Keywords: Antifungal activity / Imidazoles / Mannich reaction / N-Alkylation
Received: July 13, 2012; Revised: October 22, 2012; Accepted: November 2, 2012
DOI 10.1002/ardp.201200287
Introduction
that are resistant to antifungal treatment [8], which leads to
serious limitations in the choice of an available efficient
drug. Because transient resistance of Candida species to
azole-containing antifungals after exposure to fluconazole
has rendered the first-line drugs less and less effective, the
addition of novel azoles to the antifungal armamentarium is
necessary to address these therapeutic issues.
The last half-century has witnessed the increased incidence of
fungal infections to the point they have become one of the
most common affliction nowadays. Although most human
populations affected by mycoses present only topical super-
ficial and cutaneous varieties that are manageable, the num-
ber of nosocomial invasive and systemic fungal infections
that are associated with considerable morbidity and
mortality despite appropriate antifungal therapy has steadily
grown, especially in the case of patients at high risk [1]. Some
of the most frequent risk factors include the administration
of strong antibiotics for a long time [2], or a weakened or
compromised immune system due to organ transplant [3],
cancer [4], steroid treatments [5, 6], or HIV infections [7].
Among the different pathogens responsible for fungal infec-
tions, the yeasts belonging to the Candida genus appear to
have become the major cause for fungal nosocomial infec-
tions worldwide, with Candida albicans accounting for the
majority of candidiases. The increased incidence of fungal
infections is also accompanied by the emergence of strains
The azole antifungals that are usually used to treat Candida
infections feature either an imidazole or a 1,2,4-triazole
moiety as the pharmacophore. Their mechanism of action
relies on the inhibition of the fungal cytochrome P450-
dependent 14a-lanosterol demethylase through the binding
of the N3-atom of the azole moiety to iron heme [9, 10]. While
the presence of an azole pharmacophore in the structure of
an antifungal candidate is crucial, the nature of the substitu-
ent at N1 of the azole moiety is also important for the fine
tuning of the candidate’s antifungal efficiency. In this
respect, a higher affinity of the aromatic moieties of the
N1-substituent for the hydrophobic amino acids within the
binding pocket of the enzyme, as well the presence of sub-
stituents capable of forming hydrogen bonds within the
enzyme’s active site, could make the difference between a
good and a poor antifungal azole-containing candidate [11].
Many imidazole-containing antifungals in use have a
linker of two carbon atoms between the pharmacophore
and an aromatic moiety, but only limited information is
available on the structure–antifungal activity for analogs
Correspondence: Dr. Gheorghe Roman, Petru Poni Institute of
˘
Macromolecular Chemistry, 41A Aleea Gr. Ghica Voda, Ias¸i 700487,
Romania.
E-mail: gheorghe.roman@icmpp.ro
Fax: þ40 232 211 299
ß 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

Arch. Pharm. Chem. Life Sci. 2013, 346, 110–118
Novel Imidazoles as Antifungal Agents
111
having a three-carbon atom bridge between the pharmaco-
phore and the aromatic moiety. Recently, the evaluation of
the antifungal activity of a series of 1-(3-(substituted aryloxy)-
alcohols corresponding to the compounds in the initial
collection was synthesized and evaluated also.
3-(substituted aryl)propyl)-1H-imidazoles has shown that Results and discussion
novel potent antifungal agents active against C. albicans could
be designed by adept manipulation of the number, nature,
and position of substituents in the phenyl ring and phenoxy
groups [12, 13]. A few compounds in a small series of esters
and tertiary alcohols having a propyl bridge between the
imidazole pharmacophore and an unsubstituted phenyl ring
possess also a minimal inhibitory concentration (MIC) com-
parable to that of miconazole or tioconazole [14]. These
favorable results encouraged us to undertake the design
and synthesis of a collection of 1-(3-(substituted aryl)-3-oxo-
propyl)-1H-imidazoles with the view of exploring the
relevance of diverse substitution patterns in the aromatic
moiety towards the antifungal activity. In addition, in order
to garner insight into the influence of the oxygen-containing
function on the propyl bridge on the antifungal activity of
these imidazoles, a second library comprising the secondary
Chemistry
Four commercially unavailable 20-benzyloxyacetophenones
2–5, required as starting materials in the preparation of
antifungal candidates, have been obtained in good yields
through the O-alkylation of 20-hydroxyacetophenone 1 with
substituted benzyl halides in ethanol in the presence of
sodium ethoxide (Scheme 1). Compounds 2–5 and other 11
commercially available ketones 6–15 were subjected to ami-
nomethylation in the conditions of the Mannich reaction [15]
to afford the ketonic Mannich bases 16–29 as hydrochlorides.
The aminomethylated ketones 16–24 and 29 are known
compounds, and their identities have been confirmed by
comparing their melting points (see Experimental section)
and 1H- and 13C NMR data with the ones reported in the
literature. Compounds 25–28 are novel, and they have been
Scheme 1. Synthetic pathway for the preparation of imidazole–ketones 30–43 and imidazole–alcohols 44–54. Reagents and condi-
tions: (a) substituted benzyl halide, sodium ethoxide, ethanol, reflux, 5 h; (b) dimethylamine hydrochloride, paraformaldehyde, 37% HCl,
ethanol, reflux 4–10 h; (c) imidazole, water, reflux, 1 h; (d) NaBH4, methanol, rt, overnight.
ß 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

112
G. Roman et al.
Arch. Pharm. Chem. Life Sci. 2013, 346, 110–118
fully characterized. N-Alkylation of imidazole with the afore-
mentioned Mannich bases proceeded smoothly in water at
reflux temperature to yield imidazole–ketones 30–43 as free
bases (Scheme 1). With the exception of compounds 33 and
38, the free bases were converted into the hydrochlorides by
treatment of a solution of the crude imidazole–ketone in
diethyl ether–2-propanol with ethereal HCl. Reduction of
selected compounds from the imidazole–ketone collection
by means of NaBH4 in methanol gave imidazole–alcohols 44–
54 as racemic mixtures (Scheme 1). The hydrochlorides of
imidazole–alcohols 44–46, 49, and 54 were obtained in a
similar manner as the hydrochlorides of imidazole–ketones.
Evaluation of antifungal activity
Compounds 30–54 were evaluated for their in vitro antifungal
activity against a series of 16 strains of Candida belonging to
the species C. albicans, C. glabrata, C. guilliermondii, C. kefyr,
C. krusei, C. parapsilosis, C. peliculosa, and C. tropicalis. The anti-
fungal screening of compounds 30–54 was carried out using
the broth microdilution technique [16]. The antifungal
activity of these compounds was compared to that of the
standard antifungal drug fluconazole. Minimum inhibition
concentrations (MICs) for the candidates and the standard
drug were determined in 96-well tissue culture plates, and
are presented in Table 1. Due to its very low solubility in
dimethylsulfoxide, compound 38 could not be included in
the investigation. One compound from this collection,
namely 3-(1H-imidazol-1-yl)-1-(4-biphenylyl)-1-propanone 33,
emerged from the antifungal screening as a broad-spectrum
antifungal agent. Compound 33 inhibited the growth of all of
the strains of Candida used in this investigation. This candi-
date was more potent than fluconazole towards C. glabrata
and C. krusei, and as potent as fluconazole towards C. tropicalis.
Furthermore, out of the eight species of Candida in this study,
the strains of C. kefyr appear to be sensitive to 13 candidates in
this collection in various degrees. Although the antifungal
activities of most of these candidates were similar for both
strains of C. kefyr, the growth of one of these strains (RTCC
1019) was more inhibited by candidates 39–42 and 51–54.
In fact, compound 40 is twofold less potent, whereas com-
pounds 39, 41, and 42 are fourfold less potent than the
standard drug fluconazole towards this strain. Compounds
30, 36, 38, 44, 45, and 48–50 exhibited MIC values higher
than 64 mg/L against all of the Candida strains investigated in
this study.
Structure–activity relationship
This study reports the antifungal activity for two structurally
related series of imidazole-containing compounds. One series
is comprised of compounds 30–43, which have a 3-oxo-3-
(substituted aryl)propyl moiety attached at N1 of the
imidazole ring, whereas the other series includes candidates
ß 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

Arch. Pharm. Chem. Life Sci. 2013, 346, 110–118
Novel Imidazoles as Antifungal Agents
113
44–54 featuring
a
3-hydroxy-3-(substituted aryl)propyl Conclusion
appendage at N1 of the imidazole ring. As a general obser-
vation, most of the compounds are ineffective towards the
strains of Candida used in this study (MIC > 64 mg/L), irre-
spective of the substitution pattern in the aryl moiety, or the
nature of the oxygen-containing function on the linker.
However, within this collection, a small group consisting
of compounds 39–42 and 51–54, which all share a common
20-(substituted benzyloxy)phenyl moiety at the end of
the linker opposite to the pharmacophore, showed moderate
to good activity towards C. kefyr. It is noteworthy that the
most active candidates in this sub-group, namely compounds
39–42, have a carbonyl function on the linker, whereas the
corresponding alcohols 51–54 are less potent than the parent
imidazole–ketones. This suggests that a more hydrophobic
carbonyl function on the linker is better tolerated than
the hydrophilic secondary alcohol function. Furthermore,
it has been previously noted [17, 18] that the number of
the chlorine atoms in the aromatic rings in the structure
of antifungal candidates is one factor that contributes to the
enhancement of the antifungal activity. However, in our
hands, only a minor increase could be noticed in the anti-
fungal activity of compound 42 (two chlorine atoms) com-
pared to that of compounds 40 (one chlorine atom) or 39
(no chlorine atom). In the end, the compound that stands out
as the most efficient and comprehensive antifungal agent
within this collection is candidate 33, 3-(1H-imidazol-1-yl)-1-
(4-biphenylyl)-1-propanone. When compared to the analo-
gous imidazole–ketones within this collection of com-
pounds, the hit compound 33 presents an aromatic moiety
that is amongst the most hydrophobic. Nevertheless, despite
the fact that they also have highly hydrophobic naphthyl
residues in their structure, compounds 34 and 35 are not
potent antifungal agents. Therefore, we hypothesize that
compound 33 owes its unique ability to inhibit broadly
the growth of Candida yeasts not only to the hydrophobicity
of the biphenyl residue, but also to the length of its molecule,
which most likely allow compound 33 to interact extensively
with hydrophobic amino acid residues within the active site
of lanosterol 14-a-demethylase in Candida. In addition, com-
pound 33 may exert its antifungal action through a dual
mechanism of action, in a manner similar to bifonazole [19],
another antifungal agent having a biphenyl moiety in its
structure. Also, it appears that the excellent antifungal
activity of compound 33 is the result of an unusually particu-
lar combination of structural elements, if one takes into
consideration the lack of activity of the structurally related
imidazole–alcohol 47. Thus, despite the preservation of all
the other structural characteristics, the simple replacement
of the carbonyl function in 33 with a secondary alcohol group
in 47 results in a compound that is no longer able to inhibit
the growth of Candida yeasts.
The antifungal evaluation of a small library of novel, easily
accessible imidazoles led to the discovery of 3-(1H-imidazol-1-
yl)-1-(4-biphenylyl)-1-propanone as a broad-spectrum anti-
fungal agent. This hit compound represents a novel and
exciting template for future developments of more potent
antifungal candidates through rational design that relies on
the modifications pertaining to the length of the linker, the
nature of the functional groups on the linker, or the substi-
tution pattern of the biphenyl moiety.
Experimental
Materials and methods
Melting points were taken on a Mel-Temp II apparatus and are
uncorrected. Elemental analysis was conducted in-house, on a
PerkinElmer 2400 Series II CHNS/O system. 1H and 13C NMR
spectra were recorded on a Bruker Avance 400-MHz spec-
trometer. The signals owing to residual protons in the deuter-
ated solvents were used as internal standards for the 1H NMR
spectra. The chemical shifts for the carbon atoms are given
relative to CDCl3 (d ¼ 77.16 ppm) or d6-DMSO (d ¼ 39.52 ppm).
High-resolution mass spectra (HRMS) were obtained on an
Applied Biosystems/MDS Sciex QSTAR XL spectrometer equipped
with an Agilent HP1100 Cap-LC system in electron ionization (EI)
mode. A microplate reader model MR-96A (Mindray, China) was
used to determine the MIC values.
The ketones 1 and 6–15, the benzyl halides (4-methylbenzyl
bromide, 4-chlorobenzyl bromide, 4-bromobenzyl bromide, 3,4-
dichlorobenzyl chloride), paraformaldehyde, dimethylamine
hydrochloride, and NaBH4 used as starting materials and
reagents in the synthesis were purchased from Sigma–Aldrich.
The following ketonic Mannich bases were synthesized from the
corresponding ketone through an adaptation of the procedure
reported [20] for the direct aminomethylation of acetophenone
with paraformaldehyde and dimethylamine hydrochloride:
3-dimethylamino-1-phenyl-1-propanone hydrochloride 16 (mp
153–1548C; lit. mp 153.6–153.78C [21]), 1-(4-chlorophenyl)-3-
dimethylamino-1-propanone hydrochloride 17 (mp 173–1748C;
lit. mp 172.5–173.58C [22]), 1-(4-bromophenyl)-3-dimethylamino-
1-propanone hydrochloride 18 (mp 194–1958C; lit. mp 1938C
[23]), 1-(4-biphenyl-1-yl)-3-dimethylamino-1-propanone hydro-
chloride 19 (mp 187–1888C; lit. mp 182–1838C [24]), 3-dimeth-
ylamino-1-(naphthalen-1-yl)-1-propanone hydrochloride 20 (mp
156–1578C; lit. mp 157–1588C [25]), 3-dimethylamino-1-(naphtha-
len-2-yl)-1-propanone hydrochloride 21 (mp 174–1758C; lit. mp
155–1578C [26]), 3-dimethylamino-1-(thiophen-2-yl)-1-propanone
hydrochloride 22 (mp 184–1858C; lit. mp 1848C [27]), 3-dimethyl-
amino-1-(2-hydroxyphenyl)-1-propanone hydrochloride 23
(mp 174–1758C; lit. mp 175–1768C [28]), 3-dimethylamino-1-(4-
hydroxyphenyl)-1-propanone hydrochloride 24 (mp 199–2008C;
lit. mp 1928C [29]), and (ꢀ )-2-dimethylaminomethyl-3,4-dihydro-
naphthalen-1(2H)-one hydrochloride 29 (mp 159–1608C; lit. mp:
154–155.58C [30], 1508C [31], 1458C [32]).
The 16 yeast reference strains belonging to eight species that
were used in this study, namely C. albicans RTCC 1003 and RTCC
1024, C. glabrata RTCC 1040 and RTCC 1054, C. guilliermondii RTCC
1248 and RTCC 1377, C. kefyr RTCC 1019 and RTCC 1074, C. krusei
ß 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

114
G. Roman et al.
Arch. Pharm. Chem. Life Sci. 2013, 346, 110–118
RTCC 1001 and RTCC 1090, C. parapsilosis RTCC 1018 and RTCC
1079, C. pelliculosa RTCC 1029 and RTCC 1075, C. tropicalis
RTCC 1065 and RTCC 1095, were obtained from the Romanian
Type Culture Collection, and cultured according to the
manufacturer’s recommendation. Fluconazole, RPMI-1640
medium, 3-(N-morpholino)propanesulfonic acid (MOPS), glucose,
and dimethylsulfoxide (DMSO) were obtained from Sigma–
Aldrich.
136.6, 157.5, 199.7; HRMS (EI): Calcd. for C15H12Cl2O2: 294.0214
(Mþ). Found: 294.0218.
General procedure for the synthesis of ketonic Mannich
bases as hydrochlorides
A mixture of alkyl aryl ketone 2–15 (20 mmol), paraformalde-
hyde (1.2 g, 40 mmol), dimethylamine hydrochloride (1.79 g,
22 mmol), and 37% HCl (five drops) either in 2-propanol (10–
15 mL) was heated under reflux for 6 h. The mixture was then
cooled to approximately 508C, and acetone (50 mL) was added
gradually under efficient stirring. The mixture was kept in a
freezer for 24 h, and then the crystals were filtered, washed with
acetone, air-dried, and recrystallized from the appropriate
solvent.
Chemistry
General procedure for the synthesis of 2 0-(substituted-
benzyloxy)acetophenones 2–5
To a solution of sodium ethoxide (prepared by stirring ethanol
(20 mL) and metallic sodium (460 mg, 20 g-atoms) at room
temperature for 30 min) was added 20-hydroxyacetophenone 1
(2.72 g, 20 mmol), and the mixture was stirred at room tempera-
ture for 5 min. After the substituted benzyl halide (20 mmol)
had been added, the mixture was refluxed for 5 h and cooled to
room temperature. Addition of water (50 mL) followed by 1%
KOH solution (40 mL) resulted in the separation of the benzylox-
yacetophenone. The solid compounds 3–5 were filtered, washed
with water, and dried. Compound 2, which separated as an oil,
was extracted with ethyl acetate (2ꢁ 40 mL), the organic phase
was washed with water (30 mL), and brine (30 mL), and then
the solvent was removed under reduced pressure to give a
residue that crystallized under high vacuum. Recrystallization
from the appropriate solvent afforded the pure ketones.
3-Dimethylamino-1-(2 0-(4-methylbenzyloxy)phenyl)-1-
propanone hydrochloride 25
Colorless crystals, 4.20 g (63%), mp 169–1708C (ethanol);
1H NMR (CD3OD): d 2.36 (s, 3H), 2.75 (s, 6H), 3.38–3.50 (m, 4H),
7.02–7.10 (m, 1H), 7.22–7.30 (m, 3H), 7.43 (d, J ¼ 8.0 Hz, 2H),
7.53–7.61 (m, 1H), 7.80 (dd, J ¼ 2.0 and 8.0 Hz, 1H); 13C NMR
(CD3OD): d 21.2, 39.6, 43.5, 54.3, 72.1, 114.6, 122.0, 127.6, 129.7,
130.5, 131.4, 134.7, 136.1, 139.6, 160.2, 199.0; Anal. calcd.
for C19H24ClNO2: C 68.35, H 7.25, N 4.20. Found: C 68.58,
H 7.16, N 4.07.
1-(2 0-(4-Chlorobenzyloxy)phenyl)-3-dimethylamino-1-
propanone hydrochloride 26
1-(2 0-(4-Methylbenzyloxy)phenyl)ethanone 2
Colorless crystals, 5.59 g (79%), mp 177–1788C (ethanol); 1H NMR
Colorless crystals, 2.54 g (56%), mp 48–498C (2-propanol–hex-
anes); 1H NMR (CDCl3): d 2.38 (s, 3H), 2.60 (s, 3H), 5.13 (s, 2H),
6.98–7.06 (m, 2H), 7.21 (d, J ¼ 8.0 Hz, 2H), 7.33 (d, J ¼ 8.0 Hz, 2H),
7.41–7.49 (m, 1H), 7.76 (dd, J ¼ 2.0 and 8.0 Hz, 1H); 13C NMR
(CDCl3): d 21.3, 32.3, 70.7, 112.9, 120.9, 127.8, 128.8, 129.5, 130.6,
133.3, 133.7, 138.2, 158.2, 200.1; HRMS (EI): Calcd. for C16H16O2:
240.1150 (Mþ). Found: 240.1155.
(d6-DMSO):
d
2.66 (s, 6H), 3.32 (t, J ¼ 7.2 Hz, 2H), 3.51
(t, J ¼ 7.2 Hz, 2H), 5.28 (s, 2H), 7.08 (t, J ¼ 7.6 Hz, 1H), 7.28
(d, J ¼ 8.4 Hz, 1H), 7.49 (d, J ¼ 8.4 Hz, 2H), 7.54–7.61 (m, 1H),
7.63 (d, J ¼ 8.4 Hz, 2H), 7.70 (dd, J ¼ 1.6 and 7.6 Hz, 1H), 10.90
(s, 1H); 13C NMR (d6-DMSO): d 38.2, 42.0, 51.7, 69.3, 113.8,
120.8, 126.7, 128.6, 129.9, 130.0, 132.6, 134.4, 135.4, 157.5,
197.2; Anal. calcd. for C18H21Cl2NO2: C 61.02, H 5.97, N 3.95.
Found: C 61.23, H 6.11, N 3.88.
1-(2 0-(4-Chlorobenzyloxy)phenyl)ethanone 3
Colorless crystals, 3.96 g (74%), mp 74–758C (ethanol); 1H NMR
(CDCl3): d 2.58 (s, 3H), 5.13 (s, 2H), 6.96–7.07 (m, 2H), 7.38 (s, 4H),
7.40–7.49 (m, 1H), 7.74 (dd, J ¼ 2.0 and 8.0 Hz, 1H); 13C NMR
(CDCl3): d 32.1, 70.0, 112.9, 128.9, 129.0, 130.6, 133.7, 134.2,
134.8, 157.8, 199.9; HRMS (EI): Calcd. for C15H13ClO2: 260.0604
(Mþ). Found: 260.0601.
1-(2 0-(4-Bromobenzyloxy)phenyl)-3-dimethylamino-1-
propanone hydrochloride 27
Colorless crystals, 5.74 g (72%), mp 172–1738C (ethanol); 1H NMR
(d6-DMSO):
d
2.66 (s, 6H), 3.32 (t, J ¼ 7.4 Hz, 2H), 3.51
(t, J ¼ 7.4 Hz, 2H), 5.27 (s, 2H), 7.07 (t, J ¼ 7.6 Hz, 1H), 7.28
(d, J ¼ 8.4 Hz, 1H), 7.53–7.65 (m, 5H), 7.70 (dd, J ¼ 1.6 and
7.6 Hz, 1H), 10.94 (s, 1H); 13C NMR (d6-DMSO): d 38.2, 42.0,
51.7, 69.3, 113.8, 120.8, 121.2, 126.7, 129.9, 130.3, 131.5,
134.4, 135.8, 157.4, 197.2; Anal. calcd. for C18H21BrClNO2:
C 54.22, H 5.31, N 3.51. Found: C 54.40, H 5.15, N 3.68.
1-(2 0-(4-Bromobenzyloxy)phenyl)ethanone 4
Colorless crystals, 4.94 g (81%), mp 85–868C (ethanol); 1H NMR
(CDCl3): d 2.58 (s, 3H), 5.11 (s, 2H), 6.98 (d, J ¼ 8.4 Hz, 1H), 7.00–
7.06 (m, 1H), 7.29–7.35 (m, 2H), 7.41–7.48 (m, 1H), 7.51–7.57
(m, 2H), 7.74 (dd, J ¼ 2.0 and 7.6 Hz, 1H); 13C NMR (CDCl3):
d 32.1, 70.1, 112.9, 121.2, 122.4, 129.0, 129.3, 130.7, 132.0,
133.7, 135.4, 157.8, 199.9; HRMS (EI): Calcd. for C15H13BrO2:
304.0099 (Mþ). Found: 304.0103.
1-(2 0-(3,4-Dichlorobenzyloxy)phenyl)-3-dimethylamino-1-
propanone hydrochloride 28
Colorless crystals, 5.13 g (66%), mp 159–1608C (ethanol); 1H NMR
(d6-DMSO):
d
2.69 (s, 6H), 3.34 (t, J ¼ 7.4 Hz, 2H), 3.52
1-(2 0-(3,4-Dichlorobenzyloxy)phenyl)ethanone 5
(t, J ¼ 7.4 Hz, 2H), 5.29 (s, 2H), 7.09 (t, J ¼ 7.2 Hz, 1H), 7.27
(d, J ¼ 8.4 Hz, 1H), 7.55–7.66 (m, 2H), 7.67–7.74 (m, 2H), 8.78
(d, J ¼ 1.6 Hz, 1H), 10.82 (s, 1H); 13C NMR (d6-DMSO): d 38.0, 42.0,
51.7, 68.6, 113.8, 121.0, 126.8, 128.4, 129.9, 130.6, 130.9, 131.1,
134.4, 137.6, 157.2, 197.3; Anal. calcd. for C18H20Cl3NO2: C 55.62,
H 5.19, N 3.60. Found: C 55.43, H 5.04, N 3.79.
Colorless crystals, 4.84 g (82%), mp 84–858C (ethanol); 1H NMR
(CDCl3): d 2.59 (s, 3H), 5.11 (s, 2H), 6.96 (d, J ¼ 8.4 Hz, 1H), 7.00–
7.07 (m, 1H), 7.24–7.32 (m, 1H), 7.40–7.50 (m, 2H), 7.54 (s, 1H),
7.74 (dd, J ¼ 2.0 and 7.6 Hz, 1H); 13C NMR (CDCl3): d 32.0, 69.4,
112.9, 121.5, 126.8, 129.1, 129.5, 130.7, 130.9, 132.5, 133.1, 133.7,
ß 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

Arch. Pharm. Chem. Life Sci. 2013, 346, 110–118
Novel Imidazoles as Antifungal Agents
115
General procedure for the N-alkylation of imidazole with
ketonic Mannich bases hydrochlorides
3-(1H-Imidazol-1-yl)-1-(naphthalen-1-yl)-1-propanone
hydrochloride 34
A ketonic Mannich base hydrochloride 16–29 (4 mmol) and
imidazole (272 mg, 4 mmol) were heated under reflux in water
(10 mL) for 1 h. The reaction mixture was then stirred in an ice
bath until the oil that had initially separated crystallizes,
and then the solid was filtered, washed thoroughly with water
and air-dried. Alternatively, for compounds that do not become
solid after 1 day, the oil was extracted with ethyl acetate
(2 ꢁ 15 mL), the organic phase was washed with water and
brine, dried over anhydrous Na2SO4, and then the solvent was
removed under reduced pressure. This crude imidazole–ketone
was dissolved in a mixture of 2-propanol (4 mL) and diethyl
ether (20–30 mL), treated with an excess of ethereal hydrogen
chloride, and kept at room temperature overnight. The crystals
were filtered, washed with diethyl ether, and recrystallized
from the appropriate solvent to yield the imidazole–ketone
hydrochloride.
Off-white crystals, 640 mg (56%), mp 131–1328C (2-propanol–
ethyl acetate); 1H NMR (d6-DMSO): d 3.91 (t, J ¼ 6.4 Hz, 2H),
4.63 (t, J ¼ 6.4 Hz, 2H), 7.56–7.67 (m, 3H), 7.68 (s, 1H), 7.89
(s, 1H), 8.03 (dd, J ¼ 1.2 and 8.0 Hz, 1H), 8.15–8.24 (m, 2H),
8.52 (d, J ¼ 8.4 Hz, 1H), 9.29 (s, 1H); 13C NMR (d6-DMSO):
d 40.8, 44.1, 119.6, 122.2, 124.8, 125.1, 126.5, 128.0, 128.6,
129.1, 129.3, 133.3, 133.5, 133.9, 135.6, 200.8; Anal. calcd. for
C16H15ClN2O: C 67.02, H 5.27, N 9.77. Found: C 66.79, H 5.46,
N 9.96.
3-(1H-Imidazol-1-yl)-1-(naphthalen-2-yl)-1-propanone
hydrochloride 35
Off-white crystals, 480 mg (42%), mp 185–1868C (ethanol);
1H NMR (d6-DMSO): d 3.95 (t, J ¼ 6.6 Hz, 2H), 4.62 (t, J ¼ 6.6 Hz,
2H), 7.60–7.72 (m, 3H), 7.88 (s, 1H), 7.96–8.07 (m, 3H), 8.13
(d, J ¼ 8.0 Hz, 1H), 8.73 (s, 1H), 9.28 (s, 1H); 13C NMR (d6-DMSO):
d 38.1, 44.0, 119.6, 122.2, 123.3, 127.1, 127.7, 128.4, 128.9,
129.6, 130.3, 132.1, 133.2, 135.2, 135.6, 197.1; Anal. calcd.
for C16H15ClN2O: C 67.02, H 5.27, N 9.77. Found: C 66.85,
H 5.40, N 9.69.
3-(1H-Imidazol-1-yl)-1-phenyl-1-propanone hydrochloride
30
Off-white crystals, 570 mg (60%), mp 175–1768C (2-propanol)
(lit. mp 174–1768C [33]); 1H NMR (CD3OD): d 3.77 (t, J ¼ 6.0 Hz,
2H), 4.69 (t, J ¼ 6.0 Hz, 2H), 7.47–7.56 (m, 3H), 7.59–7.67
(m, 1H), 7.34 (t, J ¼ 1.6 Hz, 1H), 7.97–8.05 (m, 2H), 9.05
3-(1H-Imidazol-1-yl)-1-(thiophen-2-yl)-1-propanone
hydrochloride 36
(s, 1H); 13C NMR (CD3OD):
d 39.2, 45.5, 120.9, 123.6,
Tan crystals, 515 mg (53%), mp 136–1378C (2-propanol); 1H NMR
(d6-DMSO): d 3.74 (t, J ¼ 6.6 Hz, 2H), 4.54 (t, J ¼ 6.6 Hz, 2H), 7.27
(dd, J ¼ 4.0 and 4.8 Hz, 1H), 7.66 (t, J ¼ 1.6 Hz, 1H), 7.83
(t, J ¼ 1.6 Hz, 1H), 8.02 (dd, J ¼ 1.2 and 4.0 Hz, 1H), 8.06
(dd, J ¼ 1.2 and 4.8 Hz, 1H), 9.25 (s, 1H); 13C NMR (d6-DMSO):
d 38.3, 43.8, 119.5, 122.2, 128.9, 134.1, 135.5, 135.6, 142.8,
190.1; Anal. calcd. for C10H11ClN2OS: C 49.48, H 4.57, N 11.54.
Found: C 49.75, H 4.79, N 11.29.
129.2, 129.9, 134.9, 137.2, 137.4, 198.3; Anal. calcd.
for C12H13ClN2O: C 60.89, H 5.54, N 11.84. Found: C 60.56,
H 5.73, N 11.61.
1-(4-Chlorophenyl)-3-(1H-imidazol-1-yl)-1-propanone
hydrochloride 31
Off-white crystals, 630 mg (58%), mp 174–1758C (2-propanol);
1H NMR (CD3OD): d 3.73 (t, J ¼ 6.0 Hz, 2H), 4.67 (t, J ¼ 6.0 Hz,
2H), 7.49–7.57 (m, 3H), 7.69 (t, J ¼ 1.2 Hz, 1H), 7.99 (d, J ¼ 8.8 Hz,
2H), 8.98 (br s, 1H); 13C NMR (CD3OD): d 39.3, 45.4, 120.9,
123.6, 130.1, 130.9, 135.9, 137.2, 141.1, 197.2; Anal. calcd.
for C12H12Cl2N2O: C 53.16, H 4.46, N 10.33. Found: C 52.91,
H 4.65, N 10.14.
1-(2-Hydroxyphenyl)-3-(1H-imidazol-1-yl)-1-propanone
hydrochloride 37
Colorless crystals, 215 mg (21%), mp 153–1548C (2-propanol);
1H NMR (d6-DMSO):
d
3.80 (t, J ¼ 6.6 Hz, 2H), 4.55
(t, J ¼ 6.6 Hz, 2H), 6.90–6.97 (m, 1H), 7.06 (dd, J ¼ 0.8 and
8.4 Hz, 1H), 7.46–7.54 (m, 1H), 7.66 (d, J ¼ 1.6 Hz, 1H), 7.78–
7.86 (m, 2H), 9.23 (s, 1H), 11.47 (s, 1H); 13C NMR (d6-DMSO):
d 40.2, 43.7, 117.7, 119.2, 119.5, 121.1, 122.2, 130.3, 135.6,
135.9, 160.0, 201.0; Anal. calcd. for C12H13ClN2O2: C 57.04,
H 5.19, N 11.09. Found: C 57.32, H 5.44, N 10.81.
1-(4-Bromophenyl)-3-(1H-imidazol-1-yl)-1-propanone
hydrochloride 32
Off-white crystals, 670 mg (53%), mp 173–1748C (2-propanol);1H NMR
(d6-DMSO): d 3.80 (t, J ¼ 6.6 Hz, 2H), 4.55 (t, J ¼ 6.6 Hz, 2H), 7.66
(s, 1H), 7.77 (d, J ¼ 8.4 Hz, 2H), 7.83 (s, 1H), 7.91 (d, J ¼ 8.4 Hz,
2H), 9.25 (s, 1H); 13C NMR (d6-DMSO): d 38.0, 43.7, 119.5,
122.2, 127.8, 130.0, 131.8, 134.9, 135.5, 196.4; Anal. calcd.
for C12H12BrClN2O: C 45.67, H 3.83, N 8.88. Found: C 45.88,
H 3.98, N 9.09.
1-(4-Hydroxyphenyl)-3-(1H-imidazol-1-yl)-1-propanone 38
Off-white crystals, 750 mg (87%), mp 198–1998C; 1H NMR
(d6-DMSO): d 3.46 (t, J ¼ 6.8 Hz, 2H), 4.29 (t, J ¼ 6.8 Hz, 2H),
6.81–6.87 (m, 3H), 7.19 (s, 1H), 7.64 (s, 1H), 7.85 (d, J ¼ 8.8 Hz,
2H), 10.47 (br s, 1H); 13C NMR (d6-DMSO): d 38.7, 41.4, 115.2,
119.4, 127.9, 128.2, 130.3, 137.4, 162.3, 195.7; Anal. calcd.
for C12H12N2O2: C 66.65, H 5.59, N 12.96. Found: C 66.39,
H 5.81, N 12.65.
1-(4-Biphenyl-1-yl)-3-(1H-imidazol-1-yl)-1-propanone 33
Off-white crystals, 1015 mg (81%), mp 147–1488C (2-propanol)
(lit. mp 149–1518C [34]); 1H NMR (d6-DMSO): d 3.47 (t, J ¼ 6.6 Hz,
2H), 4.45 (t, J ¼ 6.6 Hz, 2H), 6.99 (s, 1H), 7.05 (s, 1H), 7.37–7.51
(m, 3H), 7.57 (s, 1H), 7.59–7.65 (m, 2H), 7.68 (d, J ¼ 8.4 Hz, 2H),
7.98 (d, J ¼ 8.4 Hz, 2H); 13C NMR (d6-DMSO): d 40.0, 41.6, 119.2,
127.4, 127.5, 128.5, 128.7, 129.1, 129.8, 134.9, 137.6, 139.7, 146.5,
196.3; Anal. calcd. for C18H16N2O: C 78.24, H 5.84, N 10.14.
Found: C 78.47, H 5.97, N 10.02.
3-(1H-Imidazol-1-yl)-1-(2 0-(4-methylbenzyloxy)phenyl)-1-
propanone hydrochloride 39
Colorless crystals, 1025 mg (72%), mp 182–1838C (ethanol);
1H NMR (d6-DMSO): d 2.31 (s, 3H), 3.62 (t, J ¼ 6.8 Hz, 2H), 4.47
(t, J ¼ 6.8 Hz, 2H), 5.20 (s, 2H), 7.05 (t, J ¼ 7.4 Hz, 1H), 7.17
ß 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

116
G. Roman et al.
Arch. Pharm. Chem. Life Sci. 2013, 346, 110–118
(d, J ¼ 7.6 Hz, 2H), 7.27 (d, J ¼ 8.0 Hz, 1H), 7.35 (d, J ¼ 7.6 Hz,
2H), 7.53–7.60 (m, 1H), 7.63–7.69 (m, 3H), 9.13 (s, 1H); 13C NMR
(d6-DMSO): d 20.8, 43.5, 44.0, 70.1, 114.0, 119.5, 120.7, 122.0,
126.7, 128.0, 129.0, 129.8, 133.2, 134.5, 135.4, 137.4, 157.9,
197.7; Anal. calcd. for C20H21ClN2O2: C 67.32, H 5.93, N 7.85.
Found: C 67.11, H 6.03, N 8.02.
under good stirring, at room temperature. The reaction mixture
was then stirred at room temperature overnight. The solvent was
removed under reduced pressure, and the residue was parti-
tioned between water (30 mL) and ethyl acetate (15 mL).
The aqueous phase was further extracted with ethyl acetate
(15 mL), the organic phases were combined, washed with water
(15 mL) and brine (10 mL), and dried over anhydrous Na2SO4.
The solvent was then removed under reduced pressure to give
a residue. In the case of compounds 47, 48, and 50–53, the
residue was crystallized from the appropriate solvent. The
other imidazole–alcohols were converted into the corresponding
hydrochlorides by treating a solution of the residue in a
mixture of 2-propanol (4 mL) and diethyl ether (20–30 mL) with
an excess of ethereal hydrogen chloride. After being kept at
room temperature overnight, the crystals were filtered, washed
with diethyl ether, and recrystallized from the appropriate
solvent to yield the imidazole–alcohol hydrochlorides 44–46,
49, and 54.
1-(2 0-(4-Chlorobenzyloxy)phenyl)-3-(1H-imidazol-1-yl)-1-
propanone hydrochloride 40
Colorless crystals, 1220 mg (81%), mp 177–1788C (ethanol);
1H NMR (d6-DMSO): d 3.64 (t, J ¼ 6.6 Hz, 2H), 4.49 (t, J ¼ 6.6 Hz,
2H), 5.25 (s, 2H), 7.06 (t, J ¼ 7.6 Hz, 1H), 7.26 (d, J ¼ 8.4 Hz, 1H),
7.44 (d, J ¼ 8.4 Hz, 2H), 7.52 (d, J ¼ 8.4 Hz, 2H), 7.53–7.60 (m, 1H),
7.64 (t, J ¼ 1.6 Hz, 1H), 7.67 (dd, J ¼ 1.6 and 7.6 Hz, 1H), 7.71
(t, J ¼ 1.6 Hz, 1H), 9.17 (s, 1H); 13C NMR (d6-DMSO): d 43.3, 44.0,
69.3, 113.9, 119.5, 120.9, 122.0, 126.7, 128.5, 129.7, 129.8, 132.6,
134.4, 135.4, 135.5, 157.5, 197.7; Anal. calcd. for C19H18Cl2N2O2:
C 60.49, H 4.81, N 7.43. Found: C 60.62, H 4.89, N 7.28.
(ꢀ)-3-(1H-Imidazol-1-yl)-1-phenyl-1-propanol
1-(2 0-(4-Bromobenzyloxy)phenyl)-3-(1H-imidazol-1-yl)-1-
propanone hydrochloride 41
hydrochloride 44
Off-white crystals, 385 mg (54%), mp 100–1018C (2-propanol–
hexanes); 1H NMR (d6-DMSO): d 2.03–2.25 (m, 2H), 4.26–4.40
(m, 2H), 4.54 (dd, J ¼ 3.8 and 9.0 Hz, 1H), 5.68 (br s, 1H), 7.19–
7.37 (m, 5H), 7.67 (t, J ¼ 1.6 Hz, 1H), 7.83 (t, J ¼ 1.6 Hz, 1H), 9.23
(s, 1H), 14.93 (br s, 1H); 13C NMR (d6-DMSO): d 38.8, 46.0, 69.1,
119.6, 122.0, 125.6, 126.9, 128.1, 135.3, 145.1; Anal. calcd.
for C12H15ClN2O: C 60.38, H 6.33, N 11.74. Found: C 60.52, H
6.21, N 11.62.
Off-white crystals, 1435 mg (85%), mp 178–1798C (ethanol);
1H NMR (d6-DMSO): d 3.64 (t, J ¼ 6.8 Hz, 2H), 4.49 (t, J ¼ 6.8 Hz,
2H), 5.24 (s, 2H), 7.06 (t, J ¼ 7.4 Hz, 1H), 7.25 (d, J ¼ 8.4 Hz, 1H),
7.45 (d, J ¼ 8.4 Hz, 2H), 7.53–7.61 (m, 3H), 7.64 (s, 1H), 7.67
(dd, J ¼ 1.6 and 7.6 Hz, 1H), 7.72 (s, 1H), 9.17 (s, 1H); 13C NMR
(d6-DMSO): d 43.2, 44.0, 69.3, 113.9, 119.5, 120.9, 121.2, 122.0,
126.7, 129.8, 130.0, 131.4, 134.4, 135.5, 135.8, 157.5, 197.7; Anal.
calcd. for C19H18BrClN2O2: C 54.11, H 4.30, N 6.64. Found: C
54.27, H 4.16, N 6.83.
(ꢀ)-1-(4-Chlorophenyl)-3-(1H-imidazol-1-yl)-1-propanol
hydrochloride 45
1-(2 0-(3,4-Dichlorobenzyloxy)phenyl)-3-(1H-imidazol-1-
yl)-1-propanone hydrochloride 42
Colorless crystals, 345 mg (42%), mp 149–1508C (2-propanol–
diethyl ether); 1H NMR (d6-DMSO): d 2.01–2.13 (m, 1H), 2.13–
2.25 (m, 1H), 4.24–4.38 (m, 2H), 4.55 (dd, J ¼ 3.6 and 9.2 Hz,
1H), 5.81 (br s, 1H), 7.37 (s, 4H), 7.67 (s, 1H), 7.83 (s, 1H), 9.23
(s, 1H), 14.91 (br s, 1H); 13C NMR (d6-DMSO): d 38.6, 45.9, 68.4,
119.6, 122.1, 127.6, 128.0, 131.4, 135.3, 144.2; Anal. calcd.
for C12H14Cl2N2O: C 52.76, H 5.17, N 10.26. Found: C 52.60,
H 5.32, N 10.07.
Colorless crystals, 1270 mg (77%), mp 164–1658C (ethanol);
1H NMR (d6-DMSO): d 3.66 (t, J ¼ 6.8 Hz, 2H), 4.49 (t, J ¼ 6.8 Hz,
2H), 5.27 (s, 2H), 7.07 (t, J ¼ 7.6 Hz, 1H), 7.24 (d, J ¼ 8.0 Hz, 1H),
7.49 (dd, J ¼ 1.6 and 8.0 Hz, 1H), 7.54–7.61 (m, 1H), 7.62–7.67
(m, 2H), 7.69 (dd, J ¼ 1.6 and 7.6 Hz, 1H), 7.73 (s, 1H), 7.78
(d, J ¼ 1.6 Hz, 1H), 9.18 (s, 1H); 13C NMR (d6-DMSO): d 43.2,
44.0, 68.6, 113.9, 119.5, 121.0, 122.0, 126.7, 128.0, 129.7,
129.9, 130.6, 130.7, 131.1, 134.5, 135.5, 137.6, 157.3, 197.6;
Anal. calcd. for C19H17Cl3N2O2: C 55.43, H 4.16, N 6.80. Found:
C 55.25, H 4.33, N 6.68.
(ꢀ)-1-(4-Bromophenyl)-3-(1H-imidazol-1-yl)-1-propanol
hydrochloride 46
Off-white crystals, 665 mg (70%), mp 165–1668C (2-propanol–
diethyl ether); 1H NMR (d6-DMSO): d 2.00–2.13 (m, 1H), 2.13–
2.25 (m, 1H), 4.24–4.38 (m, 2H), 4.54 (dd, J ¼ 3.6 and 9.2 Hz,
1H), 5.80 (br s, 1H), 7.31 (d, J ¼ 8.4 Hz, 2H), 7.51 (d, J ¼ 8.4 Hz,
2H), 7.67 (t, J ¼ 1.6 Hz, 1H), 7.83 (t, J ¼ 1.6 Hz, 1H), 9.22 (s, 1H),
(ꢀ)-2-(1H-Imidazol-1-ylmethyl)-3,4-dihydronaphthalen-
1(2H)-one hydrochloride 43
Off-white crystals, 545 mg (52%), mp 156–1578C (2-propanol);
1H NMR (d6-DMSO): d 1.73–1.88 (m, 1H), 1.99–2.09 (m, 1H), 2.92–
3.14 (m, 2H), 3.30–3.43 (m, 1H), 4.45 (dd, J ¼ 6.4 and 13.6 Hz, 1H),
4.71 (dd, J ¼ 6.0 and 14.0 Hz, 1H), 7.32–7.40 (m, 2H), 7.54–7.61
(m, 1H), 7.69 (t, J ¼ 1.6 Hz, 1H), 7.79 (t, J ¼ 1.6 Hz, 1H), 7.88
(d, J ¼ 7.2 Hz, 1H), 9.24 (s, 1H); 13C NMR (d6-DMSO): d 26.1, 27.9,
46.8, 48.4, 119.6, 122.6, 126.5, 126.7, 129.1, 131.5, 133.9, 135.9,
144.2, 197.1; Anal. calcd. for C14H15ClN2O: C 64.00, H 5.75, N 10.66.
Found: C 64.26, H 5.51, N 10.47.
14.89 (br s, 1H); 13C NMR (d6-DMSO):
d 38.6, 45.9, 68.5,
119.6, 119.9, 122.0, 127.9, 131.0, 135.3, 144.6; Anal. calcd.
for C12H14BrClN2O: C 45.38, H 4.44, N 8.82. Found: C 45.54,
H 4.26, N 9.01.
(ꢀ)-1-(4-Biphenyl-1-yl)-3-(1H-imidazol-1-yl)-1-propanol 47
Colorless crystals, 590 mg (71%), mp 141–1428C (2-propanol)
(lit. mp 144–1458C [34]); 1H NMR (CDCl3): d 2.04–2.25 (m, 2H),
3.99–4.09 (m, 1H), 4.19–4.29 (m, 1H), 4.53 (dd, J ¼ 3.6 and 8.8 Hz,
1H), 4.58 (br s, 1H), 6.93 (s, 1H), 6.97 (s, 1H), 7.31–7.47 (m, 6H),
7.53–7.60 (m, 4H); 13C NMR (CDCl3): d 40.0, 43.8, 69.9, 118.9,
126.3, 127.2, 127.4, 127.5, 128.9, 129.3, 137.5, 140.7, 140.8,
General procedure for the reduction of imidazole–ketones
To the solution of imidazole–ketone (3 mmol) in methanol
(20 mL), NaBH4 (342 mg, 9 mmol) was added in small portions,
ß 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

Arch. Pharm. Chem. Life Sci. 2013, 346, 110–118
Novel Imidazoles as Antifungal Agents
117
(ꢀ)-1-(2 0-(4-Bromobenzyloxy)phenyl)-3-(1H-imidazol-1-yl)-
143.5; Anal. calcd. for C18H18N2O: C 77.67, H 6.52, N 10.06. Found:
C 77.85, H 6.33, N 9.89.
1-propanol 53
Colorless crystals, 870 mg (75%), mp 131–1328C (2-propanol);
1H NMR (CDCl3): d 2.02–2.26 (m, 2H), 3.85 (br s, 1H), 3.97–4.07
(m, 1H), 4.15–4.26 (m, 1H), 4.83 (dd, J ¼ 3.2 and 9.2 Hz, 1H), 4.94
(dd, J ¼ 11.6 and 24.4 Hz, 2H), 6.78 (s, 1H), 6.87 (d, J ¼ 8.0 Hz, 1H),
6.91 (s, 1H), 7.01 (t, J ¼ 7.6 Hz, 1H), 7.15 (d, J ¼ 8.4 Hz, 2H), 7.21–
7.27 (m, 1H), 7.41 (s, 1H), 7.44–7.51 (m, 3H); 13C NMR (CDCl3): d 38.0,
43.8, 65.9, 69.4, 111.7, 118.9, 121.6, 122.2, 126.8, 128.7, 129.1, 129.2,
132.0, 132.6, 135.7, 137.6, 155.0; Anal. calcd. for C19H19BrN2O2:
C 58.93, H 4.95, N 7.23. Found: C 59.13, H 5.09, N 7.11.
(ꢀ)-3-(1H-Imidazol-1-yl)-(naphthalen-1-yl)-1-propanol 48
Tan crystals, 535 mg (71%), mp 152–1538C (2-propanol); 1H NMR
(CDCl3): d 2.10–2.35 (m, 2H), 3.99–4.11 (m, 1H), 4.27–4.39 (m, 1H),
4.49 (br s, 1H), 5.20 (dd, J ¼ 3.0 and 9.4 Hz, 1H), 6.92 (s, 1H), 6.97
(s, 1H), 7.35–7.51 (m, 4H), 7.65–7.73 (m, 2H), 7.75 (d, J ¼ 8.4 Hz,
1H), 7.83 (d, J ¼ 8.0 Hz, 1H); 13C NMR (CDCl3): d 39.2, 44.0, 66.9,
118.9, 122.6, 123.0, 125.6, 125.7, 126.3, 128.1, 129.1, 129.5, 130.1,
133.9, 137.8, 140.1; Anal. calcd. for C16H16N2O: C 76.16, H 6.39,
N 11.10. Found: C 76.31, H 6.12, N 11.31.
(ꢀ)-1-(2 0-(3,4-Dichlorobenzyloxy)phenyl)-3-(1H-imidazol-
(ꢀ)-3-(1H-Imidazol-1-yl)-(naphthalen-2-yl)-1-propanol
1-yl)-1-propanol hydrochloride 54
hydrochloride 49
Colorless crystals, 845 mg (68%), mp 115–1168C (ethanol);
1H NMR (d6-DMSO): d 1.95–2.09 (m, 1H), 2.13–2.27 (m, 1H),
4.23–4.43 (m, 2H), 4.86 (dd, J ¼ 2.4 and 8.8 Hz, 1H), 5.11
(dd, J ¼ 13.2 and 14.4 Hz, 2H), 5.55 (br s, 1H), 6.94–7.03 (m, 2H),
7.17–7.25 (m, 1H), 7.35 (dd, J ¼ 1.6 and 8.4 Hz, 1H), 7.47 (dd, J ¼ 1.2
and 7.6 Hz, 1H), 7.61 (s, 1H), 7.65–7.72 (m, 2H), 7.75 (s, 1H), 9.21
(s, 1H), 14.79 (br s, 1H); 13C NMR (d6-DMSO): d 37.3, 45.9, 63.2, 67.7,
111.8, 119.6, 120.9, 122.0, 126.3, 127.4, 127.9, 129.2, 130.3, 130.8,
131.1, 133.2, 135.4, 138.4, 153.8; Anal. calcd. for C19H19Cl3N2O2:
C 55.16, H 4.63, N 6.77. Found: C 55.29, H 4.44, N 6.90.
Colorless crystals, 657 mg (76%), mp 165–1668C (2-propanol);
1H NMR (d6-DMSO): d 2.14–2.25 (m, 1H), 2.25–2.36 (m, 1H),
4.28–4.44 (m, 2H), 4.72 (dd, J ¼ 3.6 and 8.8 Hz, 1H), 5.80
(br s, 1H), 7.44–7.55 (m, 3H), 7.67 (t, J ¼ 1.6 Hz, 1H), 7.82–7.92
(m, 5H), 9.23 (s, 1H), 14.82 (br s, 1H); 13C NMR (d6-DMSO):
d 38.6, 46.0, 69.2, 119.6, 122.1, 123.9, 124.3, 125.6, 126.1,
127.5, 127.7, 132.3, 132.8, 135.3, 142.6; Anal. calcd. for
C16H17ClN2O: C 66.55, H 5.93, N 9.70. Found: C 66.37, H 6.05,
N 9.86.
Antifungal evaluation
(ꢀ)-3-(1H-Imidazol-1-yl)-1-(thiophen-2-yl)-1-propanol 50
Colorless crystals, 410 mg (66%), mp 102–1038C (2-propanol–
hexanes); 1H NMR (CDCl3): d 2.15–2.32 (m, 2H), 4.01–4.09
(m, 1H), 4.20–4.29 (m, 1H), 4.54 (br s, 1H), 4.74 (dd, J ¼ 4.6 Hz
and 9.0 Hz, 1H), 6.90–6.97 (m, 3H), 6.98 (s, 1H), 7.23 (dd, J ¼ 1.2
and 4.8 Hz, 1H), 7.46 (s, 1H); 13C NMR (CDCl3): d 40.1, 43.7, 65.8,
119.0, 123.7, 124.7, 126.9, 129.1, 137.5, 148.7; Anal. calcd.
for C10H12N2OS: C 57.67, H 5.81, N 13.45. Found: C 57.43,
H 5.98, N 13.27.
In vitro antifungal susceptibility was evaluated using the guide-
lines of EUCAST EDef. 7.1 [35]. Fluconazole was used as positive
control. The tests were performed in RPMI-1640 medium buf-
fered with MOPS, and supplemented with 2% glucose. From each
compound to be tested, a stock solution containing 12,800 mg/
mL was prepared by dissolving 100 mg substance in 7.8 mL
DMSO. Fluconazole was dissolved in pure, sterile water. The
solutions of the tested compounds were prepared by a serial
twofold dilution starting from the stock solutions, with the view
to reach the following final concentrations: 64, 32, 16, 8, 4, 2, 1,
0.5, 0.25, and 0.125 mg/L. The 96-well microplates containing the
solutions of the tested compounds at these concentrations were
prepared and stored in a freezer at approximately ꢂ208C until
they were used (but no more than 1 month). The final content of
the inoculum was adjusted to 105 CFU/mL. MIC values were
determined spectrophotometrically, by measuring the absorb-
ance at 450 nm using an MR-96A microplate reader after 24 or
48 h (depending on the species) of incubation at 368C. The MIC
endpoint was defined as the lowest concentration of tested
compound for which at least a reduction of 50% in growth
compared to that of the negative control (no tested compound
in the well) was noticed, as reflected by measurements of the
optical density.
(ꢀ)-3-(1H-Imidazol-1-yl)-1-(2 0-(4-methylbenzyloxy)-
phenyl)-1-propanol 51
Colorless crystals, 665 mg (69%), mp 128–1298C (2-propanol);
1H NMR (CDCl3): d 2.05–2.28 (m, 2H), 2.37 (s, 3H), 3.74 (br s,
1H), 3.96–4.07 (m, 1H), 4.09–4.20 (m, 1H), 4.82 (dd, J ¼ 3.6 and
9.6 Hz, 1H), 4.98 (dd, J ¼ 11.2 and 19.2 Hz, 2H), 6.76 (s, 1H), 6.89–
7.03 (m, 3H), 7.15–7.27 (m, 5H), 7.37 (s, 1H), 7.41 (dd, J ¼ 1.2 and
7.6 Hz, 1H); 13C NMR (CDCl3): d 21.3, 38.0, 43.9, 66.6, 70.2, 111.9,
118.9, 121.3, 126.7, 127.7, 128.6, 129.3, 129.5, 132.4, 133.6, 137.5,
138.2, 155.5; Anal. calcd. for C20H22N2O2: C 74.51, H 6.88, N 8.69.
Found: C 74.34, H 7.03, N 8.54.
(ꢀ)-1-(2 0-(4-Chlorobenzyloxy)phenyl)-3-(1H-imidazol-1-
yl)-1-propanol 52
The research leading to these results has received funding from the
European Union’s Seventh Framework Programme (FP7/2007–2013)
under grant agreement no. 264115 – STREAM.
Colorless crystals, 845 mg (82%), mp 144–1458C (2-propanol);
1H NMR (CDCl3): d 1.99–2.11 (m, 1H), 2.14–2.25 (m, 1H), 3.94–
4.05 (m, 1H), 4.11 (br s, 1H), 4.15–4.26 (m, 1H), 4.83 (dd, J ¼ 3.2
and 9.6 Hz, 1H), 4.95 (dd, J ¼ 11.6 and 26.4 Hz, 2H), 6.77 (s, 1H),
6.87 (d, J ¼ 8.0 Hz, 1H), 6.90 (s, 1H), 7.01 (t, J ¼ 7.6 Hz, 1H), 7.17–
7.26 (m, 3H), 7.31 (d, J ¼ 8.4 Hz, 2H), 7.39 (s, 1H), 7.48 (dd, J ¼ 1.2
and 7.6 Hz, 1H); 13C NMR (CDCl3): d 37.9, 43.8, 65.7, 69.4, 111.7,
118.9, 121.5, 126.8, 128.6, 128.8, 129.0, 129.2, 132.7, 134.1, 135.2,
137.6, 155.0; Anal. calcd. for C19H19ClN2O2: C 66.57, H 5.59, N
8.17. Found: C 66.41, H 5.77, N 8.06.
The authors have declared no conflict of interests.
References
[1] S. K. Fridkin, W. R. Jarvis, Clin. Microbiol. Rev. 1996, 9, 499–511.
ß 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

118
G. Roman et al.
Arch. Pharm. Chem. Life Sci. 2013, 346, 110–118
[2] M. Nucci, A. Colombo, Eur. J. Clin. Microbiol. Infect. Dis. 2002, 21,
209–211.
[18] G. Menozzi, L. Merello, P. Fossa, S. Schenone, A. Ranise,
L. Mosti, F. Bondavalli, R. Loddo, C. Murgioni, V. Mascia,
P. La Colla, E. Tamburini, Bioorg. Med. Chem. 2004, 12, 5465–
5483.
[3] K. A. Marr, Med. Mycol. 2008, 46, 293–302.
´
[4] R. Sabino, C. Verıssimo, J. Branda˜o, C. Alves, H. Parada,
L. Rosado, E. Paixa˜o, Z. Videira, T. Tendeiro, P. Sampaio,
[19] D. Berg, E. Regel, H. E. Harenberg, M. Plempel, Arzneim.
Forsch. 1984, 34, 139–146.
C. Pais, Med. Mycol. 2010, 48, 346–354.
[20] C. E. Maxwell, Org. Syn. 1955, Coll. Vol. 3, 305–306.
[5] M. S. Lionakis, D. P. Kontoyiannis, Lancet 2003, 362, 1828–
1838.
[21] S. Kaiser, S. P. Smidt, A. Pfaltz, Angew. Chem. Int. Ed. 2006, 45,
5194–5197.
˚
[22] F. Lehman, A. Pilotti, K. Luthman, Mol. Divers. 2003, 7, 145–152.
[6] G. G. Fareau, R. Vassilopoulou-Sellin, Infect. Dis. Clin. N. Am.
2007, 21, 639–657.
[7] M. Tumbarello, E. Tacconelli, K. de Gaetano Donati,
G. Morace, G. Fadda, R. Cauda, Eur. J. Clin. Microbiol. Infect.
Dis. 1999, 18, 478–483.
[23] D. Sielemann, R. Keuper, N. Risch, J. Prakt. Chem. 1999, 341,
487–491.
[24] N. Mann, W. Back, E. Mutschler, Arch. Pharm. (Weinheim) 1973,
306, 625–631.
[8] M. A. Pfaller, D. J. Diekema, J. Clin. Microbiol. 2004, 42, 4419–
4431.
[25] S. W. Pelletier, J. Org. Chem. 1952, 17, 313–315.
[9] F. Odds, A. J. P. Brown, N. A. R. Gow, Trends Microbiol. 2003, 11,
272–279.
[26] G. R. Brown, A. M. Bamford, J. Bowyer, D. S. James,
N. Rankine, E. Tang, V. Torr, E. J. Culbert, Bioorg. Med.
Chem. Lett. 2000, 10, 575–579.
[10] J. S. Hamdan, R. C. Hahn, Anti-Infect. Agents Med. Chem. 2006, 5,
403–412.
[27] Y.-W. Ho, C.-T. Yao, J. Chin. Chem. Soc. 2003, 50, 283–296.
[11] R. Di Santo, A. Tafi, R. Costi, M. Botta, M. Artico, F. Corelli,
M. Forte, F. Caporuscio, L. Angiolella, A. T. Palamara, J. Med.
Chem. 2005, 48, 5140–5153.
[28] E. Comani¸t˘a G. Roman, I. Popovici, B. Comani¸ta˘, J. Serb. Chem.
Soc. 2001, 66, 9–16.
[29] E. B. Knott, J. Chem. Soc. 1947, 1190–1195.
[12] R. Silvestri, M. Artico, G. La Regina, A. Di Pasquali,
G. De Martino, F. D. D’Auria, L. Nencioni, A. T. Palamara,
J. Med. Chem. 2004, 47, 3924–3926.
[30] W. M. Welch, C. A. Harbert, R. Sarges, W. P. Stratten,
A. Weissman, J. Med. Chem. 1977, 20, 699–705.
[31] P. Horstmann, B. Unterhalt, Arch. Pharm. Pharm. Med. Chem.
1997, 330, 362–364.
[13] G. La Regina, F. D. D’Auria, A. Tafi, F. Piscitelli, S. Olla,
F. Caporuscio, L. Nencioni, R. Cirilli, F. La Torre, N. R.
de Melo, S. L. Kelly, D. C. Lamb, M. Artico, M. Botta, A. T.
Palamara, R. Silvestri, J. Med. Chem. 2008, 51, 3841–3855.
[32] U. Westerwelle, A. Esser, N. Risch, Chem. Ber. 1991, 124, 571–
576.
[33] A. F. Popov, Zh. P. Piskunova, V. N. Matvienko, G. P. Kondratenko,
Y. I. Nikolenko, Pharm. Chem. J. 1989, 23, 847–849.
[14] M. N. Aboul-Enein, A. Abd El-Sattar El-Azzouny, M. I. Attia,
O. A. Saleh, A. L. Kansoh, Arch. Pharm. Chem. Life Sci. 2011, 344,
794–801.
[34] D. Nardi, A. Tajana, A. Leonardi, R. Pennini, F. Portioli, M. J.
Magistretti, A. Subissi, J. Med. Chem. 1981, 24, 727–731.
[15] M. Tramontini, Synthesis 1973, 703–775.
[16] P. K. Mukherjee, M. Wang, in Antifungal Therapy (Eds: M. A.
Ghannoum, J. R. Perfect), Informa Healthcare Inc., New
York, NY 2010, p. 63–86.
[35] J. L. Rodriguez-Tudela, M. C. Arendrup, F. Barchiesi, J. Bille,
E. Chryssanthou, M. Cuenca-Estrella, E. Dannaoui, D. W.
Denning, J. P. Donnelly, F. Dromer, W. Fegeler, C. Lass-
Flo¨rl, C. Moore, M. Richardson, P. Sandven, A. Velegraki,
P. Verweij, Clin. Microbiol. Infect. 2008, 14, 398–405.
[17] S. El Hage, B. Lajoie, C. Feuillolay, C. Roques, G. Baziard, Arch.
Pharm. Chem. Life Sci. 2011, 344, 402–410.
ß 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com