Synthesis, antibacterial and antifungal activities of bifonazole derivatives

Article abstract of DOI:10.1002/ardp.201000304

Two series of chlorinated benzhydryl imidazole and triazole derivatives were synthesized and tested in vitro against representative strains of potent pathogenic bacteria (Staphylococcus aureus CIP 4.83, Escherichia hirae CIP 5855, Pseudomonas aeruginosa CIP 82118, Escherichia coli CIP 53126) and fungi (Aspergillus niger IP 1431.83, Candida albicans IP 48.72, Candida krusei IP 208.52, Trichophython rubrum IP 1657.86). Most of these compounds were devoid of any antimicrobial activity, but several of them inhibited T. rubrum with MIC values in the range of 0.125 to 32 μg/mL, similar or superior to those of bifonazole and clotrimazole, used as standard controls. The replacement of the imidazole ring with a triazole moiety in these compounds led to derivatives with less antifungal activity. A preliminary SAR was undertaken on the effect of the number and the position of chlorine atoms on the distribution of negative charge on the surface of some compounds on antifungal activity. Copyright

Full text of DOI:10.1002/ardp.201000304

402
Arch. Pharm. Chem. Life Sci. 2011, 11, 402–410
Full Paper
Synthesis, Antibacterial and Antifungal Activities
of Bifonazole Derivatives
´
Salome El Hage, Barbora Lajoie, Catherine Feuillolay, Christine Roques, and Genevieve Baziard
`
´
Universite Toulouse III, Faculte de Pharmacie, LU- 49, Toulouse, France
´
Two series of chlorinated benzhydryl imidazole and triazole derivatives were synthesized and tested
in vitro against representative strains of potent pathogenic bacteria (Staphylococcus aureus CIP 4.83,
Escherichia hirae CIP 5855, Pseudomonas aeruginosa CIP 82118, Escherichia coli CIP 53126) and fungi
(Aspergillus niger IP 1431.83, Candida albicans IP 48.72, Candida krusei IP 208.52, Trichophython rubrum
IP 1657.86). Most of these compounds were devoid of any antimicrobial activity, but several of them
inhibited T. rubrum with MIC values in the range of 0.125 to 32 mg/mL, similar or superior to those of
bifonazole and clotrimazole, used as standard controls. The replacement of the imidazole ring with a
triazole moiety in these compounds led to derivatives with less antifungal activity. A preliminary SAR
was undertaken on the effect of the number and the position of chlorine atoms on the distribution of
negative charge on the surface of some compounds on antifungal activity.
Keywords: Antibacterial activity / Antifungal activity / Imidazole derivatives / Triazole derivatives
Received: October 12, 2010; Revised: November 23, 2010; Accepted: November 30, 2010
DOI 10.1002/ardp.201000304
Introduction
ing the antifungal potency and selectivity and improving the
bio-availability.
In the recent years, the widespread use of antifungal and
antibacterial agents has resulted in the development of
multi-drug resistant pathogens causing an increase in mor-
bidity and mortality, particularly in immuno-compromised
hosts [1]. The class of azoles (imidazole and triazole deriva-
tives) has given rise to many effective antifungal drugs that
are currently in clinical use. The mechanism of their anti-
fungal action includes the inhibition of cytochrome
P45014DM which is essential for ergosterol biosynthesis at
the step of lanosterol 14-demethylation [2, 3]. The under-
standing of their therapeutic target and the identification
of the pharmacophore responsible for their activity has led to
the development of new promising antifungal molecules.
Since the discovery of bifonazole, used in the therapy of
various dermatomycoses, many modifications to the struc-
ture of azoles have been carried out, with the goal of increas-
Bifonazole is derived from the structure of clotrimazole
but contains no halogen atoms (Fig. 1). Fluorine or chlorine
atoms are present as common substituents on the aromatic
rings of the next generation of the most potent antifungal
azoles (imidazole or triazole derivatives) such as clotrimazole,
fluconazole, voriconazole, ketoconazole. Different studies
[3, 4] have shown that the introduction of halosubstituents
on the phenyl rings linked to the pyrazole nucleus of bifona-
zole analogs produced modifications in the microbiological
profile. In particular, derivatives bearing 2 or 3 chlorine atoms
emerged as the most interesting antifungal or antibacterial
compounds. In parallel, it was found that triazole compounds
showed better antimicrobial activity and lower toxicity than
imidazole derivatives [5]. In order to improve the antifungal
and antibacterial activities of bifonazole, we have carried out
various structural modifications such as the introduction of
chlorine atoms on the aromatic rings and the replacement of
the imidazole ring by a triazole nucleus.
In this paper, we present the synthesis and the in-vitro
biological evaluation of some halogenated bifonazole deriva-
tives in order to investigate their preliminary structure–
activity relationships (SARs).
`
Correspondence: Prof. Genevieve Baziard, Universite Toulouse III,
Faculte de Pharmacie, LU- 49, Toulouse 31062 Cedex 09, France.
E-mail: baziard@cict.fr
Fax: þ33562256881
´
´
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Arch. Pharm. Chem. Life Sci. 2011, 11, 402–410
Bifonazole Derivatives
403
benzoyl chloride with halogenobenzene in the presence
of aluminium trichloride. Usually imidazole and triazole
derivatives were synthesized directly from alcohols with
1,10-carbonyldiimidazole (CDI) under mild conditions [6].
However, as it has been reported in the literature [7, 8],
the treatment of compounds 2a and 2i led to the corre-
sponding carbamates 4a and 4i, but the subsequent
decarboxylation by heating in refluxing toluene, gave
N-imidazole derivatives 5a and 5i in very low yields.
Therefore, in order to obtain the required imidazole and
triazole derivatives, we followed another route: treatment
of carbinols with SOCl2 and successive reactions of crude
chloro derivatives with 1,3-imidazole or 1,2,4-triazole in
the presence of triethylamine.
Cl
N
N
N
N
Bifonazole
Clotrimazole
Figure 1. Structures of bifonazole and clotrimazole.
Results and discussion
Chemistry
Biological activities
The synthesis of carbamates 4a, 4i, imidazoles 5a–i and
triazoles 6b–j derivatives is depicted in Scheme 1.
Non-commercially available carbinols 2b, 2c, 2e, 2f, 2h–j
were obtained by sodium borohydride reduction of com-
mercially accessible ketones (1b, 1c, 1e, 1f, 1j), or ketones
synthesized in our laboratory (1h, 1i) by the reaction of
The prepared compounds 5–6 were evaluated in vitro for their
antimicrobial activities against representative Gram-positive
and Gram-negative bacterial strains (S. aureus CIP 4.83, E. hirae
CIP 5855, P. aeruginosa CIP 82118, E. coli CIP 53126) and fungal
species (C. albicans IP 48.72, A. niger IP 1431.83, C. krusei
IP 208.52, T. rubrum IP 1657.86). The determined minimal
R2
R2
R2
R4
R4
R4
NaBH4
MeOH
SOCl2
C
O
CH
OH
CH
R1
Cl
3 a-i
R1
R1
R3
R3
R3
2 a-i
CDI
1 a-i
H
N
H
N
N
N
N
R2
R2
R2
R4
CH
O
R4
R4
CH
CH
R1
R3
N
N
R1
CO
R1
N
R3
R3
N
N
N
N
4a, 4i
5 a-i
6 b-j
R1
H
R2
R3
H
H
H
H
H
H
4-Cl
R4
H
H
H
H
H
H
H
H
H
H
H
H
a
b
c
d
e
f
2-Cl
3-Cl
4-Cl
2-Cl 4-Cl
3-Cl 4-Cl
4-Cl
H
g
h
i
2-Cl 4-Cl 4-Cl
2-Cl 4-Cl 2-Cl 4-Cl
C6H5
H
H
H
j
Scheme 1. Schematic diagram showing the synthesis of compounds 4, 5 and 6.
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404
S. El Hage et al.
Arch. Pharm. Chem. Life Sci. 2011, 11, 402–410
Table 1. In-vitro antibacterial activity of compounds 5a–i and 6b–j (MIC and MBC in mg/mL).
Compounds
Microorganisms
P. aeruginosa CIP 82118
S. aureus CIP 4.83
E. hirae CIP 5855
E. coli CIP 53126
MIC
MBC
MIC
MBC
MIC
MBC
MIC
MBC
5a
5b
5c
5d
5e
5f
5g
5h
5i
6b
6c
6d
6e
32
256
128
256
256
16
64
512
512
512
512
256
512
64
512
512
512
512
512
512
256
512
256
128
0.25
256
256
256
256
256
256
256
16
512
256
512
512
512
512
256
512
256
128
0.25
512
512
512
512
512
512
512
16
512
256
512
512
512
512
256
512
256
128
0.25
256
256
256
256
256
256
512
256
256
128
256
256
256
256
128
256
128
64
512
512
512
512
512
512
512
512
512
256
512
512
512
512
256
512
256
128
0.25
512
512
512
512
512
256
512
256
512
256
512
512
512
512
256
512
256
128
0.25
512
512
512
512
512
512
512
512
512
256
512
512
512
512
256
512
256
128
0.25
256
16
256
512
512
512
512
512
256
512
256
128
0.25
6f
6g
6h
6i
6j
Ciprofloxacin
0.25
Table 2. In-vitro antifungal activity of compounds 5a–i and 6b–j (MIC and MFC in mg/mL).
Compounds
Microorganisms
C. albicans IP 208.52
A. niger IP 1431.83
C. krusei IP 1657.86
T. rubrum
MIC MFC
MIC
MFC
MIC
MFC
MIC
MFC
5a
5b
5c
5d
5e
5f
5g
5h
5i
6b
6c
6d
6e
16
4
32
128
16
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
32
32
16
32
128
128
16
256
256
128
128
128
256
256
128
256
128
64
32
64
64
64
32
32
64
128
256
64
256
64
256
256
32
256
256
512
512
256
256
256
256
256
64
2
0.5
2
32
8
8
32
16
16
128
16
128
256
256
128
256
256
128
256
256
256
256
128
256
256
64
8
32
0.125
4
16
4
32
8
128
64
128
512
128
512
128
512
256
512
512
256
256
256
128
4
128
256
16
128
128
256
256
256
256
128
256
128
64
128
64
256
256
128
512
256
256
128
128
8
16
6f
6g
6h
6i
256
128
256
128
64
6j
Bifonazole
Clotrimazole
128
4
256
8
128
0.125
128
0.5
4
0.25
1
8
inhibitory concentrations (MIC) and minimal germicidal con-
centrations (MBC or MFC) are reported in Tables 1 and 2.
Bifonazole, clotrimazole and ciprofloxacin were used as refer-
ence drugs in the antifungal and antibacterial assays.
Antibacterial activity
Most of the tested compounds were devoid of any antibacte-
rial activity. Only compounds 5a, 5f and 5h showed
weak inhibition against S. aureus (MIC/MBC: 32/64 mg/mL,
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Arch. Pharm. Chem. Life Sci. 2011, 11, 402–410
Bifonazole Derivatives
405
16/256 mg/mL and 16/64 mg/mL, respectively) and compound
5h against E. hirae (MIC/MBC: 16/16 mg/mL).
volume and superficial area, partial atomic charges (electro-
static potential), and the energy of the HOMO and LUMO
frontier orbitals (ionization potential, hardness, polarizabil-
ity). The calculated values are listed in Table 3.
Antifungal activity
All synthesized imidazole compounds 5 showed inhibitory
effects against T. rubrum, with MIC in the range of 0.125 to
32 mg/mL, comparable to those of bifonazole and clotrima-
zole. Compound 5b, containing one chlorine atom at the
2-position of the phenyl ring, and compound 5e, bearing two
chorine atoms on the same benzyl ring at the 2- and
4-positions, emerged as the most potent derivatives with
an MIC/MFC of 0.5/8 mg/mL and 0.125/16 mg/mL, respectively.
Other compounds turned out to be weakly effective against
the tested yeast species and only compound 5b showed
similar activity to that of bifonazole against A. niger (MIC
4 mg/mL). The MIC values (MIC/MFC: 16/64 mg/mL and
16/128 mg/mL respectively) for compounds 5c and 5g against
C. albicans, and the MIC/MFC: 16/32 mg/mL of compound 5h
against C. krusei, demonstrated their antifungal activity
superior to that of bifonazole towards these fungi.
Imidazole derivatives 5 had higher antifungal activity than
the triazoles 6 towards the different fungal strains tested.
Only compounds 6b and 6e showed weak inhibitor activity
against T. rubrum (MIC/MFC: 8/64 mg/mL and 16/128 mg/mL,
respectively).
Geometry of compounds
Our molecules show limited flexibility due to the presence of
two aromatic rings near to the azole moiety. Moreover, the
presence of chlorine atoms on the aromatic rings can
decrease their ability to rotate. Consequently, the phenyl
rings are disposed in perpendicular planes and only the azole
ring, linked by a single bond to the aromatic rings, can rotate
around 1808. The difference in the heat of formation for
these two conformers is inferior to 1 kJ/mol for compounds
5, except for compounds 5e and 5h with a difference of about
2 kJ/mol. These conformers could instead easily convert one
into the other.
logP, molecular volume and surface
These data have become a key parameter in studies of ADMET
properties. The lipophilic character is described by log P. The
range of the calculated values of log P of the imidazole 5 and
triazole 6 derivatives was between 3.08 and 5.94; these values
were similar to those of bifonazole and clotrimazole. We
observed a slight rise in the lipophilicity with the increasing
number of chlorine atoms on the aromatic rings.
The replacement of the imidazole moiety of bifonazole
with a triazole ring (compound 6j) led to a significant
decrease in the antifungal activity against T. rubrum, the
MIC/MFC was 4/8 mg/mL for bifonazole and 64/128 mg/mL
for compound 6j.
Small molecules exhibit faster diffusion rates through the
cell membrane than the large ones [9]. The size of molecules
may play a key role in their entry into cells. The azole
derivatives 5 and 6 are small molecules, with surfaces
2
between 264 and 345 A and volumes between 298 and
˚
Thus, the results of the microbiological assays showed that
the presence of the imidazole ring, and the number of
chlorine atoms and their position on the aromatic ring,
had a notable effect on the antifungal activity. As already
observed [3, 4] the number and the position of chloro sub-
stituents on phenyl rings have emerged as determinant fac-
tors for antifungal activities, but we did not find the
beneficial effect of the triazole ring as described in the liter-
ature [5].
3
387 A , inferior to that of bifonazole and clotrimazole,
˚
and therefore may interact with the active site of the target
without steric hinderance.
Molecular electrostatic potential
The results of molecular modeling showed (Fig. 2) several
areas of negative potential situated on the nitrogen atom of
the azole ring and on the aromatic ring bearing chlorine
atoms. The negative charge on the nitrogen N(3) of the
imidazole derivatives 5 dropped from ꢀ0.31 to ꢀ0.29,
increasing with the number of chlorine atoms on the phenyl
rings; these values are close to that of bifonazole (ꢀ0.303) and
clotrimazole (ꢀ0.296). For the triazole derivatives 6, that
showed no antifungal activity, the negative charge of the
triazole ring is shared between the two nitrogen atoms N(2)
and N(4). The negative charge of N(2) is about ꢀ0.25 and of
N(4) ꢀ0.31, greater than that of the nitrogen N(3) of the
imidazole ring. It is possible that these electronic character-
istics of azole compounds are not suitable for antifungal
activity, as demonstrated by the lower efficacy of the triazole
derivatives in comparison with the imidazole derivatives.
Structure–activity relationship
We were interested in assigning the appropriate molecular
parameters required for the optimal binding of azole anti-
fungal compounds to the active site of cytochrome P450 and
their ability to be efficient antifungals. The introduction of
chlorine atoms on the phenyl ring linked to the azole ring led
to modifications in the physico-chemical properties and con-
sequently these parameters can affect the affinity of mol-
ecules for the iron of the heme binding site.
Therefore in this study, parallel to the microbiological
assays, we calculated the following molecular properties to
be correlated with the biological activity: logP, molecular
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Arch. Pharm. Chem. Life Sci. 2011, 11, 402–410
Table 3. Calculated molecular properties of compounds 5a–i and 6b–i.
3
Volume (A ) /
No
Number/Position
of chlorine
MW
HOMO /
LUMO (eV)
Hardness (h)
(LUMO–HOMO)/2
Charge azoleꢁ
logP
˚
˚
2
Area (A )
5a
5b
5c
5d
5e
5f
5g
5h
5i
6b
6c
6d
6e
0
234.3
268.8
268.8
268.8
303.2
303.2
303.2
337.6
372.1
269.7
269.7
269.7
304.2
304.2
304.2
338.6
373.1
311.4
311.4
345.8
298.4 / 264.4
320.1 / 274.8
324.2 / 283.8
324.9 / 283.7
346.9 / 294.1
348.4 / 300.2
349.5 / 302.7
372.5 / 313.6
386.7 / 319.1
315.2 / 270.9
317.4 / 285.7
318.3 / 285.4
341.4 / 298.4
341.0 / 302.1
341.5 / 302.5
364.1 / 315.1
382.5 / 316.4
386.5 / 345.2
393.1 / 343.2
406.1 / 320.9
ꢀ9.260 / ꢀ0.254
ꢀ9.336 / ꢀ0.465
ꢀ9.392 / ꢀ0.478
ꢀ9.390 / ꢀ0.500
ꢀ9.368 / ꢀ0.918
ꢀ9.477 / ꢀ0.761
ꢀ9.501 / ꢀ0.744
ꢀ9.492 / ꢀ1.030
ꢀ9.559 / ꢀ1.019
ꢀ9.801 / ꢀ0.480
ꢀ9.699 / ꢀ0.560
ꢀ9.642 / ꢀ0.563
ꢀ9.814 / ꢀ0.848
ꢀ9.628 / ꢀ0.798
ꢀ9.697 / ꢀ0.766
ꢀ9.736 / ꢀ0.968
ꢀ9.883 / ꢀ1.105
ꢀ9.279 / ꢀ0.395
ꢀ9.263 / ꢀ0.373
ꢀ9.227 / ꢀ0.395
4.503
4.436
4.457
4.445
4.225
4.358
4.379
4.231
4.270
4.661
4.555
4.540
4.483
4.415
4.466
4.384
4.389
4.442
4.445
4.416
ꢀ0.3037
ꢀ0.3026
3.08
3.68
3.68
3.68
4.29
4.15
4.27
4.88
5.94
3.64
3.64
3.64
4.24
4.11
4.23
4.84
5.45
4.80
4.80
5.44
1
1
1
2
2
2
3
4
1
1
1
2
2
2
3
4
0
2
3
4
2,4
ꢀ0.3015
ꢀ0.3014
ꢀ0.2965
3,4
ꢀ0.3000
4,40
2,4,40
2,20,4,40
2
ꢀ0.2976
ꢀ0.2942
ꢀ0.2933
ꢀ0.2403 / ꢀ0.3250
ꢀ0.2494 / ꢀ0.3133
ꢀ0.2483 / ꢀ0.3137
ꢀ0.2522 / ꢀ0.3148
ꢀ0.2497 / ꢀ0.3123
ꢀ0.2521 / ꢀ0.3116
ꢀ0.2546 / ꢀ0.3113
ꢀ0.2419 / ꢀ0.3217
ꢀ0.2475 / ꢀ0.3155
ꢀ0.3034
3
4
2,4
6f
6g
6h
6i
3,4
4,40
2,4,40
2,20,4,40
6j
Bifonazole
Clotrimazole
0
1
ꢀ0.2958
ꢁ
Charge on: N(3) for compounds 5; N(2)/N(4) for compounds 6.
The negative charge of aromatic rings arises at the site of the
chlorine atoms. The chlorine atoms at position 2 of the most
active compounds 5b and 5e induce a zone of negative poten-
tial in the central part of the molecule (Fig. 2), while
the chlorine at the 4-position causes the dispersion of negative
charge at the extremity of the phenyl ring, as in the less active
compounds 5g and 5i (Fig. 2). We observed a similar distri-
bution of electrostatic potential on the surface of triazole 6.
Among the triazole derivatives, only compounds 6b and 6e (2-
and 2,4-chloro derivatives) showed some inhibitory effect.
Therefore, an appropriate electrostatic potential distribution
seems indispensable for antifungal activity.
Energies of the frontier molecular orbitals (ELUMO
and EHOMO)
Chemical hardness is closely related to the polarizability that
can measure the ability of a ligand to participate in covalent
bond formation with iron at the enzyme binding site. This
parameter can be expressed using the energies of the frontier
molecular orbitals:
h ¼ ðELUMO ꢀ EHOMOÞ=2
(1)
The easily polarizable molecules (soft molecules) have a
small HOMO–LUMO gap, that corresponds to small excitation
energies to the manifold of excited states. Consequently, the
hard molecules have a large HOMO–LUMO gap.
Figure 2. Molecular electrostatic potential of compounds 5b, 5e, 5g
and 5i. Imidazole derivatives shown as sticks colored by element
(carbon: grey ; hydrogen: white ; nitrogen and chlorine: black) with
the molecular surface colored according to the distribution of the
electrostatic potential (black: negative potential, white: positive
potential). Images were generated using Accelrys DS visualizer
2.0, with Mopac 2009 molecular modeling data.
We observed that the hardness of azole derivatives
decreased slightly with the increasing number of chlorine
atoms linked to the aromatic rings. These values are very
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Arch. Pharm. Chem. Life Sci. 2011, 11, 402–410
Bifonazole Derivatives
407
close for all the compounds but the most active compound 5e
had the lowest hardness (4.225) whereas the triazole deriva-
tives had the highest. Consequently, this parameter is not a
discriminating factor for biological activity.
General procedure for the preparation of compounds 2b,
2c, 2e, 2f, 2h–j
A solution of ketone (20 mmol) in methanol (200 mL) was treated
with sodium borohydride (5.5 mmol) and stirred at room
temperature, until the disappearance of the ketone, and then
evaporated under reduced pressure. The crude pale yellow oil
was dissolved in water (100 mL), extracted with ether
(3 ꢃ 50 mL), dried over Na2SO4 and evaporated. The resulting
colorless oil solidified to give a crystalline solid.
The physico-chemical data of compounds 2b–c [13], 2e [14], 2f
[15], 2h [14], 2i [16], 2j [17] are in agreement with the literature
data.
Conclusion
Our goal was the synthesis and evaluation of the antibacterial
and antifungal activities of relative small and structurally
simple compounds that were derivatives of bifonazole. We
describe the synthesis of eighteen imidazole and triazole
derivatives with the majority of them being new compounds.
These compounds had no antibacterial activity, like bifona-
zole and clotrimazole, against strains representative of
potent pathogenic Gram negative and Gram positive bac-
teria. However, several of these new compounds (particularly
5b and 5e) may be considered as highly potential antifungal
agents against T. rubrum.
General procedure for the preparation of compounds 3b,
3c, 3e, 3f, 3h–j
A mixture of benzhydrol (20 mmol) in an excess of thionyl
chloride (10 mL) was stirred at r.t. for about 24 h. The trans-
formation of benzhydrol to chloride was monitored by IR, until
the disappearance of the absorption bands of the hydroxyl group
at 3330 cmꢀ1. The mixture was then evaporated under reduced
pressure. The brownish oily residue was dissolved in acetonitrile
(30 mL) and evaporated to remove the rest of the SOCl2. The
crude product was used without further purification.
With the aim of investigating the effect of physico-chemi-
cal properties on antifungal activity, the correlation of anti-
fungal activity against T. rubrum (log MIC) and different
calculated descriptors (electronic, physico-chemical, topo-
logic) was evaluated by using the multiple linear regression
(MLR) method (using XLStatistics software [10]) but no sta-
tistically significant relationship between the experimental
activity and any of the calculated properties was found
(supplementary material S1). However there was a corre-
lation found between the distribution of negative charge
on the molecules and antifungal activity.
General procedure for the preparation of compounds 4a
and 4i
A solution of carbinol 2a or 2i (10 mmol) and 1,10-carbonyldi-
imidazole (20 mmol) in dry toluene (150 mL) was refluxed for
4 h. After being cooled, the solvent was removed and the residue
was dissolved in ethyl acetate (300 mL). The organic solution
was washed with brine (3 ꢃ 200 mL) and dried over MgSO4.
The removal of the solvent afforded the crude product, which
was purified by recrystallization from ethanol or by column
chromatography on silica gel using DCM as eluent.
Experimental
Benzhydryl-oxycarbonyl-1H-imidazole 4a
Yield: 73%; m.p.: 126.58C; IR (KBr) n cmꢀ1 : 3150–3000 (CH), 1760
Chemistry
1
(C O), 1600, 1480 (C C); H-NMR (CDCl ) d: 8.21 (s, 1H, imidazole-
–
–
–
–
Melting points were determined on a DSC-50 Shimadzu appa-
ratus (Kyoto, Japan). Infra-red spectra were recorded on a Perkin-
Elmer Spectrum One FT IR spectrometer (Perkin-Elmer, USA).
1H- and 13C-NMR spectra were obtained in CDCl3 on a DPX
300 spectrometer (Bru¨ker Biosciences, USA), and peak positions
are given as s (singlet), d (doublet), t (triplet), q (quadruplet)
or m (multiplet). Chemical shift (d) values are given in parts
per million. Reactions were monitored by thin-layer chromatog-
raphy (TLC) using pre-coated silica gel plates 60 F-254 and prod-
uct mixtures were purified by column chromatography using
silica gel 70–200 mesh (SDS, France). All yields are calculated for
analytical pure materials. The microanalyses were performed in
the Microanalytical Laboratory of ENSIACET in Toulouse, France,
and the results obtained were within ꢂ0.4% of the theoretical
values. Commercially available compounds 1b, 1c, 1e, 1f, 1j, 2a,
3a, 3d, 3g were purchased from Acros Organics (Halluin, France).
3
H2), 7.48 (d, 1H, imidazole-H5, J ¼ 1.5 Hz), 7.39–7.35 (m, 10H,
Ar–H), 7.07 (d, 1H, imidazole-H4, J ¼ 1.5 Hz), 7.03 (s, 1H,
Ph–CH–Ph); 13C-NMR (CDCl3): 139.5 (Ar–C1 and C1 ), 135.6,
0
–
132.5 (imidazole-C2 and C ), 128.6, 128.1, 126.9 (Ar) and (C O),
4
–
117.5 (imidazole-C5), 81.1 (Ph–CH–Ph); Analysis calculated
for C17H14N2O2: C, 73.37; H, 5.07; N, 10.07. Found: C, 73.29; H,
5.19; N, 9.98.
2,20,4,40-Tetrachloro-benzhydryl-oxycarbonyl-1H-
imidazole 4i
Yield: 92%; m.p.: 818C; IR (KBr) n cmꢀ1 : 3200–3000 (CH), 1760
1
(C O), 1600, 1480 (C C); H-NMR (CDCl ) d: 8.14 (s, 1H, imidazole-H ),
–
–
–
–
3
2
7.52 (s, 1H, Ph–CH–Ph), 7.47 (d, 2H, Ar–H, J ¼ 1.9 Hz), 7.42 (d, 1H,
imidazole-H5, J ¼ 1.5 Hz), 7.28 (d, 2H, Ar–H, J ¼ 8.0 Hz), 7.17
13
(d, 2H, Ar–H, J ¼ 8.0 Hz), 7.08 (d, 1H, imidazole-H4, J ¼ 1.5 Hz);
0
C-NMR (CDCl3): 139.2 (Ar–C1 and C1 ), 135.6 (imidazole-C2 or C4),
General procedure for the preparation of compounds
1h and 1i
0
134.6, 134.1 (Ar–C2–Cl, Ar–C2 –Cl, Ar–C4–Cl and Ar–C4 –Cl),
0
–
132.5 (imidazole-C2 or C ), 130.0, 129.6, 128.4 (Ar) and (C O),
4
–
117.3 (imidazole-C5), 80.2 (Ph–CH–Ph); Analysis calculated
for C17H10N2O2Cl4: C, 49.07; H, 2.42; N, 6.73. Found: C, 49.01;
H, 2.54; N, 6.65.
Compounds 1h [11] and 1i [12] were prepared as previously
described and their physico-chemical data are in agreement with
the literature data.
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www.archpharm.com

408
S. El Hage et al.
Arch. Pharm. Chem. Life Sci. 2011, 11, 402–410
(Ar), 119.3 (imidazole-C5), 63.1 (Ph–CH–Ph); Analysis calculated
for C16H12N2Cl2: C, 63.38; H, 3.99; N, 9.24. Found: C, 63.41;
H, 3.88; N, 9.36.
General procedure for the preparation of compounds 5a–i
and 6b–j
Benzhydryl chloride derivative 3 (10 mmol) was dissolved in
dioxane (30 mL) and added dropwise to a solution of imidazole
(or 1H-1,2,4-triazole) (30 mmol) in the same solvent (20 mL).
The mixture was refluxed for several days, and the progress
of the reaction was monitored by TLC. Then the mixture was
evaporated to give a yellow oil which was dissolved in ethyl
acetate (70 mL), washed with water (3 ꢃ 50 mL), dried over
Na2SO4 and evaporated. The crude product was purified by
column chromatography on silica gel using DCM/EA as eluents.
All imidazole 5a–i and triazole 6b–j compounds gave the same
3,4-Dichlorobenzhydryl-1H-imidazole 5f
Yield: 55%; n2D2: 1.6170; 1H-NMR (CDCl3) d: 7.43–7.38 (m, 5H,
imidazole-H2 and Ar–H), 7.19 (d, 1H, Ar–H, J ¼ 2.0 Hz), 7.12–
7.10 (m, 3H, imidazole-H5 and Ar–H), 6.93 (dd, 1H, Ar–H,
J ¼ 8.5 Hz, 2.0 Hz), 6.84 (s, 1H, imidazole-H4), 6.49 (s, 1H,
Ph–CH–Ph); 13C-NMR (CDCl3): 139.4, 137.7 (Ar–C1
0
and C1 ), 137.0 (imidazole-C2), 136.0, 134.8 (Ar–C3–Cl and
Ar–C4–Cl), 130.9, 129.8, 129.6, 129.2 (Ar), 128.9 (imidazole-
C4), 128.3, 128.1, 127.2 (Ar), 119.2 (imidazole-C5), 64.1
(Ph–CH–Ph); Analysis calculated for C16H12N2Cl2: C, 63.38;
H, 3.99; N, 9.24. Found: C, 63.32; H, 4.08; N, 9.19.
IR absorption bands towards n 3000 cmꢀ1 (CH), 1600 cmꢀ1 (C C)
–
–
and 1270–1240 cmꢀ1 (C N).
–
–
The physico-chemical data of compounds 5a, 5g, and 6g [18]
are in agreement with the literature data.
2,4,40-Trichlorobenzhydryl-1H-imidazole 5h
2-Chlorobenzhydryl-1H-imidazole 5b
Yield: 23%; n2D3: 1.5953; 1H-NMR (CDCl3) d: 7.48 (d, 1H, Ar–H,
J ¼ 2.0 Hz), 7.39–7.36 (m, 3H, imidazole-H2 and Ar–H), 7.28
(dd, 1H, Ar–H, J ¼ 8.2 Hz, 2.0 Hz), 7.14 (s, 1H, imidazole-H5),
7.03 (d, 2H, Ar–H, J ¼ 8.4 Hz), 6.82 (s, 1H, Ph–CH–Ph), 6.80
(s, 1H, imidazole-H4), 6.77 (d, 1H, Ar–H, J ¼ 8.2 Hz); 13C-NMR
Yield: 65%; n2D2: 1.5672; 1H-NMR (CDCl3) d: 7.49 (dd, 1H,
Ar–H, J ¼ 7.8 Hz, 1.5 Hz), 7.44–7.38 (m, 4H, Ar–H), 7.36–
7.27 (m, 2H, imidazole-H2 and Ar–H), 7.16–7.09 (m, 3H, imid-
azole-H5 and Ar–H), 6.95 (s, 1H, imidazole-H4), 6.90 (dd, 1H,
Ar–H, J ¼ 7.8 Hz, 1.5 Hz), 6.87 (s, 1H, Ph–CH–Ph); 13C-NMR
0
(CDCl3): 137.1 (imidazole-C2), 135.6, 135.2 (Ar–C1 and C1 ),
0
134.9, 134.3 (Ar–C2–Cl and Ar–C4–Cl), 130.1, 129.8, 129.4 (Ar),
128.4 (imidazole-C4), 127.8 (Ar), 119.2 (imidazole-C5), 60.9
(Ph–CH–Ph); Analysis calculated for C16H11N2Cl3: C, 56.92;
H, 3.28; N, 8.30. Found: C, 56.80; H, 3.12; N, 8.39.
(CDCl3): 137.6, 137.5 (Ar–C1 and C1 ), 137.0 (imidazole-C2),
133.7 (Ar–C2–Cl), 130.1, 129.8, 129.3, 129.2, 128.9 (Ar), 128.9
(imidazole-C4), 128.6, 128.2, 127.3 (Ar), 119.5 (imidazole-C5),
61.9 (Ph–CH–Ph); Analysis calculated for C16H13N2Cl: C, 71.51;
H, 4.88; N, 10.42. Found: C, 71.45; H, 4.96; N, 10.49.
2,20,4,40-Tetrachlorobenzhydryl-1H-imidazole 5i
3-Chlorobenzhydryl-1H-imidazole 5c
Yield: 36%; m.p.: 1348C; 1H-NMR (CDCl3) d: 7.51 (d, 2H, Ar–H,
J ¼ 2 Hz), 7.37 (s, 1H, imidazole-H2), 7.28 (dd, 2H, Ar–H,
J ¼ 8.4 Hz, 2.0 Hz), 7.16 (s, 1H, imidazole-H5), 7.07 (s, 1H,
Ph–CH–Ph), 6.79 (s, 1H, imidazole-H4), 6.71 (d, 2H, Ar–H,
J ¼ 8.4 Hz); 13C-NMR (CDCl3): 137.4 (imidazole-C2), 135.6,
Yield: 53%; n2D2: 1.6117; 1H-NMR (CDCl3) d: 7.43 (s, 1H, Ar–H),
7.42–7.31 (m, 5H, imidazole-H2 and Ar–H), 7.10–7.14 (m, 4H,
imidazole-H5 and Ar–H), 6.97 (m, 1H, Ar–H), 6.86 (s, 1H,
imidazole-H4), 6.50 (s, 1H, Ph–CH–Ph); 13C-NMR (CDCl3):
0
0
0
141.2 (imidazole-C2), 138.2, 137.2 (Ar–C1 and C1 ), 134.9
134.6, 134.1 (Ar–C1 and C1 , Ar–C2–Cl, Ar-C2 -Cl, Ar–C4–Cl and
0
Ar-C4 -Cl), 130.2, 130.0 (Ar), 129.5 (imidazole-C4), 127.8 (Ar), 119.2
(Ar–C3–Cl), 130.2, 129.3, 129.1 (Ar), 128.8 (imidazole-C4),
128.8, 128.7, 128.1, 126.1 (Ar), 119.3 (imidazole-C5), 64.5
(Ph–CH–Ph); Analysis calculated for C16H13N2Cl: C, 71.51;
H, 4.88; N, 10.42. Found: C, 71.46; H, 4.83; N, 10.55.
(imidazole-C5), 58.5 (Ph–CH–Ph); Analysis calculated for
C16H10N2Cl4: C, 51.65; H, 2.71; N, 7.53. Found: C, 51.74;
H, 2.85; N, 7.46
2-Chlorobenzhydryl-1H-1,2,4-triazole 6b
4-Chlorobenzhydryl-1H-imidazole 5d
Yield: 35%; m.p.: 728C; 1H-NMR (CDCl3) d: 8.05 (s, 1H, triazole-H5),
7.94 (s, 1H, triazole-H3), 7.46–7.25 (m, 6H, Ar–H), 7.15 (m, 2H,
Ar–H), 6.98 (s, 1H, Ph–CH–Ph), 6.92 (d, 1H, Ar–H); 13C-NMR
(CDCl3): 152.5 (triazole-C3 and C5), 137.6, 137.5 (Ar–C1
Yield: 55%; n2D2: 1.6009; 1H-NMR (CDCl3) d: 7.42–7.32 (m, 5H,
imidazole-H2 and Ar–H), 7.12–7.02 (m, 6H, imidazole-H5 and
Ar–H), 6.84 (s, 1H, imidazole-H4), 6.51 (s, 1H, Ph–CH–Ph); 13C-
0
NMR (CDCl3): 137.5 (Ar–C1 or C1 ), 137.0 (imidazole-C2),
0
and C1 ), 133.7 (Ar–C2–Cl), 130.1, 129.8, 129.3, 129.2, 128.9,
0
136.6 (Ar–C1 or C1 ), 134.6 (Ar–C4–Cl), 129.5, 129.2, 129.1,
128.6, 128.2, 127.3 (Ar), 67.8 (Ph–CH–Ph); Analysis calculated
for C15H12N3Cl: C, 66.79; H, 4.48; N, 15.58. Found: C, 66.85;
H, 4.41; N, 15.69.
128.9, 128.1 (Ar), 128.9 (imidazole-C4), 128.3, 128.1, 127.2
(Ar), 119.2 (imidazole-C5), 65.6 (Ph–CH–Ph); Analysis calculated
for C16H13N2Cl: C, 71.51; H, 4.88; N, 10.42. Found: C, 71.60;
H, 4.95; N, 10.35.
3-Chlorobenzhydryl-1H-1,2,4-triazole 6c
2,4-Dichlorobenzhydryl-1H-imidazole 5e
Yield: 41%; n2D2: 1.5982; 1H-NMR (CDCl3) d: 8.06 (s, 1H,
triazole-H5), 7.97 (s, 1H, triazole-H3), 7.46–7.29 (m, 5H,
Ar–H), 7.17 (m, 2H, Ar–H), 7.13 (s, 1H, Ar–H), 7.02 (d, 1H,
Ar–H, J ¼ 6.5 Hz); 6.74 (s, 1H, Ph–CH–Ph); 13C-NMR (CDCl3):
Yield: 45%; n2D2: 1.6093; 1H-NMR (CDCl3) d: 7.44 (d, 1H, Ar–H,
J ¼ 2.1Hz), 7.38–7.34 (m, 4H, imidazole-H2 and Ar–H), 7.22
(dd, 1H, Ar–H, J ¼ 8.5 Hz, 2.0 Hz), 7.12 (s, 1H, imidazole-
H5), 7.07–7.04 (m, 2H, Ar–H), 6.83 (s, 1H, imidazole-H4),
6.80 (s, 1H, Ph–CH–Ph), 6.77 (d, 1H, Ar–H, J ¼ 8.4 Hz); 13C-
NMR (CDCl3): 137.0 (imidazole-C2), 135.8, 135.3 (Ar–C1
0
152.5 (triazole-C3 and C5), 138.2, 137.2 (Ar–C1 and C1 ),
134.9 (Ar–C3–Cl), 130.2, 129.3, 129.1, 128.8, 128.7, 128.1,
126.1 (Ar), 67.5 (Ph–CH–Ph); Analysis calculated for
C15H12N3Cl: C, 66.79; H, 4.48; N, 15.58. Found: C, 66.88;
H, 4.53; N, 15.43.
0
and C1 ), 134.4, 134.3 (Ar–C2–Cl and Ar–C4–Cl), 130.4,
129.9, 129.2, 129.1 (Ar), 128.8 (imidazole-C4), 128.2, 127.6
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Arch. Pharm. Chem. Life Sci. 2011, 11, 402–410
Bifonazole Derivatives
409
4-Chlorobenzhydryl-1H-1,2,4-triazole 6d
Microbiological assays
Yield: 31%; m.p.: 888C; 1H-NMR (CDCl3) d: 8.05 (s, 1H, triazole-H5),
7.95 (s, 1H, triazole-H3), 7.43–7.35 (m, 5H, Ar–H), 7.15 (dd, 2H,
Ar–H, J ¼ 7.5 Hz, 2.0 Hz), 7.09 (m, 2H, Ar–H), 6.75 (s, 1H,
Ph–CH–Ph); 13C-NMR (CDCl3): 152.4 (triazole-C3 and C5), 137.5,
Bifonazole, clotrimazole and ciprofloxacin (Sigma, Saint
Quentin Fallavier, France) were used as reference compounds
in microbiological assays.
The test compounds were dissolved in a solution consisting
of 1/3 DMSO and 2/3 5% aqueous Tween 80 solution to obtain
a final concentration of 1000 mg/mL. The resulting solutions
were then diluted in microtiter plates in culture medium:
0
136.6 (Ar–C1 and C1 ), 134.6 (Ar–C4–Cl), 129.5, 129.2, 129.1, 128.9,
128.1 (Ar), 67.1 (Ph–CH–Ph); Analysis calculated for C15H12N3Cl:
C, 66.79; H, 4.48; N, 15.58. Found: C, 66.70; H, 4.43; N, 15.66.
´
trypcase soja (Biomerieux, Craponne, France) for bacteria
and Sabouraud (Biomerieux, Craponne, France) for fungi.
´
2,4-Dichlorobenzhydryl-1H-1,2,4-triazole 6e
Gram-positive strains S. aureus CIP 4.83, E. hirae CIP 5855, and
Gram-negative strains P. aeruginosa CIP 82118, E. coli CIP 53126
were used for the antibacterial assays. For the antifungal
assays, cultures of yeasts C. albicans IP 48.72, C. krusei IP 208.52,
A. niger IP 1431.83 and a dermatophyte strain T. rubrum IP 1657.86
were used. Strains were obtained from the Collection of
the Pasteur Institute (Paris, France). Minimal inhibitory
concentrations (MICs) and minimal germicidal concentrations
(MBCs or MFCs) were determined after incubation of
bacterial strains at 378C and fungal strains at 30 or 22.58C
for 24–48 h (5 days for T. rubrum) in the presence of serial
23
Yield: 42%; nD ¼ 1.5450; 1H-NMR (CDCl3) d: 8.04 (s, 1H, triazole-
H5), 7.95 (s, 1H, triazole-H3), 7.46 (d, 1H, Ar–H, J ¼ 2.0 Hz), 7.39
(m, 3H, Ar–H), 7.29 (dd, 1H, Ar–H, J ¼ 8.5 Hz, 2.0 Hz), 7.14 (m, 2H,
Ar–H), 7.08 (s, 1H, Ph–CH–Ph), 6.88 (d, 1H, Ar–H, J ¼ 8.4 Hz); 13C-
NMR (CDCl3): 152.0 (triazole-C3 and C5), 135.9, 135.3 (Ar–C1
0
and C1 ), 134.4, 134.3 (Ar–C2–Cl and Ar–C4–Cl), 130.4, 129.9,
129.2, 129.1, 128.5, 128.2, 127.6 (Ar), 64.1 (Ph–CH–Ph); Analysis
calculated for C15H11N3Cl2: C, 59.23; H, 3.65; N, 13.81. Found:
C, 59.15; H, 3.56; N, 13.93.
3,4-Dichlorobenzhydryl-1H-1,2,4-triazole 6f
dilutions of the test compounds (Tables
1 and 2). The
Yield: 25%; m.p.: 598C; 1H-NMR (CDCl3) d: 8.06 (s, 1H, triazole-H5),
7.98 (s, 1H, triazole-H3), 7.48–7.40 (m, 4H, Ar–H), 7.23–7.16 (m,
3H, Ar–H), 6.98 (dd, 1H, Ar–H, J ¼ 8.4 Hz, 2.0 Hz), 6.71 (s, 1H,
Ph–CH–Ph); 13C-NMR (CDCl3): 152.3 (triazole-C3 and C5), 139.4,
MIC was defined as the compound concentration at which
no macroscopic sign of cellular growth was detected in
comparison to the control without antimicrobial compound.
The MBC/MFC were determined by subculturing on correspond-
ing agar plates after incubation of bacterial strains at 378C
and fungal strains at 30 or 22.58C for 24–48 h (5 days for
T. rubrum). The MBC/MFC was defined as the compound concen-
tration at which no macroscopic sign of cellular growth was
detected in comparison to the control without antimicrobial
compound.
0
137.7 (Ar–C1 and C1 ), 136.1, 134.8 (Ar–C3–Cl and Ar–C4–Cl),
130.9, 129.8, 129.6, 129.2, 128.3, 128.1, 127.2 (Ar), 64.0
(Ph–CH–Ph); Analysis calculated for C15H11N3Cl2: C, 59.23;
H, 3.65; N 13.81. Found: C, 59.12; H, 3.72; N, 13.75.
2,4,40-Trichlorobenzhydryl-1H-1,2,4-triazole 6h
Yield: 41%; m.p.: 988C; 1H-NMR (CDCl3) d: 8.06 (s, 1H, triazole-H5),
7.99 (s, 1H, triazole-H3), 7.49 (d,1H, Ar–H, J ¼ 2.0 Hz), 7.41 (d, 2H,
Ar–H, J ¼ 8.4 Hz), 7.30 (dd, 1H, Ar–H, J ¼ 8.4 Hz, 2.0 Hz), 7.10
(s, 1H, Ph–CH–Ph), 7.07 (s, 2H, Ar–H), 6.92 (d, 1H, Ar–H,
J ¼ 8.4 Hz); 13C-NMR (CDCl3): 152.1 (triazole-C3 and C5), 135.6,
Molecular modeling
The starting geometries of the synthesized compounds were
initially created with the ChemDraw and geometric optimi-
zations were carried out with the PM6 method of MOPAC
2009 software [19]. The lowest energy conformation was
then selected. The partial atomic charges were calculated
with the same method. For the visualization of compounds
and the electrostatic potentials Accelrys software was used
(Accelrys DS Visualiser 2.0, 2005-2007 Accelrys software Inc.)
0
135.2 (Ar–C1 and C1 ), 134.9, 134.3 (Ar–C2–Cl and Ar–C4–Cl),
130.1, 129.8, 129.4, 127.8 (Ar), 63.1 (Ph–CH–Ph); Analysis calcu-
lated for C15H10N3Cl3: C, 53.20; H, 2.98; N, 12.41. Found: C, 53.12;
H, 2.85; N, 12.65.
2,20,4,40-Tetrachlorobenzhydryl-1H-1,2,4-triazole 6i
Yield: 15%; m.p.: 1048C; 1H-NMR (CDCl3) d: 8.05 (s, 1H, triazole-H5),
8.00 (s, 1H, triazole-H3), 7.49 (s, 2H, Ar–H), 7.33 (s, 1H, Ph–CH–Ph),
7.29 and 7.26 (2d, 2H, Ar–H, J ¼ 8.4 Hz), 6.89 (d, 2H, Ar–H,
J ¼ 8.4 Hz); 13C-NMR (CDCl3): 152.1 (triazole-C3 and C5), 135.6
We thank Laurent Amielet, Christelle Re´coche´and Alain Signoles for their
technical support, and Jean Luc Stigliani for his help in the molecular
modelling studies.
0
(Ar–C1 and C1 ), 134.6, 134.1 (Ar–C2–Cl, Ar-C2’-Cl, Ar–C4–Cl and
Ar-C40-Cl), 130.2, 130.0, 129.5, 127.8 (Ar), 61.5 (Ph–CH–Ph);
Analysis calculated for C15H9N3Cl4: C, 48.29; H, 2.43; N, 11.26.
Found: C, 48.35; H, 2.55, N, 11.21.
The authors have declared no conflict of interest.
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1-[(1,1-biphenyl)-4-yl-phenylmethyl]-1H-1,2,4-triazole 6j
Yield: 47%; m.p.: 1038C; 1H-NMR (CDCl3) d: 8.02 (s, 1H, triazole-H5),
7.96 (s, 1H, triazole-H3), 7.66–7.58 (m, 5H, Ar–H), 7.46–7.42
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