Synthesis and antifungal activity of phenacyl azoles

Article abstract of DOI:10.3184/174751914X14107905836359

A new N-(4-methoxyphenacyl)imidazole and three new substituted N-(phenacyl)triazoles were prepared by reaction of the heterocycle with a phenacyl halide. The former ketone and one example of the latter were reduced to the corresponding alcohols. All six compounds were screened in vitro for antifungal activity against two pathogenic fungal strains, Candida albicans (fluconazole-resistant) and Aspergillus fumigatus. The results revealed that most of the compounds showed activity against both strains at 100 μg mL^-1and 80 μg mL^-1, some comparable with control compound fluconazole. The alcohols were less active than the corresponding ketones.

Full text of DOI:10.3184/174751914X14107905836359

JOURNAL OF CHEMICAL RESEARCH 2014
VOL. 38 SEPTEMBER, 549–552
RESEARCH PAPER 549
Synthesis and antifungal activity of phenacyl azoles
Ronald Nelsona, Víctor Kesternicha*, Marcia Pérez-Fehrmanna, Fernanda Salazara, Laurence
Marcourtb, Philippe Christenb and Patricio Godoyc
aDepartamento de Química, Facultad de Ciencias, Universidad Católica del Norte, Antofagasta, Chile
bSchool of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Quai Ernest-Ansermet 30, CH-1211 Geneva 4, Switzerland
cInstituto de Microbiología Clínica, Facultad de Medicina, Universidad Austral de Chile, Valdivia, Chile
A new N-(4-methoxyphenacyl)imidazole and three new substituted N-(phenacyl)triazoles were prepared by reaction of the
heterocycle with a phenacyl halide. The former ketone and one example of the latter were reduced to the corresponding
alcohols. All six compounds were screened in vitro for antifungal activity against two pathogenic fungal strains, Candida
albicans (fluconazole-resistant) and Aspergillus fumigatus. The results revealed that most of the compounds showed activity
against both strains at 100 µg mL–1 and 80 µg mL–1, some comparable with control compound fluconazole. The alcohols were
less active than the corresponding ketones.
Keywords: N-(4-methoxyphenacyl)imidazole, N-(phenacyl)-1,2,4-triazoles, fluconazole, antifungal activity
Fungal infections are an important complication, as well as the
major cause of morbidity and mortality, in immunosuppressed
patients such as transplant recipients and those with cancer
and HIV.1,2 Additionally, the appearance of microorganisms
resistant to multiple conventional treatments has become a
severe global health problem.3 Therefore, there is an urgent
need to develop new antifungal agents that are safe, effective
and non-toxic with a broad spectrum of activity.4
In the last 30 years, only amphotericin B and 5-fluorocytosine
have been used for the treatment of systemic fungal infections,
although their effectiveness is unsatisfactory. A series of
ergosterol synthesis inhibitors (the main sterol in fungal
membranes) has shown excellent antifungal activity, and some
are active after oral or parenteral administration.5 Importantly,
azoles such as imidazoles and triazoles (Fig. 1), inhibit fungal
sterol synthesis by inhibiting cytochrome P450-dependent
14α-lanosterol demethylase (CYP51), ultimately affecting
fungal growth and reproduction.6–8
Previous structure–activity relationship studies (SAR) have
shown that azoles and phenyl rings are essential parts of the
pharmacophore for this family of antifungal molecules.9,10
We now report the synthesis of a new 4-methoxyphenacyl
imidazole, three new substituted phenacyl triazoles and
two related alcohols (Fig. 2), which possess the minimal
pharmacophore structure, and evaluation of their antifungal
activity against cultures of Candida albicans (fluconazole
resistant) and Aspergillus fumigatus.
Results and discussion
Synthesis of α-bromoketones 2b and 2c (Scheme 1) was
performed by brominating compounds 1b–c in chloroform at
room temperature.11 Nucleophilic substitution of α-bromoketone
2b with 1H-imidazole yielded the phenacyl imidazole 3b,12
while 2a was converted to the phenacyl triazole derivative 5a
in alkaline medium under reflux using toluene and 1H-1,2,4-
triazole in excess.13 The phenacyl triazoles 5b and 5c were
N
N
N
O
N
O
N
Cl
N
N
N
N
O
O
l
C
N
N
F
N
N
N
N
N
O
N
OH
OH
O
O
O
O
N
N
N
N
N
N
N
Cl
Cl
F
F
Cl
Cl
F
F
Cl
Itraconazole
Cl
Miconazole
Ketoconazole
Fluconazole
Voriconazole
Fig. 1 Some antifungal azoles.
R3
R1
Az:1H-imidazol-1-yl; 1H-1,2,4-triazol-1-yl
R1: H, F
R2: F, OMe, NO
z
A
R2: C=O; H,OH 2
R2
Fig. 2 General structure of phenacyl azoles and related alcohols.
* Correspondent. E-mail: vkestern@ucn.cl
JCR1402689_FINAL.indd 549
23/09/2014 15:52:57

550 JOURNAL OF CHEMICAL RESEARCH 2014
N
N
H
O
O
NaBH4
N
N
MeOH, rt
98
%
e
M
MeO
O
3b
4b
1H-imidazole
CHCl3 rt,
58%
,
O
O
r
B
Br2
2b:
2c:
R1= H, R2= OMe (73%)
R1= H, R2= NO2 (81%)
CHCl3
0 °C to ,rt
R2
R1
R2
R1
1b:
1c:
R1= H, R2= OMe
R1= H, R2= NO2
1H-1,2,4-triazole
Et3N, CHCl3, rt
N
N
O
OH
F
O
F
N
N
N
Cl
NaBH4
1H-1,2,4-triazole
N
NaHCO3, Toluene
110 °C
MeOH, rt
85%
R2
R1
F
F
a
2 ´
6a
5a:
5b:
5c:
R1 and R2= F (60%)
R1= H, R2= OMe (41%)
R1= H, R2= NO2 (20%)
Scheme 1
obtained from 2b and 2c through nucleophilic substitution at
room temperature by adding 1H-1,2,4-triazole dissolved in
chloroform and using triethylamine as the catalyst.12,14 The
reduction of ketones 3b and 5a with sodium borohydride in
methanol produced alcohols 4b and 6a in good yields.11
system in the range of δH 4.01 to 5.15 corresponding to H1a, H1b
and H2 protons was indicative of C2 reduction. The structure
of compound 6a was also confirmed by an X-ray diffraction
study.16
The in vitro antifungal activity (percent inhibition) of azole
compounds (3–6) was assessed against clinical isolates of
Candida albicans (fluconazole-resistant) and Aspergillus
fumigatus by the standard broth microdilution technique
described in the NCCLS guidelines and using fluconazole
as the standard for comparison (control antifungal).17,18 The
antifungal activities of the phenacyl azoles, expressed as
percentages of inhibition at 80 and 100 µg mL–1, are seen
in Table 2. All azoles showed good activity at 100 µg mL–1
against both fungal strains. Moreover, compounds 3b, 4b and
5a showed greater inhibition than fluconazole (control), though
no significant differences were seen between compounds with
imidazole or triazole rings. At 80 µg mL–1, only phenacyl
imidazole 3b showed greater than 50% inhibition of Candida
albicans, while for Aspergillus fumigatus, compounds 4b, 5a
and 5b showed greater activity than the control.
Spectroscopic data (1H NMR, 13C NMR, IR and MS) were
consistent with the proposed structures of compounds 3–6
(Table 1). The imidazole ring of compounds 3b and 4b was
characterised by the presence of a band at 1606 or 1610 cm–1
corresponding to C=N stretching in FT-IR and three broad
singlets at δH 6.97 or 6.82 (H2′), 7.16 or 7.06 (H3′) and 7.65 or 7.45
(H1′) in the 1H NMR spectrum. The IR spectra of compounds
5a–c and 6a showed absorption due to C=N stretching in
1
the range of 1600–1609 cm–1. In their H NMR spectra, two
singlets were observed in the aromatic region at δH 7.75–8.04
and 8.11–8.52 corresponding to H2´ and H1´ of the triazole
ring, respectively. In the 13C NMR spectra, chemical shifts
at δC 144.2–145.7 and 150.7–151.9 were attributed to C1´ and
C2´, respectively. Additionally, the structure of compound 5b
was confirmed by an X-ray diffraction study.15 The structures
of the alcohol derivatives 4b and 6a were characterised by
an IR absorption band at 3181–3424 cm–1 attributed to O–H
Our limited SAR study on the phenyl ring, revealed that when
R2 was a nitro group only weak activity was shown against
Candida albicans, whereas a methoxyl substituent showed
1
stretching. In their H NMR spectra, the presence of an ABX
Table 1 Spectroscopy data of phenacyl azole compounds
1´
N
N
R3
2´
X
3´
2
1
X: CH or N
R2
R1
IR/cm–1
C=O
1H NMR δ/ppm
13C NMR δ/ppm
Comp.
X
C=N
O–H
H1´
H2´
H3´
H2
C1´
C2´
C3´
C2
3b
4b
5a
5b
5c
6a
CH
CH
N
N
N
1606
1610
1609
1600
1601
1618
1682
–
1689
1678
1704
–
–
3424
–
–
–
7.65
7.45
8.15
8.22
8.52
8.11
6.97
6.82
7.91
7.96
8.04
7.75
7.16
7.06
–
–
–
–
4.76
–
–
–
138.6
138.1
145.0
145.7
145.5
144.2
127.8
127.4
151.9
151.6
151.3
150.8
121.0
120.2
–
–
–
–
191.8
71.7
187.7
189.0
192.0
65.5
N
3181
–
5.15
JCR1402689_FINAL.indd 550
23/09/2014 15:52:58

JOURNAL OF CHEMICAL RESEARCH 2014 551
Table 2 Antifungal activity of phenacyl azoles
Inhibition/%
A. fumigatus
Compound
R1
R2
R3
X
C. albicans
100 µg mL–1
80 µg mL–1
100 µg mL–1
80 µg mL–1
3b
4b
5a
5b
5c
6a
H
H
F
H
H
F
OMe
OMe
F
OMe
NO2
F
C=O
H,OH
C=O
C=O
C=O
H,OH
CH
CH
N
N
N
79
74
81
60
23
44
69
55
39
27
35
16
24
42
72
73
78
64
93
54
73
46
47
45
48
12
38
42
N
Fluconazole
chromatography using dichloromethane as the eluent. Compound 3b
was obtained as a white solid, yield 58%; m.p. 134–136 °C. IR (cm–1)
ν: 3118 and 3014 (CArH), 2962, 2933 and 2838 (Csp3-H), 1682 (C=O),
1606 (C=N), 1509 (CAr–CAr); 1H NMR (DMSO-d6) δ (ppm): 3.87 (s,
3H), 5.69 (s, 2H), 6.97 (brs, 1H), 7.11 (d, 2H, J=8.8 Hz), 7.16 (brs, 1H),
7.65 (brs, 1H), 8.02 (d, 2H, J=8.8 Hz); 13C NMR (DMSO-d6) δ (ppm):
52.4 (CH2), 55.6 (CH3), 114.1 (CH), 121.0 (CH), 127.3 (C), 127.8 (CH),
130.3 (CH), 138.6 (CH), 163.7 (C), 191.8 (C=O); HRESIMS calcd for
C12H13N2O2 [M+H]+ 217.0977, found 217.0971.
increased activity compared to difluorinated compounds 5a, 6a
and fluconazole. With respect to alcoholic derivatives 4b and
6a, reduction of the C2-carbonyl resulted in decreased activity
of the fluorinated compounds, consistent with the findings
recently described by Scipione et al.,19 whereas antifungal
activity for the methoxylated alcohol 4b against both strains
was similar to fluconazole.
Experimental
Synthesis of 1-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-yl)
ethanone (5a)
Melting points were determined on a Kofler-type apparatus and
are uncorrected. The IR spectra were taken on a Perkin-Elmer 200
spectrophotometer in KBr discs. NMR spectra were obtained in
DMSO-d6 or CDCl3 with a Varian Unity Inova 500 MHz spectrometer
equipped with a 5 µL microflow probe from Protasis (1H NMR at
500 Hz, 13C NMR at 125 Hz). Chemical shifts were reported in parts
per million (δ) using the residual solvent signals (DMSO-d6: δH 2.50,
A mixture of 2-chloro-2′,4′-difluroacetophenone (9.25 g, 48.53 mmol)
(2a), 1H-1,2,4-triazole (4.01 g, 58.06 mmol) and sodium bicarbonate
(4.90 g, 58.33 mmol) in toluene (50 mL) was refluxed for 5 h with
magnetic stirring. Subsequently, cold water (50 mL) was added and
the solution extracted with toluene (3×40 mL). The organic phase
was washed with saturated sodium bicarbonate solution, dried
over anhydrous sodium sulfate and concentrated under reduced
pressure. The crude product was purified by chromatography using
dichloromethane as the eluent. Compound 5a was obtained as a white
solid; yield 60%; m.p. 101–103 °C (lit.22 103–105 °C). IR (cm–1) ν: 3045
(CArH), 2982 and 2946 (Csp3-H), 1689 (C=O), 1609 (C=N), 1592 and
1
δC 39.5) (CDCl3; δH 7.26, δC 77.2) as the internal standards for H
and 13C NMR and coupling constants (J) in Hz. UHPLC-TOFMS
spectra were recorded on a Micromass-LCT Premier Time-of-Flight
electrospray (ESI) spectrometer with an Acquity UHPLC (ultra-high
performance liquid chromatography) interface system. TLC was
performed on Al Si gel Merck 60 F254 and spots were visualised by
spraying with phosphomolybdic acid reagent and heating. The starting
materials and reagents used were acquired commercially from Sigma-
Aldrich or Merck.
1
1508 (CAr–CAr); H NMR (CDCl3) δ (ppm): 5.53 (s, 2H), 6.92 (ddd,
1H, J=11.0, 8.4, 2.3 Hz), 6.98 (ddd, 1H, J=9.6, 7.0, 2.3 Hz), 7.91 (s,
1H), 7.96 (td, 1H, J=8.5, 7.0 Hz), 8.15 (s, 1H); 13C NMR (CDCl3) δ
(ppm): 58.4 (d, J=13.5 Hz, CH2), 105.0 (t, J=26.6 Hz, CH), 113.2 (d,
J=21.7 Hz, CH), 119.0 (d, J=11.4 Hz, CH), 133.1 (dd, J=10.7, 3.9 Hz,
CH), 145.0 (CH), 151.9 (CH), 163.2 (dd, J=256.9, 12.7 Hz, C–F),
166.8 (dd, J=260.3, 12.6 Hz, C–F), 187.7 (C=O); HRESIMS calcd for
C10H8F2N3O [M+H]+ 224.0635, found 224.0624.
Synthesis of 2b and 2c; general procedure
A solution of bromine (2.90 g, 18.0 mmol) in chloroform (150 mL)
was slowly added to a cooled solution (0 °C) of acetophenone 1b–c
(17.0 mmol) in chloroform (150 mL), over a period of 1 h, the mixture
stirred at room temperature for 15 h and quenched with ice-cold water.
The organic layer was washed with saturated sodium bicarbonate
solution, water and brine. The organic phase was dried over anhydrous
sodium sulfate, concentrated under vacuum and purified on a silica
gel (100–200 mesh) column. Elution with hexane–ethyl acetate (9:1)
yielded pure compounds 2b and 2c.
2-Bromo-1-(4-methoxyphenyl)ethanone (2b): White crystals; yield
73%; m.p. 67–69 °C (hexane-dichloromethane) (lit.20 69–73 °C). IR
(cm–1) ν: 3068 (CArH), 2980 and 2938 (Csp3-H), 1687 (C=O), 1599 and
1510 (CAr–CAr); 1H NMR (CDCl3) δ (ppm): 3.80 (s, 3H), 4.35 (s, 2H),
6.88 (d, 2H, J=8.9 Hz), 7.88 (d, 2H, J=8.9 Hz); 13C NMR (CDCl3) δ
(ppm): 31.0 (CH2), 55.5 (CH3), 114.0 (CH), 126.7 (C), 131.0 (CH), 164.0
(C), 189.8 (C=O); HRESIMS calcd for C9H10BrO2 [M+H]+ 228.9864,
found 228.9865.
Synthesis of compounds 5b and 5c; general procedure
A solution containing 3.12 mmol of 2b or 2c, 0.64 g (9.27 mmol) of
1H-1,2,4-triazole, chloroform (50 mL) and triethylamine (500 µL) was
stirred at room temperature for 48 h. Upon completion of the reaction,
the mixture was filtered and the solvent distilled off under reduced
pressure. The crude product was purified on a chromatographic
column with dichloromethane as the mobile phase.
1-(4-Methoxyphenyl)-2-(1H-1,2,4-triazol-1-yl)ethanone (5b): White
crystals; yield 41%; m.p. 98–99 °C (chloroform–methanol). IR (cm–1)
ν: 3121 and 3055 (CArH), 2973 and 2838 (Csp3-H), 1678 (C=O), 1600
(C=N), 1506 (CAr–CAr); 1H NMR (CDCl3) δ (ppm): 3.86 (s, 3H), 5.59
(s, 2H), 6.96 (d, 2H, J=8.6 Hz), 7.92 (d, 2H, J=8.6 Hz), 7.96 (s, 1H),
8.22 (s, 1H); 13C NMR (CDCl3) δ (ppm): 54.8 (CH2), 55.7 (CH3), 114.4
(CH), 127.0 (C), 130.5 (CH), 145.7 (CH), 151.6 (CH), 164.6 (C), 189.0
(C=O); HRESIMS calcd for C11H12N3O2 [M+H]+ 218.0930, found
218.0927.
2-Bromo-1-(4-nitrophenyl)ethanone (2c): Yellow crystals (81%)
m.p. 100–102 °C (hexane-dichloromethane) (lit.21 m.p. 98–101 °C). IR
(cm–1) ν: 3102 and 3071 (CArH), 2937, 2853 and 2870 (Csp3-H), 1703
(C=O), 1599 and 1500 (Car–CAr); 1H NMR (DMSO-d6) δ (ppm): 5.00
(s, 2H), 8.21 (d, 2H, J=8.9 Hz), 8.33 (d, 2H, J=8.9 Hz).
1-(4-Nitrophenyl)-2-(1H-1,2,4-triazol-1-yl)ethanone (5c): Yellow
solid; yield 20%; m.p. 148–149 °C. IR (cm–1) ν: 3116 and 3067 (CArH);
2989, 2950 and 2856 (Csp3-H), 1704 (C=O), 1601 (C=N), 1518 (CAr–
1
Synthesis of 2-(1H-imidazol-1-yl)-1-(4-methoxyphenyl)ethanone (3b)
A solution containing 2.00 g (8.73 mmol) of 2b, 1.78 g (26.1 mmol) of
imidazole and chloroform (100 mL) was stirred at room temperature
for 24 h. Upon completion of the reaction, the mixture was
concentrated on a rotary evaporator and the oil (3b) was purified by
CAr and C–NO2), 1347 (C–NO2); H NMR (DMSO-d6) δ (ppm): 6.08
(2H, s, H1), 8.04 (s, 1H), 8.28 (d, J=8.9 Hz, 2H), 8.41 (d, J=8.9 Hz, 2H),
8.52 (s, 1H); 13C NMR (DMSO-d6) δ (ppm): 55.6 (CH2), 123.9 (CH),
129.6 (CH), 138.8 (C), 145.5 (CH), 150.4 (C), 151.3 (CH), 192.0 (C=O);
HRESIMS calcd for C10H9N4O3 [M+H]+ 233.0675, found 233.0674.
JCR1402689_FINAL.indd 551
23/09/2014 15:52:58

552 JOURNAL OF CHEMICAL RESEARCH 2014
Synthesis of compounds 4b and 6a; general procedure
inhibitory activity greater than fluconazole (control) against
Aspergillus fumigatus, while only compound 3b had activity
equivalent to fluconazole against Candida albicans. The
importance of this work lies in that these new compounds might
be more efficacious anti-fungal drugs, which could be helpful
in designing more potent antifungal agents for therapeutic use.
Samples of the compounds 3b, 4b, 5b and 6a are available
from the authors.
Sodium borohydride (0.15 g, 4.03 mmol) dissolved in methanol
(20 mL) was added drop-wise to a mixture of 3.36 mmol 3b or 6a
in 40 mL of methanol, and the reaction mixture was stirred at room
temperature for 30 min and then taken to dryness by distillation. The
solid product was suspended in saturated sodium bicarbonate and
extracted with dichloromethane (3×40 mL). The organic phase was
dried over anhydrous sodium sulfate and concentrated in a rotary
evaporator.
2-(1H-Imidazol-1-yl)-1-(4-methoxyphenyl)ethanol (4b): White solid;
We acknowledge the European ChemBioFight project (grant
agreement 269301) for financial support.
yield 98%; m.p. 160–162 °C. IR (cm–1) ν: 3424 (O–H), 2967, 2934 and
1
2844 (Csp3-H); 1610 (C=N), 1584 and 1512 (CAr–CAr); H NMR
(DMSO-d6) δ (ppm): 3.73 (s, 3H), 4.01 (dd, J=13.8, 7.4 Hz, 1H), 4.09
(dd, J=13.8, 7.4 Hz, 1H), 4.76 (dd, J=7.4, 4.0 Hz, 1H), 5.59 (brs, 1H,
OH), 6.82 (brs, 1H), 6.85 (d, J=8.6 Hz, 2H), 7.06 (brs, 1H), 7.23 (d,
J=8.6 Hz, 2H), 7.45 (brs, 1H); 13C NMR (DMSO-d6) δ (ppm): 53.7
(CH2), 54.9 (CH3), 71.7 (CH), 113.3 (CH), 120.2 (CH), 127.1 (CH),
127.4 (CH), 134.5 (C), 138.1 (CH), 158.5 (C); HRESIMS calcd for
C12H15N2O2 [M+H]+ 219.1134, found 219.1128.
Received 27 May 2014; accepted 4 August 2014
Paper 1402689 doi: 10.3184/174751914X14107905836359
Published online: 25 September 2014
References
1-(2,4-Difluorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethanol (6a): White
crystals; yield 85%; m.p. 118–120 °C (ethanol). IR (cm–1) ν: 3182
(O–H), 3131 and 3071 (CArH), 2913, 2953 and 2865 (Csp3-H); 1618
(C=N), 1567 and 1504 (CAr–CAr); 1H NMR (CDCl3 +DMSO-d6)
δ (ppm): 4.17 (dd, J=13.6, 7.5 Hz, 1H), 4.31 (d, J=13.6 Hz, 1H), 5.15
(d, J=7.5 Hz, 2H), 6.66 (dt, J=9.6, 1.9 Hz, 1H), 6.73 (ddd, J=9.6, 7.0,
1.9 Hz, 1H), 7.32 (dt, J=8.2, 7.0 Hz, 1H), 7.75 (s, 1H), 8.11 (s, 1H);
13C NMR (CDCl3 +DMSO-d6) δ (ppm): 55.4 (CH2), 65.5 (CH), 103.4
(t, J=25.5 Hz, CH), 111.3 (d, J=21.0 Hz, CH), 124.0 (d, J=11.6 Hz,
C), 128.5 (dd, J=9.0, 6.0 Hz, CH), 144.3 (CH), 150.7 (CH), 159.3
(dd, J=248.4, 11.9 Hz, C–F), 162.3 (dd, J=248.5, 11.8 Hz, C–F);
HRESIMS calcd for C10H10F2N3O [M+H]+ 226.0792, found 226.0787.
1
N.H. Georgopapadakou and T.J. Walsh, Antimicrob. Agents Chemother.,
1996, 40, 279.
S.P. Fisher-Hoch and L. Hutwagner, Clin. Infect. Dis., 1995, 21, 897.
B. Narasimhan, S. Ohlan, R. Ohlan, V. Judge and R. Narang, Eur. J. Med.
Chem., 2009, 44, 689.
S.J. Aarons, I.W. Sutherland, A.M. Chakrabarty and M.P. Gallagher,
Microbiology, 1997, 143, 641.
R. Fromtling and J. Castañer, Drug Future, 1996, 21, 266.
J. Fortún, Medicine, 1998, 91, 4231.
W.W. Turner and M.J. Rodrigues, Curr. Pharm. Des., 1996, 2, 209.
G.P. Bodey, Clin. Infect. Dis., 1992, 14, S161.
A. Rosello, S. Bertini, A. Lapucci, M. Macchia, A. Martinelli, S.
Rapposelli, E. Herreros and B. Macchia, J. Med. Chem., 2002, 45, 4903.
2
3
4
5
6
7
8
9
10 Y. Wahbi, R. Caujolle, C. Tournaire, M. Payard, M.D. Linas and J.P.
Seguela, Eur. J. Med. Chem., 1995, 30, 955.
11 R.S. Upadhayaya, G.M. Kulkarni, N.R. Vasireddy, J.K. Vandavasi, S.S.
Dixit, V. Sharma and J. Chattopadhyaya, Bioorg. Med. Chem., 2009, 17,
4681.
12 F. Schiaffella, M. Macchiarulo, L. Milanese, A. Vecchiarelli, G.
Costantino, D. Pietrella and R. Fringuelli, J. Med. Chem., 2005, 48, 7658.
13 R.S. Upadhayaya, S. Jain, N. Sinha, N. Kishore, R. Chandra and S. Arora,
Eur. J. Med. Chem., 2004, 39, 579.
14 K. Dawood, H. Abdel-Gawad, E. Rageb, M. Ellithey and H. Mohamed,
Bioorg. Med. Chem., 2006, 14, 3672.
Antifungal activity
The percent inhibition of azole compounds against clinical isolates of
Candida albicans (fluconazole-resistant) and Aspergillus fumigatus
was determined by broth microdilution testing in accordance with
the guidelines in NCCLS documents M27-A and M38-P. Briefly,
testing was performed in flat-bottom 96-well tissue culture plates
in RPMI 1640 medium buffered to pH 7.0 with 0.165 M MOPS
(3-[morpholino]propanesulfonic acid). Stock solutions of fluconazole
and compounds were prepared in DMSO and tested at 1–100 µg mL–1
(the final concentration of the solvent did not exceed 1% in any well).
An inoculum of 1×103 to 5×103 CFU mL–1 was prepared by the UV
spectroscopy method for each organism tested. The plates were
incubated at 35 °C and absorbance at 530 nm recorded on a BioTek
Symergy 2 apparatus after 48 h for Candida albicans and 72 h for
Aspergillus fumigatus.
15 V. Kesternich, I. Brito, M. Bolte, M. Pérez-Fehrmann and R. Nelson, Acta
Crystallogr., 2010, E66, o1978.
16 V. Kesternich, R. Nelson-González, M. Pérez-Fehrmann, A. Cárdenas and
I. Brito, Acta Crystallogr., 2012, E68, o1727.
17 National Committee for Clinical Laboratory Standard (NCCLS) 2005,
Reference method for broth dilution antifungal susceptibility testing of
yeast. Approved standard – Second Edition. NCCLS document M27-A2.
18 National Committee for Clinical Laboratory Standard (NCCLS) 1998,
Reference method for broth dilution antifungal susceptibility testing of
conidia forming filamentous fungi. Proposed standard. NCCLS document
M38-P.
19 D. De Vita, L. Scipione, S. Tortorella, P. Mellini, B. Di Rienzo, G.
Simonetti, F.D. D´Auria, S. Panella, R. Cirilli, R. Di Santo and A.T.
Palamara, Eur. J. Med. Chem., 2012, 49, 334.
Conclusions
Several 2-(1H-azol-1-yl)-1-(substituted phenyl)ethanone (3
and 5) and 2-(1H-azol-1-yl)-1-(substituted phenyl)ethanol
derivatives (4 and 6) were synthesised and their antifungal
activity evaluated against two pathogenic fungal strains,
Candida albicans (fluconazole-resistant) and Aspergillus
fumigatus. Compounds with a methoxylated phenyl ring R2
group (3b, 4b, 5b) or fluorine atoms [5a (R1, R2 =F)] exhibited
20 S. Kumar, V. Gawandi, N. Capito and R. Philips, Biochemistry, 2010, 49,
7913.
21 A. Arrieta, I. Ganboa and C. Palomo, Synth. Commun., 1984, 14, 939.
22 K. Richardson, US Patent (1983) US4404216.
JCR1402689_FINAL.indd 552
23/09/2014 15:52:58

Copyright of Journal of Chemical Research is the property of Science Reviews 2000 Ltd. and
its content may not be copied or emailed to multiple sites or posted to a listserv without the
copyright holder's express written permission. However, users may print, download, or email
articles for individual use.