Synthesis and evaluation of some substituted heterocyclic fluconazole analogues as antifungal agents

Article abstract of DOI:10.14233/ajchem.2014.15956

A new series of fluconazole analogues of 1-(1H-1,2,4-triazol-1-yl)-2-(2,4- difluoro-phenyl)-3-4-(substituted-heterocyclic ring-1H-1,2,3- triazol-1-yl)-2-propanols (1-10) were designed, synthesized and evaluated as antifungal agents. Preliminary antifungal tests showed that most of the title compounds exhibited moderate activity with broad spectrum against eight human pathogenic fungi in vitro, compounds 1 and 6 had the best antifungal activity against Candida albicans with the value of MIC₈₀ = 0.5 μg/mL respectively.

Full text of DOI:10.14233/ajchem.2014.15956

Asian Journal of Chemistry; Vol. 26, No. 8 (2014), 2362-2364
ASIAN JOURNAL OF CHEMISTRY
http://dx.doi.org/10.14233/ajchem.2014.15956
Synthesis and Evaluation of Some Substituted Heterocyclic
Fluconazole Analogues as Antifungal Agents
1,†
2
1
1
1,*
SHUDONG WANG , LEI ZHANG2,3,†, YONGSHENG JIN , JIN HAO TANG , HUA SU , SHICHONG YU2,* and HAIXIANG REN
1Department of Pharmacy, General Hospital of Nanjing Military Region, Chinese People's Liberation Army, Zhongshan East Road 305,
Nanjing 210002, P.R. China
2College of Pharmacy, Second Military Medical University, Guohe Road 325, Shanghai 200433, P.R. China
3College of Pharmacy, Yantai University, Qingquan Road 30, Yantai 264005, P.R. China
*Corresponding authors: E-mail: yuscc1008@163.com; haixiangreng@163.com
†Shudong Wang and Lei Zhang contributed equally to this work
Received: 25 June 2013;
Accepted: 25 September 2013;
Published online: 15 April 2014;
AJC-15026
A new series of fluconazole analogues of 1-(1H-1,2,4-triazol-1-yl)-2-(2,4-difluoro-phenyl)-3-4-(substituted-heterocyclic ring-1H-1,2,3-
triazol-1-yl)-2-propanols (1-10) were designed, synthesized and evaluated as antifungal agents. Preliminary antifungal tests showed that
most of the title compounds exhibited moderate activity with broad spectrum against eight human pathogenic fungi in vitro, compounds
1 and 6 had the best antifungal activity against Candida albicans with the value of MIC80 = 0.5 µg/mL respectively.
Keywords: Triazole, Synthesis, Antifungal activity, 1,3,4-Oxadiazol.
TMS as internal standard NMR solvent. Mass spectra were
performed on an API-3000 LC-MS and Agilent Q-TOF-MS
spectrometer.
INTRODUCTION
During the past few decades, fungal infections are the
commonly prevalent diseases from which a large proportion
of the human population suffers1-5. The increased emergence
of both the superficial and systemic fungal infections has led
to the massive increase in the rate of mortality, especially in
the immuno-compromised individuals, those suffering from
tuberculosis, cancer orAIDS6,7. In clinic, azoles, especially triazole
antifungal agents, were used most widely and efficiently. For
example, fluconazole, voriconazole and itraconazole, presently
play an important role in the treatment of fungal infections.
However, their clinical use has been limited by the emergence
of drug resistance, high risk of toxicity, insufficiencies in their
antifungal activity and undesirable side effects8-10. Hence, there
is still a need to develop the safe and efficient chemotherapeutic
agents with potent broad spectrum antifungal activities10.
Synthesis of target compounds: The general synthetic
methodology for the preparation of title compounds is outlined
in Scheme-I. The key intermediate 1 was synthesized by the
reported procedure11,12, the triazolone-containing side chains
were prepared via four steps. Various substituted benzoic acid
1-10a were converted to methyl benzoate 1-10b by reacting
with methanol, followed by treating with hydrazine hydrate
to give benzohydrazide 1-10c. 1-10d were synthesized by
reacting the 1-10c with carbon disulphide in presence of KOH
and conc sulfuric acid and then reacted with 3-bromo-1-
propyne to give the side chains 1-10e. The compounds 1-10
were carried out under the click-reaction13,14 condition in the
presence of CuSO4 and sodium ascorbate. All the title com-
pounds (1-10) described above were characterized by ESI and
NMR spectroscopic analysis.
EXPERIMENTAL
1
Compound 1: Yellow oil, yield: 81 %; H NMR (300
Analytical TLC was carried out on Silica Gel 60 F254
plates (E. Merck) with detection by fluorescence and/or by
charring with 10 % (v/v) H2SO4 in EtOH. Column chroma-
tograph was performed on silica gel (200-300 mesh, Qindao
Ocean Chemical Co., China). All chemicals and solvents were
purchased from commercial sources unless specified other-
wise. 1H and 13C NMR spectra were recorded in CDCl3, using
MHz, CDCl3) δ 8.02 (s, 1H), 7.94-7.73 (m, 3H), 7.50-7.26
(m, 4H), 6.78-6.70 (dd, 2H, J = 16.8, 7.3 Hz), 5.35 (s, 1H),
4.89-4.84 (d, 1H, J = 14.2 Hz), 4.75-4.72 (m, 2H), 4.63-4.46
(m, 2H), 4.33-4.29 (d, 1H, J = 14.3 Hz), 2.69 (s, 3H); [M
+
+ H] 511.14, found 511.57.
Compound 2: Yellow oil, yield: 83 %; H NMR (300
MHz, CDCl3) δ 8.16-7.67 (m, 5H), 7.41-7.39 (m, 3H), 6.72-
1

Vol. 26, No. 8 (2014)
Synthesis and Evaluation of Some Substituted Heterocyclic Fluconazole Analogues 2363
Scheme-I: Synthesis of the target compounds 1-10
1
6.69 (m, 2H), 5.36 (s, 1H), 4.88-4.84 (d, 1H, J = 14.3 Hz),
4.78-4.62 (m, 2H), 4.61-4.42 (m, 2H), 4.33-4.29 (d, 1H, J =
14.1 Hz), 2.43 (s, 3H); [M + H]+ 511.14, found 511.64.
Compound 8: Yellow oil, yield: 83 %; H NMR (300
MHz, CDCl3) δ 8.01 (s, 1H), 7.82 (s, 1H), 7.74 (1H, s), 7.39-
7.31 (dd, 3H, J = 15.5, 9.1 Hz), 6.85-6.68 (m, 3H), 4.86-4.81(d,
1H, J = 14.3 Hz), 4.74-4.73 (d, 2H, J = 2.8 Hz), 4.54-4.53 (d,
2H, J = 2.1 Hz), 4.34-4.29 (d, 1H, J = 14.3 Hz), 1.25 (s, 9H);
[M + H]+ 552.18, found 552.57.
1
Compound 3: Yellow oil, yield: 86 %; H NMR (300
MHz, CDCl3) δ 8-7.80 (m, 5H), 7.68-7.60 (m, 1H), 7.52-7.27
(m, 1H), 6.87-6.66 (m, 4H), 4.87-4.86 (m, 1H), 4.79-4.69 (m,
3H), 4.60-4.47 (m, 1H), 3.71-3.67 (d, 1H, J = 12.8 Hz), 3.56-
3.51 (d, 1H, J = 12.8 Hz), 2.38 (3H, s); [M + H]+ 511.14,
found 511.51.
1
Compound 9: Yellow oil, yield: 89 %; H NMR (300
MHz, CDCl3) δ 8.14-8.11 (d, 2H, J = 8.1 Hz), 8.04 (s, 1H),
7.85 (s, 1H), 7.84-7.73 (m, 3H), 7.37 (m, 1H), 6.82-6.65 (m,
2H), 4.89-4.84 (d, 1H, J = 14.4 Hz), 4.80-4.69 (q, 2H, J =
14.3 Hz), 4.56 (s, 2H), 4.35-4.31 (d, 1H, J = 14.2 Hz), 2.63-
2.60 (m, 2H), 1.66-1.65 (m, 6H), 1.45-1.15 (m, 3H); [M + H]+
566.20, found 566.62.
Compound 4: Pale yellow oil, yield: 88 %; 1H NMR (300
MHz, CDCl3) δ 8 (s, 1H), 7.84 (s, 1H), 7.75 (s, 1H), 7.45-7.31
(m, 3H), 6.85-6.62 (m, 3H), 4.88-4.83 (d, 1H, J = 14.2 Hz),
4.74-4.72 (d, 2H, J = 6.5 Hz), 4.56-4.55 (d, 2H, J = 2.9 Hz),
4.32-4.27 (d, 1H, J = 14.3 Hz); [M + H]+ 586.09, found 586.42.
1
Compound 10: Yellow oil, yield: 80 %; H NMR (300
1
Compound 5: Yellow oil, yield: 82 %; H NMR (300
MHz, CDCl3) δ 8.0-7.96 (d, 3H, J = 13.4 Hz), 7.83-7.76 (m,
2H), 7.61-7.42 (m, 3H), 7.39-7.31(m, 1H), 6.86-6.55 (m, 2H),
5.46 (s, 1H), 4.87-4.82 (d, 1H, J = 14.3 Hz), 4.77-4.63 (m,
2H), 4.53 (s, 1H), 4.35-4.40 (d, 1H, J = 14.3 Hz); [M + H]+
496.12, found 496.43.
MHz, CDCl3) δ 8.02 (s, 1H), 7.86 (s, 1H), 7.76 (s, 1H), 7.47-
7.31 (m, 1H), 6.85-6.68 (m, 2H), 4.89-4.84 (d, 1H, J = 14.1
Hz), 4.79-4.67 (d, 2H, J = 14.2 Hz), 4.61-4.56 (d, 2H, J = 7.4
Hz), 4.32-4.27 (d, 1H, J = 14.2 Hz); [M + H]+ 568.08, found
568.35.
RESULTS AND DISCUSSION
1
Compound 6: Brown oil, yield: 81 %; H NMR (300
All the title compounds (1-10) were screened for anti-
fungal activity against eight pathogenic fungi. The in vitro
minimal inhibitory concentrations (MICs) of the compounds
were determined by the micro-broth dilution method in 96-
well microtest plates according to the methods defined by
the National Committee for Clinical Laboratory Standards
(NCCLS)15. Itraconazole (ICZ) and fluconazole (FCZ) served
as the positive controls were obtained from their respective
manufacturers. Table-1 showed that all the synthesized comp-
ounds show moderate activity against all the tested fungal
pathogens. Most of our compounds showed the good antifungal
MHz, CDCl3) δ 8.06-7.71 (4H, m), 7.52-7.29 (3H, m), 6.80-
6.74 (3H, m), 5.18-5.16 (1H, d, J = 6.2 Hz), 4.95-4.68 (4H,
m), 4.56-4.54 (1H, d, J = 6 Hz), 2.63-2.61 (2H, d, J = 6.1 Hz),
1.68 (2H, m), 1.45-1.12 (3H, m); [M + H]+ 538.17, found
538.55.
1
Compound 7: Yellow oil, yield: 85 %; H NMR (300
MHz, CDCl3) δ 8.11-7.74 (m, 4H), 7.52-7.29 (m, 3H), 6.82-
6.74 (m, 3H), 5.17-5.15 (d, 1H, J = 6.2 Hz), 4.85-4.69 (m,
4H), 4.57-4.53 (d, 1H, J =12 Hz), 2.62-2.58 (m, 2H),1.68-
1.64 (m, 4H), 1.45-1.22 (m, 3H); [M + H]+ 552.18, found
552.57.

2364 Wang et al.
Asian J. Chem.
TABLE-1
ANTIFUNGAL ACTIVITY OF THE TARGET COMPOUNDS in vitro (MIC80: µg/mL)
Compd.
R
C. alb Y0109
C. alb SC5314
C. pra
C. neo
C. gla
0.5
1
A. fum
> 64
> 64
64
T. rub
M. gyp
> 64
32
2-CH3
3-CH3
0.5
1
0.5
2
0.5
1
0.5
0.5
1
64
32
8
1
2
4-CH3
1
4
2
0.25
2
16
3
3,5-NO2
2,3,4,5,6-F
4-(CH2)2CH3
4-(CH2)3CH3
4-C(CH2)3
4-(CH2)4CH3
H
1
1
1
2
> 64
> 64
> 64
> 64
> 64
32
64
64
32
> 64
32
16
> 64
2
64
4
2
2
2
2
2
64
5
0.5
2
0.5
2
8
8
0.5
2
64
6
16
4
8
> 64
32
7
4
2
2
0.5
1
8
8
8
16
4
4
16
9
1
4
0.5
4
1
> 64
8
> 64
2
10
ICZ
FCZ
-
8
4
8
8
-
0.5
0.5
1
1
1
> 64
8
8
Abbreviations: C. alb. Y0109 = Candida albicans Y0109; C. alb. SC5314 = Candida albicans SC5314; C. par. = Candida parapsilosis; C. neo. =
Cryptococcus neoformans; C. gla. = Candida glabrata; A. fum. = Aspergillus fumigatus; T. rub. = Trichophyton rubrum; M. gyp. = Microsporum
gypseum. ICZ = Itraconazole; FCZ = Fluconazole.
activities than the positive control itraconazole. It is noted that
the MIC80 values of compounds 1 and 6 were equal or a little
bit lower than that of fluconazole and itraconazole against C.
albicans, C. parapsilosis, C. neoformans and C. glabrata.
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