Synthesis of Substituted Chalcones and Assessment of their Antifungal Activity Against Trichophyton rubrum

Full text of DOI:10.1007/s10600-018-2281-7

DOI 10.1007/s10600-018-2281-7
Chemistry of Natural Compounds, Vol. 54, No. 1, January, 2018
SYNTHESIS OF SUBSTITUTED CHALCONES AND ASSESSMENT
OF THEIR ANTIFUNGAL ACTIVITY AGAINST Trichophyton rubrum
1
2*
1
Kai-Xia Zhang, Wei Wang, Fei Zhao,
1*
1,3*
Qing-Guo Meng, and Yong-Sheng Jin
Fungal infections can include superficial and systemic ones. The anthropophilic species Trichophyton rubrum is an
important etiologic agent of dermatophytosis and accounts for 69.5% of all dermatophytic infections [1, 2]. Infections caused
by this species are difficult to treat, especially in immunocompromised patients. Although many antifungal drugs are available,
their side effects and interactions with other drugs, as well as the emergence of resistant strains, have limited their clinical use
[3]. Therefore, novel drugs with more specific and effective mechanisms of action against dermatophytes are urgently needed.
Some studies have reported that chalcones can exert antitumor, anti-inflammatory, and cardiovascular effects [4–6].
In light of their extremely high values, chalcones have become a popular focus of research and development. Several studies
[7–10] have reported that certain natural and synthetic chalcone derivatives could exert antifungal effects. Bitencourt et al.
reported that non-substituted chalcones were effective against T. rubrum [11] by down-regulating fatty acid synthase gene
expression and reducing ergosterol content. We therefore designed and synthesized chalcones and screened them for antifungal
activity against T. rubrum. Previous studies identified structure–activity relationships (SARs) between chalcones and antifungal
activity, but to our knowledge the actions of 2ꢀ-substituted chalcones have not been characterized. In this work, we synthesized
2ꢀ-substituted chalcones and screened them for antifungal activity against T. rubrum. As expected, most compounds exhibited
good activity (Table 1). Herein we report the results and discuss the SARs.
In total, 25 compounds were synthesized (Scheme 1) and evaluated for in vitro antifungal activity against T. rubrum;
Table 1 summarizes the findings.
2'
R
R
1
1
4'
a
H
R
2
+
1
R
2
2
3
6'
O
O
O
1 - 25
1-13: R = OH, 14-24: R = NH
2
1
1
1: R = 3-NO -Ph; 2: R =2-F-Ph; 3: R = 3-F-Ph; 4: R = 4-F-Ph
2
2
2
2
2
5: R = 3-Cl-Ph; 6: R = 3,4-diCl-Ph; 7: R = 2,4-diCl-Ph
2
2
2
8: R = 2-Br-Ph; 9: R = 4-Br-Ph; 10: R =2-Furyl
2
2
2
11: R = 5-CH OH-2-Furyl; 12: R = 2-Naphthyl
2
2
2
13: R = 4-OH-3-OCH -Ph; 14: R = 3,4-(OCH ) -Ph
2
3
2
3 2
15: R = 3-NO -Ph; 16: R = 4-NO -Ph; 17: R = 2-F-Ph
2
2
2
2
2
18: R = 3-F-Ph; 19: R = 4-F-Ph; 20: R = 2,4-diCl-Ph
2
2
2
21: R = 3,4-diCl-Ph; 22: R = 2-Br-Ph; 23: R = 2-Naphthyl
2
2
2
24: R = 2-Furyl; 25: R = NO , R = 3,4-(OCH ) -Ph
2
1
2
2
3 2
a. 10% NaOH, EtOH, r.t.
Scheme 1
1) School of Pharmacy, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in
Universities of Shandong, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of
Education, Yantai University, 264005, Yantai, P. R. China, fax: +86 21 81871227, e-mail: ysjinsmmu@163.com,
ysjin@smmu.edu.cn; 2) No. 455 Hospital of PLA, 200052, Shanghai, P. R. China; 3) School of Pharmacy, Second Military
Medical University, 200433, Shanghai, P. R. China. Published in Khimiya Prirodnykh Soedinenii, No. 1, January–February,
2018, pp. 133–135. Original article submitted March 9, 2016.
158
0009-3130/18/5401-0158 02018 Springer Science+Business Media, LLC

TABLE 1. Antifungal Activities of the Title Compounds in vitro (MIC , ꢁg/mL)
80
Compound
Compound
MIC80, ꢁg/mL
MIC80, ꢁg/mL
16
16
4
> 64
> 64
4
1
0.5
1
8
16
16
> 64
4
> 64
> 64
0.5
0.5
> 64
1
1
3
5
7
2
4
6
8
9
10
11
13
15
17
19
21
23
25
12
14
16
18
20
22
24
1
> 64
> 64
16
> 64
0.25
Fluconazole
Sixteen compounds (1–6, 10, 11, 13, 15–19, 22, and 25) exhibited antifungal activity. Values of the minimum inhibitory
concentration required to inhibit 80% of cells (MIC ) ranged from 0.5 to 16 ꢁg/mL; compounds 15, 16, and 18 were the most
80
potent (MIC = 0.5 ꢁg/mL). These findings suggest that 2ꢀ-amino substituents are more effective than 2ꢀ-hydroxy substituents.
80
In addition, almost all compounds exhibited potent activity, with the exception of compounds 14, 20, 21, 23, and 24. Substituents
of the B-ring appeared to exert notable effects on antifungal activity. In general, nitro substituents (1, 15, and 16),
fluorosubstituents (2–4, 17–19), and a hydroxy substituent (11) exhibited better antifungal activity than other compounds.
A benzene ring appeared to be superior to a naphthalene nucleus (12 and 23), and a single substituent appeared to be better
than disubstituents (6, 7, 14, 20, 21, and 25). The natural compound 13 also exhibited good antifungal activity (MIC = 1 ꢁg/mL)
80
[12], suggesting that some natural chalcones could act as antifungal agents. The 2ꢀ-nitrochalcone (25) exerted an antifungal
effect against T. rubrum, but replacing the 2ꢀ-nitro group with a 2ꢀ-amino group (14) resulted in no antifungal activity. The 2ꢀ-nitro
substituent could therefore be a factor in antifungal activity, but this hypothesis requires further study.
In conclusion, 25 chalcones were synthesized and screened for antifungal activity against T. rubrum. Seven compounds
(13, 15–19, and 22) displayed promising antifungal activities (MIC ꢂ 1 ꢁg/mL). Assessment of the SARs indicated that the
80
introduction of –NH on ring A at the 2 position may improve antifungal activity. The present findings may guide the design
2
of chalcone analogs with high antifungal activity, although the underlying mechanism has not been elucidated yet. Further
work is already in progress.
1
General Comments. H NMR spectra were obtained on a BrukerAvance II 300 or 600 spectrometer (Bruker, Billerica,
1
MA, USA), and chemical shifts are reported in parts per million relative to CDCl (7.27 ppm for H) and DMSO-d (2.53 ppm
3
6
1
for H). Unless otherwise noted, the materials were obtained from commercially available sources and were used without
further purification.
Synthesis of Chalcones (general method). A solution of acetophenone (1 mmol) in ethanol (10 mL) was treated
with 10% NaOH aqueous solution (4 mmol) and benzaldehyde (1 mmol) in ethanol with stirring at room temperature for
12–24 h. The reaction was monitored by TLC. The mixture was then cooled on ice, and AcOH was added; pH was adjusted to
3–4. The mixture was then filtered, dried, and recrystallized from ethanol to yield the title compounds.
Identification of all title compounds was performed by NMR and MS [13].
(E)-1-(2ꢀ-Hydroxyphenyl)-3-(3-nitrophenyl)prop-2-en-1-one (1), mp 162–164ꢃC.
(E)-3-(2-Fluorophenyl)-1-(2ꢀ-hydroxyphenyl)prop-2-en-1-one (2), mp 80–82ꢃC.
(E)-3-(3-Fluorophenyl)-1-(2ꢀ-hydroxyphenyl)prop-2-en-1-one (3), mp 104–106ꢃC.
(E)-3-(4-Fluorophenyl)-1-(2ꢀ-hydroxyphenyl)prop-2-en-1-one (4), mp 114–115ꢃC.
(E)-3-(3-Chlorophenyl)-1-(2ꢀ-hydroxyphenyl)prop-2-en-1-one (5), mp 94–96ꢃC.
(E)-3-(3,4-Dichlorophenyl)-1-(2ꢀ-hydroxyphenyl)prop-2-en-1-one (6), mp 153–155ꢃC.
(E)-3-(2,4-Dichlorophenyl)-1-(2ꢀ-hydroxyphenyl)prop-2-en-1-one (7), mp 168–170ꢃC.
(E)-3-(2-Bromophenyl)-1-(2ꢀ-hydroxyphenyl)prop-2-en-1-one (8), mp 92–94ꢃC.
(E)-3-(4-Bromophenyl)-1-(2ꢀ-hydroxyphenyl)prop-2-en-1-one (9), mp 146–148ꢃC.
(E)-3-(Furan-2-yl)-1-(2ꢀ-hydroxyphenyl)prop-2-en-1-one (10), mp 100–102ꢃC.
159

(E)-3-(5-(Hydroxymethyl)furan-2-yl)-1-(2ꢀ-hydroxyphenyl)prop-2-en-1-one (11), mp 92–94ꢃC.
(E)-1-(2ꢀ-Hydroxyphenyl)-3-(naphthalen-2-yl)prop-2-en-1-one (12), mp 152–154ꢃC.
(E)-3-(4-Hydroxy-3-methoxyphenyl)-1-(2ꢀ-hydroxyphenyl)prop-2-en-1-one (13), mp 123–125ꢃC.
(E)-1-(2ꢀ-Aminophenyl)-3-(3,4-dimethoxyphenyl)prop-2-en-1-one (14), mp 84–86ꢃC.
(E)-1-(2ꢀ-Aminophenyl)-3-(3-nitrophenyl)prop-2-en-1-one (15), mp 152–153ꢃC.
(E)-1-(2ꢀ-Aminophenyl)-3-(4-nitrophenyl)prop-2-en-1-one (16), mp 144–147ꢃC.
(E)-1-(2ꢀ-Aminophenyl)-3-(2-fluorophenyl)prop-2-en-1-one (17), mp 91–93ꢃC.
(E)-1-(2ꢀ-Aminophenyl)-3-(3-fluorophenyl)prop-2-en-1-one (18), mp 102–104ꢃC.
(E)-1-(2ꢀ-Aminophenyl)-3-(4-fluorophenyl)prop-2-en-1-one (19), mp 87–90ꢃC.
(E)-1-(2ꢀ-Aminophenyl)-3-(2,4-dichlorophenyl)prop-2-en-1-one (20), mp 132–134ꢃC.
(E)-1-(2ꢀ-Aminophenyl)-3-(3,4-dichlorophenyl)prop-2-en-1-one (21), mp 118–120ꢃC.
(E)-1-(2ꢀ-Aminophenyl)-3-(2-bromophenyl)prop-2-en-1-one (22), mp 76–78ꢃC.
(E)-1-(2ꢀ-Aminophenyl)-3-(naphthalen-2-yl)prop-2-en-1-one (23), mp 118–121ꢃC.
(E)-1-(2ꢀ-Aminophenyl)-3-(furan-2-yl)prop-2-en-1-one (24), mp 63–66ꢃC.
(E)-3-(3,4-Dimethoxyphenyl)-1-(2ꢀ-nitrophenyl)prop-2-en-1-one (25), mp 120–122ꢃC.
Antifungal Activity Assay. The in vitro antifungal activities of the synthesized compounds were evaluated against
T. rubrum, and fluconazole served as the positive control. The in vitro MIC values of the compounds were determined by the
broth microdilution method in 96-well microtest plates using the protocols of the Clinical and Laboratory Standards Institute,
USA [14]. The MIC was determined as the first well to exhibit an approximately 80% reduction in growth compared with
80
growth in drug-free wells. The compounds were dissolved in DMSO, serially diluted in growth medium, inoculated, and
incubated at 35ꢃC. The growth MIC was determined at 24 h. The data points in Table 1 represent the mean of the replicates.
All tests were conducted in triplicate for each compound.
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