Antifungal agents. Part 3: Synthesis and antifungal activities of 3-acylindole analogs against phytopathogenic fungi in vitro

Article abstract of DOI:10.1111/j.1747-0285.2011.01212.x

To find more potent antifungal compounds, twenty 3-acylindole analogs were synthesized and bio-evaluated for their antifungal activities against seven phytopathogenic fungi. Structure-activity relationships investigations revealed that 4- or 6-methyl and 3-acetyl or propionyl groups were the important structural properties of 3-acylindoles for the activities. Especially 4-methyl-3-propionylindole, 12, displayed the more potent activities than hymexazol, a commercially available agricultural fungicide, and might be considered as a new promising lead candidate for further design and synthesis of agricultural fungicides.

Full text of DOI:10.1111/j.1747-0285.2011.01212.x

ª 2011 John Wiley & Sons A/S
doi: 10.1111/j.1747-0285.2011.01212.x
Chem Biol Drug Des 2011; 78: 864–868
Research Article
Antifungal Agents. Part 3: Synthesis and
Antifungal Activities of 3-Acylindole Analogs
against Phytopathogenic Fungi In Vitro
and silica gel column chromatography were used with silica gel 60
GF254 and 200–300 mesh, respectively (Qingdao Haiyang Chemical Co.,
Ltd., Quingdao, China). Melting points were determined on a digital
melting-point apparatus and were uncorrected. Proton nuclear mag-
netic resonance spectra (1H NMR) were recorded on a Bruker Avance
DMX 300 or 400 MHz instrument using tetramethylsilane as the inter-
nal standard and CDCl3 or DMSO-d6 as the solvent. Electron ionization
mass spectra (EI-MS) were carried out with the HP 5988 instrument.
Hui Xu*, Wen-bin Yang and Qin Wang
Laboratory of Pharmaceutical Design and Synthesis, College of
Sciences, Northwest A&F University, Yangling 712100, China
*Corresponding author: Hui Xu, orgxuhui@nwsuaf.edu.cn
To find more potent antifungal compounds,
twenty 3-acylindole analogs were synthesized and
bio-evaluated for their antifungal activities against
seven phytopathogenic fungi. Structure–activity
relationships investigations revealed that 4- or 6-
methyl and 3-acetyl or propionyl groups were the
important structural properties of 3-acylindoles
for the activities. Especially 4-methyl-3-propiony-
lindole, 12, displayed the more potent activities
than hymexazol, a commercially available agricul-
tural fungicide, and might be considered as a new
promising lead candidate for further design and
synthesis of agricultural fungicides.
Synthesis of compounds
Procedure A: synthesis of compounds 1–7
To N,N-dimethylformamide (DMF, 7 mL) was added drop-wise phos-
phorus oxychloride (POCl3, 1 mL) at 0 ꢀC. The mixture was stirred for
20 min, and a solution of indole (10 mmol) in DMF (3 mL) was added
drop-wise. After the mixture was stirred at 35 ꢀC for 1 h, ice was
added, followed by 20% aq. sodium hydroxide (NaOH), and the mix-
ture was refluxed for 6 h. On cooling, the mixture was poured into
ice water, and the precipitated product was collected, washed by
water, and dried (9) (Scheme 1).
Key words: 3-acylindole, antifungal activity, phytopathogenic fungi,
synthesis
Received 9 June 2010, revised 17 June 2011 and accepted for
publication 2 August 2011
1
3-Formylindole (1): Pink solid, yield 96%, m.p. 190–192 ꢀC; H NMR
(400 MHz, DMSO-d6): d 9.93 (s, 1H, CHO), 8.29 (s, 1H), 8.08 (d,
J = 8.0 Hz, 1H), 7.50 (d, J = 8.0 Hz, 1H), 7.20–7.28 (m, 2H); EI-MS,
m ⁄ z (%) 145 (M+, 96).
Recently, the chemistry of 3-acylindole derivatives has received much
attention (1), because some compounds derived from 3-acylindoles
exhibited the broad spectrum of biological activities, e.g., anticancer
activity (2), anti-inflammatory activity (3), and inhibitors of the cyto-
solic phospholipase A(2) (4). To the best of our knowledge, however,
little attention has been paid to the antifungal activities of 3-acylin-
dole analogs against phytopathogenic fungi. Meanwhile, phytopatho-
genic fungi, which are continually becoming resistant to the existing
fungicides and hard to control, easily infect many crops; the develop-
ment of bioactive compounds for effective control of those agricul-
tural diseases is therefore highly desirable. In continuation of our
program aimed at the discovery and development of bioactive mole-
cules (5–8), herein we designed and synthesized a series of 3-acylin-
dole analogs as the antifungal agents, and wanted to investigate
the structure–activity relationships (SAR) of these compounds.
4-Methyl-3-formylindole (2): Brown solid, yield 83%, m.p. 189–
1
191 ꢀC; H NMR (400 MHz, DMSO-d6): d 9.91 (s, 1H, CHO), 8.25 (s,
1H), 7.31 (d, J = 8.0 Hz, 1H), 7.12 (t, J = 8.0 Hz, 1H), 6.98 (d,
J = 7.2 Hz, 1H), 2.77 (s, 3H); EI-MS, m ⁄ z (%) 159 (M+, 91).
6-Methyl-3-formylindole (3): Brown solid, yield 92%, m.p. 190–
191 ꢀC; 1H NMR (400 MHz, DMSO-d6): d 9.89 (d, J = 2.0 Hz, 1H,
CHO), 8.21 (s, 1H), 7.95 (d, J = 8.4 Hz, 1H), 7.30 (s, 1H), 7.04 (d,
J = 8.0 Hz, 1H), 2.41 (s, 3H); EI-MS, m ⁄ z (%) 159 (M+, 68).
7-Methyl-3-formylindole (4): White solid, yield 96%, m.p. 203–
1
204 ꢀC; H NMR (400 MHz, DMSO-d6): d 9.94 (s, 1H, CHO), 8.30 (s,
1H), 7.92 (d, J = 7.6 Hz, 1H), 7.05–7.15 (m, 2H), 2.50 (s, 3H); EI-MS,
m ⁄ z (%) 159 (M+, 71).
Materials and Methods
2-Methyl-3-formylindole (5): White solid, yield 93%, m.p.
196–198 ꢀC; H NMR (400 MHz, DMSO-d6): d 10.05 (s, 1H, CHO),
Reagents and analysis
All reagents and solvents were of reagent grade or purified accord-
ing to standard methods before use. Thin-layer chromatography (TLC)
1
864

Synthesis and Antifungal Activities of 3-Acylindole Analogs
O
H
Me
N
R1
POCl3
R1
83–96%
H
+
Me
N
H
N
O
H
1-7
1 R1 = H; 2 R1 = 4-Me; 3 R1 = 6-Me; 4 R1 = 7-Me
5 R1 = 2-Me; 6 R1 = 5-CN; 7 R1 = 5-NO2
Scheme 1: The synthetic route of compounds 1–7.
8.04–8.06 (m, 1H), 7.38 (dd, J = 6.4, 2.0 Hz, 1H), 7.15–7.18 (m, 2H),
2.68 (s, 3H); EI-MS, m ⁄ z (%) 159 (M+, 67).
3-Acyl-N-(p-toluenesulfonyl)indoles (11): To a magnetically stirred
mixture of AlCl3 (7 mmol) and acetic anhydride (3 mmol) in CH2Cl2
(15 mL) at room temperature, a solution of N-(p-methyl)phenylsulf-
onylindoles (1 mmol) in CH2Cl2 (5 mL) was added drop-wise. After
adding, the mixture was stirred at room temperature for 2 h and
poured into crushed ice. The organic phase was separated from the
mixture, and the aqueous phase was extracted with CH2Cl2. Then,
the combined organic phase was washed with saturated aq. NaH-
CO3 and brine, dried over anhydrous sodium sulfate, concentrated
in vacuo, and purified by silica gel column chromatography to afford
3-acyl-(p-methyl)phenylsulfonylindoles.
5-Cyano-3-formylindole (6): Yellow solid, yield 94%, m.p. 256–
1
258 ꢀC; H NMR (400 MHz, DMSO-d6): d 10.01 (s, 1H, CHO), 8.52
(s, 1H), 8.47 (s, 1H), 7.71 (d, J = 8.4 Hz, 1H); 7.65 (d, J = 8.0 Hz,
1H); EI-MS, m ⁄ z (%) 170 (M+, 70).
5-Nitro-3-formylindole (7): Yellow solid, yield 86%, m.p. 293–
1
294 ꢀC; H NMR (400 MHz, DMSO-d6): d 10.03 (s, 1H, CHO), 8.94
(d, J = 2.0 Hz, 1H), 8.58 (s, 1H), 8.15 (dd, J = 9.2, 2.4 Hz, 1H), 7.71
(d, J = 9.2 Hz, 1H); EI-MS, m ⁄ z (%) 190 (M+, 100).
3-Acylindole analogs (8–20) (12): A mixture of 3-acyl-N-(p-toluene-
sulfonyl)indoles (1 mmol) and t-BuOK (1.8 mmol) in anhydrous tet-
rahydrofurame (THF) (5 mL) was stirred at reflux under argon. The
progress of the reaction was monitored by TLC analysis. After
1–3 h, the mixture was poured into ice water, and the solution
was extracted with ethyl acetate. The organic phase was com-
bined, washed with brine, dried over anhydrous sodium sulfate,
concentrated in vacuo, and purified by silica gel column chroma-
tography to give the target products (Scheme 2).
Procedure B: synthesis of compounds 8–20
N-(p-Toluenesulfonyl)indoles (10): To a mixture of indoles (10 mmol),
triethylbenzylammonium chloride (TEBA) (1 mmol) and NaOH
(17.5 mmol) in CH2Cl2 (10 mL) were added the p-methylphenylsulfo-
nyl chloride (12 mmol), and the mixture was stirred at room temper-
ature. After stirring for 1 h, the reaction was complete according to
TLC analysis, CH2Cl2 and H2O was added to the mixture, and the
organic layer was separated from the mixture. Subsequently, the
organic phase was washed with brine, dried over anhydrous sodium
sulfate, concentrated under reduced pressure, and purified by silica
gel column chromatography to afford N-(p-methyl)phenylsulfonylin-
doles.
3-Acetylindole (8): Yellow solid, yield 73%, m.p.189–190 ꢀC; 1H-
NMR (300 MHz, DMSO-d6) d: 11.93 (s, 1H, NH), 8.31 (s, 1H), 8.18
(d, J = 6.6 Hz, 1H), 7.46 (d, J = 7.0 Hz, 1H), 7.15–7.21 (m, 2H), 2.46
(s, 3H); EI-MS, m ⁄ z (%) 159 (M+, 52).
SO2Cl
R1
(R2CO)2O or R2COCl
R1
NaOH/TEBA
+
N
O2S
N
H
DCM/r.t.
92–96%
AlCl3/DCM/r.t.
82–99%
Me
Me
O
R2
O
R2
R1
t-BuOK/THF/reflux
R1
N
O2S
40–73%
N
H
8-20
Me
8 R1 = H, R2 = Me; 9 R1 = H, R2 = Et; 10 R1 = H, R2 = n-pentyl;
11 R1 = 4-Me, R2 = Me; 12 R1 = 4-Me, R2 = Et; 13 R1 = 4-Me, R2 = n-pentyl;
14 R1 = 6-Me, R2 = Me; 15 R1 = 6-Me, R2 = Et; 16 R1 = 6-Me, R2 = n-pentyl;
17 R1 = 5-CN, R2 = Me; 18 R1 = 5-CN, R2 = Et; 19 R1 = 5-CN, R2 = n-pentyl;
20 R1 = 5-NO2, R2 = n-pentyl
Scheme 2: The synthetic route of compounds 8–20.
Chem Biol Drug Des 2011; 78: 864–868
865

Xu et al.
1
3-Propionylindole (9): White solid, yield 63%, m.p. 162–163 ꢀC; H-
NMR (300 MHz, CDCl3) d: 8.69 (s, 1H, NH), 8.42 (s, 1H), 7.89 (s,
1H), 7.26–7.41 (m, 3H), 2.93–2.95 (m, 2H), 1.26–1.30 (m, 3H); EI-
MS, m ⁄ z (%) 173 (M+, 32).
5-Nitro-3-hexanoylindole (20): Yellow solid, yield 51%, m.p. 209–
210 ꢀC; H-NMR (300 MHz, DMSO-d6) d: 12.54 (s, 1H, NH), 9.08 (s,
1
1H), 8.61 (s, 1H), 8.10 (d, J = 8.1 Hz, 1H), 7.65 (d, J = 8.9 Hz, 1H),
2.87–2.92 (m, 2H), 1.67 (s, 2H), 1.33–1.34 (m, 4H), 0.88 (s, 3H); EI-
MS, m ⁄ z (%) 260 (M+, 2).
3-Hexanoylindole (10): White solid, yield 71%, m.p. 146–148 ꢀC;
1H-NMR (300 MHz, CDCl3) d: 8.76 (s, 1H, NH), 8.42 (s, 1H), 7.88 (s,
1H), 7.52 (s, 1H), 7.29–7.41 (m, 2H), 2.85 (t, J = 6.8 Hz, 2H), 1.79 (s,
2H), 1.38 (s, 4H), 0.90 (s, 3H); EI-MS, m ⁄ z (%) 215 (M+, 24).
Biological assay
Twenty 3-acylindole analogs (1–20) were screened in vitro for
their antifungal activities against seven phytopathogenic fungi by
poisoned food technique (8). Seven phytopathogenic fungi, namely
Fusarium graminearum, Alternaria alternata, Bipolaris sorokinianum,
Pyricularia oryzae, Fusarium oxysporum f. sp. vasinfectum, Fusarium
oxysporum f. sp. cucumarinum, and Alternaria brassicae, were
used for the assays. Potato dextrose agar (PDA) medium was pre-
pared in the flasks and sterilized. Compounds 1–20 were dis-
solved in acetone before mixing with PDA, and the concentration
of test compounds in the medium was fixed at 100 lg ⁄ mL. The
medium was then poured into sterilized Petri dishes. All types of
fungi were incubated in PDA at 28 € 1 ꢀC for 5 days to obtain
new mycelium for the antifungal assays, and a mycelia disk of
approximately 5 mm diameter cut from culture medium was picked
up with a sterilized inoculation needle and inoculated in the cen-
ter of the PDA Petri dishes. The inoculated Petri dishes were incu-
bated at 28 € 1 ꢀC for 4 days. Acetone without any compounds
mixed with PDA was served as a control, while hymexazol, a com-
mercial agricultural fungicide, and N-(p-toluenesulfonyl)-3-acetylin-
dole (21), N-(p-toluenesulfonyl)-3-acetyl-6-methylindole (22), and
N-(p-toluenesulfonyl)-3-acetyl-5-cyanoindole (23), were used as
positive controls. For each treatment, three replicates were con-
ducted. The radial growths of the fungal colonies were measured
and the data were statistically analyzed. The inhibitory effects of
the test compounds on these fungi in vitro were calculated by the
formula:
4-Methyl-3-acetylindole (11): Yellow solid, yield 49%,
m.p.184–186 ꢀC; 1H-NMR (300 MHz, DMSO-d6) d: 11.89 (s, 1H,
NH), 8.29 (s, 1H), 7.25 (d, J = 7.9 Hz, 1H), 7.06 (t, J = 7.7 Hz, 1H),
6.89 (d, J = 6.8 Hz, 1H), 2.72 (s, 3H), 2.48 (s, 3H); EI-MS, m ⁄ z (%)
173 (M+, 55).
4-Methyl-3-propionylindole (12): White solid, yield 63%, m.p. 151–
155 ꢀC; 1H-NMR (400 MHz, CDCl3) d: 8.72 (s, 1H, NH), 7.81 (d,
J = 3.2 Hz, 1H), 7.15–7.23 (m, 2H), 7.03 (d, J = 7.2 Hz, 1H), 2.89 (q,
J = 7.2 Hz, 2H), 2.83 (s, 3H), 1.23 (t, J = 7.6 Hz, 3H); EI-MS, m ⁄ z
(%) 187 (M+, 22).
4-Methyl-3-hexanoylindole (13): White solid, yield 54%, m.p. 145–
1
146 ꢀC; H-NMR (300 MHz, CDCl3) d: 8.91 (s, 1H, NH), 7.77 (s, 1H),
7.02–7.25 (m, 3H), 2.82–2.88 (m, 5H), 1.77 (s, 2H), 1.37 (s, 4H), 0.90
(s, 3H); EI-MS, m ⁄ z (%) 229 (M+, 21).
6-Methyl-3-acetylindole (14): White solid, yield 64%, m.p. 188–
1
189 ꢀC; H-NMR (300 MHz, DMSO-d6) d: 11.77 (s, 1H, NH), 8.21 (s,
1H), 8.03 (d, J = 7.6 Hz, 1H), 7.25 (s, 1H), 6.99 (d, J = 7.5 Hz, 1H),
2.40 (s, 3H), 2.43 (s, 3H); EI-MS, m ⁄ z (%) 173 (M+, 54).
6-Methyl-3-propionylindole (15): White solid, yield 40%, m.p. 202–
206 ꢀC; 1H-NMR (400 MHz, CDCl3) d: 8.42 (s, 1H, NH), 8.25 (d,
J = 8.0 Hz, 1H), 7.81 (s, 1H), 7.20 (s, 1H), 7.12 (d, J = 8.0 Hz, 1H),
2.88 (q, J = 7.2 Hz, 2H), 2.43 (s, 3H), 1.24 (t, J = 7.2 Hz, 3H); EI-
MS, m ⁄ z (%) 187 (M+, 56).
Inhibition rate (%) = (C ) T ) · 100 ⁄ C,
where C represents the diameter of fungi growth on untreated
PDA, and T represents the diameter of fungi on treated PDA.
6-Methyl-3-hexanoylindole (16): White solid, yield 64%, m.p. 176–
177 ꢀC; 1H-NMR (300 MHz, CDCl3) d: 8.44 (s, 1H, NH), 8.25 (d,
J = 7.5 Hz, 1H), 7.80 (s, 1H), 7.11–7.25 (m, 2H), 2.83 (t, J = 6.8 Hz,
2H), 2.46 (s, 3H), 1.78 (s, 2H), 1.37 (s, 4H), 0.90 (s, 3H); EI-MS, m ⁄ z
(%) 229 (M+, 8).
Results and Discussion
Synthesis
5-Cyano-3-acetylindole (17): White solid, yield 53%, m.p. 295–
1
As outlined in Scheme 1, seven 3-formylindole analogs (1–7)
were directly synthesized from indoles and DMF in the presence
of phosphorus oxychloride by means of the Vilsmeier reaction.
The other 3-acylindoles (8–20) were prepared from indoles as
shown in Scheme 2. Indoles were firstly protected with p-toluene-
sulfonyl chloride in the presence of sodium hydroxide (NaOH) and
TEBA at room temperature to give N-(p-toluenesulfonyl)indoles in
92–96% yields. Subsequently, treatment of N-(p-toluenesulfonyl)in-
doles with acetic anhydride, propionic anhydride or n-hexanoyl
chloride by a regioselective Friedel-Crafts acylation reaction fol-
lowed by indole deprotection led to 3-acylindole analogs (8–20)
in 40–73% yields, which were well characterized by 1H NMR,
EI-MS, and mp.
296 ꢀC; H-NMR (300 MHz, DMSO-d6) d: 12.45 (s, 1H, NH), 8.54 (s,
2H), 7.61–7.65 (m, 2H), 2.50 (s, 3H); EI-MS, m ⁄ z (%) 184 (M+, 9).
5-Cyano-3-propionylindole (18): White solid, yield 62%, m.p. 252–
254 ꢀC; H-NMR (300 MHz, DMSO-d6) d: 12.41 (s, 1H, NH), 8.53–
1
8.56 (m, 2H), 7.60–7.67 (m, 2H), 2.91–2.93 (m, 2H), 1.13 (s, 3H);
EI-MS, m ⁄ z (%) 198 (M+, 10).
5-Cyano-3-hexanoylindole (19): White solid, yield 50%, m.p.
157–158 ꢀC; 1H-NMR (300 MHz, DMSO-d6) d: 12.39 (s, 1H, NH),
8.52–8.54 (m, 2H), 7.55–7.65 (m, 2H), 2.85 (d, J = 7.0 Hz, 2H),
1.62 (s, 2H), 1.30 (s, 4H), 0.85 (s, 3H); EI-MS, m ⁄ z (%) 240 (M+,
10).
866
Chem Biol Drug Des 2011; 78: 864–868

Synthesis and Antifungal Activities of 3-Acylindole Analogs
Table 1: Antifungal activities of 3-acylindoles (1–20) at 100 lg ⁄ mL in vitro
Antifungal activities (inhibition %)
Fusarium
Fusarium
oxysporium f. sp.
vasinfectum
Pyricularia
oryzae
Alternaria
brassicae
oxysporium f. sp.
cucumarinum
Alternaria
alternata
Compound
Fusarium graminearum
Bipolaris sorokinianum
1
2
13.1 (€1.1)
53.4 (€1.1)
47.3 (€1.4)
51.4 (€1.5)
52.1 (€1.1)
31.8 (€1.1)
17.8 (€1.4)
47.9 (€0.9)
57.1 (€0.9)
16.7 (€0.4)
59.0 (€0.6)
65.4 (€0.4)
27.9 (€0.9)
75.9 (€0.9)
65.5 (€0.9)
14.1 (€1.5)
33.6 (€1.1)
46.3 (€0.7)
31.1 (€0.7)
17.0 (€1.5)
6.3 (€0.7)
41.5 (€0.6)
69.5 (€0)
60.0 (€0)
40.0 (€1.5)
71.2 (€1.2)
48.7 (€1.0)
63.2 (€0.6)
44.7 (€1.5)
42.1 (€1.5)
8.9 (€1.2)
40.7 (€1.2)
56.8 (€2.4)
17.6 (€2.1)
52.0 (€0)
23.4 (€2.4)
61.2 (€0.7)
40.7 (€1.8)
36.6 (€1.2)
47.4 (€2.4)
21.1 (€2.4)
12.2 (€1.4)
35.9 (€1.8)
59.3 (€2.4)
11.2 (€1.4)
54.8 (€2.4)
70.1 (€1.2)
20.7 (€1.4)
42.1 (€0.7)
52.4 (€2.4)
0
16.0 (€0.7)
45.7 (€1.4)
41.7 (€1.2)
8.8 (€1.8)
10.8 (€1.4)
20.8 (€0.7)
8.5 (€0.7)
75.8 (€1.8)
36.8 (€2.0)
50.1 (€2.0)
47. 8 (€1.0)
27.9 (€2.0)
52.0 (€1.1)
29.2 (€1.1)
14.5 (€2.0)
30.1 (€1.5)
58.7 (€1.7)
17.6 (€0.6)
46.0 (€1.0)
67.5 (€2.2)
26.1 (€1.5)
47.9 (€0)
63.9 (€2.0)
7.0 (€2.0)
20.9 (€1.9)
33.7 (€0)
24.1 (€0.6)
4.1 (€1.1)
14.2 (€0.5)
22.2 (€1.0)
7.3 (€1.1)
14.6 (€1.5)
52.6 (€1.3)
33.3 (€1.3)
34.6 (€2.6)
30.3 (€3.4)
17.2 (€1.5)
10.6 (€2.6)
20.0 (€3.3)
53.3 (€2.9)
16.1 (€1.2)
44.4 (€1.2)
70.3 (€2.1)
22.7 (€1.4)
38.3 (€0)
51.4 (€1.4)
12.8 (€1.9)
0
42.4 (€1.4)
16.1 (€0)
11.9 (€1.4)
14.0 (€1.3)
11.4 (€1.5)
13.1 (€0.7)
73.5 (€2.0)
35.0 (€1.6)
65.2 (€1.2)
52.7 (€2.4)
51.5 (€1.2)
43.3 (€0.6)
26.5 (€3.2)
6.7 (€1.6)
46.2 (€1.3)
66.0 (€2.2)
8.3 (€0)
61.4 (€1.3)
78.2 (€1.3)
21.4 (€2.2)
53.5 (€1.3)
54.8 (€1.3)
6.8 (€1.3)
25.8 (€1.1)
48.5 (€1.3)
38.9 (€2.2)
6.8 (€1.3)
7.1 (€1.9)
24.7 (€0.7)
3.1 (€0.7)
67.0 (€0.7)
3
4
61.1 (€1.1)
57.5 (€0.6)
24.2 (€2.1)
23.2 (€3.2)
39.0 (€2.3)
65.5 (€2.9)
1.6 (€0.7)
58.1 (€0)
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
Hymexazol
84.2 (€0)
19.8 (€2.0)
46.5 (€0)
87.2 (€0)
25.4 (€1.2)
53.5 (€0)
68.1 (€1.3)
2.3 (€2.3)
16.3 (€2.3)
48.1 (€2.3)
18.6 (€2.3)
2.3 (€2.3)
9.8 (€1.7)
15.7 (€1.3)
11.2 (€1.3)
63.3 (€0.6)
70.4 (€0)
2.1 (€0.6)
28.1 (€2.1)
45.1 (€1.2)
23.9 (€1.1)
15.0 (€2.7)
9.4 (€1.2)
24.3 (€0.6)
21.0 (€1.7)
72.7 (€1.1)
16.3 (€0.7)
4.7 (€0.7)
66.7 (€0.4)
57.1 (€1.0)
Antifungal activities and structure-activity
relationships
the unprotected ones (21 versus 8; 22 versus 14; 23 versus 17).
For example, the inhibition rates of 21 and 8 at 100 lg ⁄ mL
against F. graminearum, B. sorokinianum, F. oxysporum f. sp. vasin-
fectum, P. oryzae, A. brassicae, F. oxysporum f. sp. cucumarinum,
and A. alternata, were 6.3% ⁄ 47.9%, 9.8% ⁄ 39.0%, 9.4% ⁄ 40.7%,
10.8% ⁄ 35.9%, 14.2% ⁄ 30.1%, 14.0% ⁄ 20.0%, and 7.1% ⁄ 46.2%,
respectively.
As shown in Table 1, among all the analogs, compounds 2, 9, 11,
12, 14, and 15 exhibited the good and broad spectrum of
antifungal activities against the seven phytopathogenic fungi at the
concentration of 100 lg ⁄ mL. Especially compound 12, 3-propionyl-
4-methylindole, displayed the more potent activities than hymexazol.
In the meantime, preliminary SAR analysis showed the following
interesting characteristics: (i) Generally, the activities of the 3-prop-
ionylindole analogs were more potent than those of the correspond-
ing 3-formyl, 3-acetyl and 3-hexanoyl ones (9 versus 1, 8 and 10;
12 versus 2, 11 and 13; 15 versus 3, 14 and 16; 18 versus 6,
17 and 19). For example, the inhibition rates of 9, 1, 8 and 10
against F. graminearum, B. sorokinianum, F. oxysporum f. sp. vasin-
fectum, P. oryzae, A. brassicae, F. oxysporum f. sp. cucumarinum,
and A. alternata, were 57.1% ⁄ 13.1% ⁄ 47.9% ⁄ 16.7%, 65.5% ⁄ 41.5%
⁄ 39.0% ⁄ 1.6%, 56.8% ⁄ 40.0% ⁄ 40.7% ⁄ 17.6%, 59.3% ⁄ 23.4% ⁄ 35.9% ⁄
11.2%, 58.7% ⁄ 36.8% ⁄ 30.1% ⁄ 17.6%, 53.3% ⁄ 14.6% ⁄ 20.0% ⁄ 16.1%,
and 66.0% ⁄ 35.0% ⁄ 46.2% ⁄ 8.3%, respectively. (ii) As described in
our previous study (13), introduction of the electron-donating group
(methyl) on the indole ring usually led to the more potent com-
pounds, on the contrary, introduction of the electron-withdrawing
group (nitro or cyano) on the indole ring usually gave less potent
ones (2, 3, 4 and 5 versus 6 and 7; 11 and 14 versus 17; 12
and 15 versus 18). (iii) In general, if the indole nitrogen was pro-
tected with p-toluenesulfonyl group, the activities of the corre-
sponding compounds were reduced sharply when compared with
Conclusion
In conclusion, twenty 3-acylindole analogs were synthesized and
evaluated in vitro for their antifungal activities against seven phyto-
pathogenic fungi. Among all the derivatives, compounds 2, 9, 11,
12, 14, and 15 showed good antifungal activities at the concen-
tration of 100 lg ⁄ mL. The SAR indicated that 4- or 6-methyl and
3-acetyl or propionyl groups were the important structural
properties of 3-acylindoles for the activities. Especially 4-methyl-
3-propionylindole (12) displayed the more potent activities than
hymexazol, and might be considered as a new promising lead can-
didate for further design and synthesis of agricultural fungicides.
Acknowledgments
This work was financially supported by National Natural Science
Foundation of China (No. 31071737), and the Special Funds of Cen-
Chem Biol Drug Des 2011; 78: 864–868
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Xu et al.
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