Synthesis and antifungal activities of 3-substituted phthalide derivatives

Article abstract of DOI:10.1515/znb-2019-0110

In order to obtain novel bioactive compounds with significant antifungal activities, two series of 3-substituted phthalide derivatives were designed and synthesized via reduction, bromine substitution, and etherification. In addition, the antifungal activities of all target compounds against nine phytopathogenic fungi in vitro were tested by using the mycelial growth rate method at the concentration of 50 μg mL^-1. Preliminary bioassay tests showed that some compounds exhibited more potent antifungal activities as compared with hymexazol. The preliminary structure-activity relationships (SARs) of all target compounds were also investigated.

Full text of DOI:10.1515/znb-2019-0110

Z. Naturforsch. 2019; aop
Lingling Fan, Bilan Luo, Zhongfu Luo, Li Zhang, Judi Fan, Wei Xue, Lei Tang* and Yong Li*
Synthesis and antifungal activities of
3-substituted phthalide derivatives
https://doi.org/10.1515/znb-2019-0110
[12, 13] activities. For example, 3-n-butylphthalide (NBP)
Received June 12, 2019; accepted September 14, 2019
(Fig. 1), an antiplatelet drug, which was approved in 2002
by the State Food and Drug Administration of China for the
clinical treatment of acute ischemic stroke [14]. Mycophe-
nolic acid (MPA) is in clinical trial for the prevention and
reversal of transplant rejection and as an anticancer drug
[15]. Corollosporine is a new phthalide derivative from
the marine fungus Corollospora maritima which exhibits
concentration-dependent antibacterial activity against
Staphylococcus aureus and other microorganisms [16].
(ꢀ )-Chrycolide is isolated from the leaves and stem of a
popular vegetable Chrysanthemum coronarium, which
shows plant growth inhibiting activity [17].
Abstract: In order to obtain novel bioactive compounds
with significant antifungal activities, two series of
3-substituted phthalide derivatives were designed and
synthesized via reduction, bromine substitution, and
etherification. In addition, the antifungal activities of all
target compounds against nine phytopathogenic fungi in
vitro were tested by using the mycelial growth rate method
at the concentration of 50 μg mL−1. Preliminary bioassay
tests showed that some compounds exhibited more potent
antifungal activities as compared with hymexazol. The
preliminary structure-activity relationships (SARs) of all
target compounds were also investigated.
Encouraged by the numerous pharmacological activi-
ties of phthalide derivatives, and in continuation of our
Keywords: antifungal activity; phthalide derivatives; ongoing work on the discovery and development of com-
phytopathogenic fungi; synthesis.
pounds with superior antifungal activities [18, 19], we
prepared two series of 3-substitued phthalide derivatives
and evaluated their antifungal activities against nine phy-
topathogenic fungi in vitro.
1 Introduction
Phytopathogenic fungi easily infect many crops and are
often hard to control. Therefore, the development of new
compounds that effectively inhibit these agricultural dis-
eases is still highly desirable. Phthalide is an important
heterocyclic scaffold found in several plants [1]. Molecules
containing this pharmacophore exhibit a broad spectrum
of biological activities [2], such as antioxidant [3], anal-
gesic [4], antithrombotic [5], antiplatelet [6], insecticidal
[7–9], bactericidal [10], antifungal [11], and anti-HIV
2 Results and discussion
As shown in Scheme 1, isobenzofuran-1(3H)-one (1) was
prepared by the reduction of phthalic anhydride with
sodium borohydride (NaBH4), followed by cyclization in
3 n hydrochloric acid (HCl) at room temperature. Com-
pound 1 was then subjected to radical bromination in the
presence of N-bromosuccinimide/azobisisobutyronitrile
(NBS/AIBN) to give the key intermediate 2. Finally, two
series of 3-substituted phthalide derivatives (3a–j and
4a–m) were synthesized from intermediate 2 by William-
son etherification reaction in the presence of potassium
carbonate (K2CO3). To our surprise, 5-methyl-2-(3-oxo-
1,3-dihydroisobenzofuran-1-yl)-3-(3-oxo-1,3-dihydroisoben-
zofuran-1-yloxy)is-oxazol bromide (3j) was obtained when
compound 2 reacted with the nucleophile 5-methylisoxa-
zol-3-ol (5) under the same conditions. Closer scrutiny of
this reaction revealed that it was completely determined
by the reaction time. If the reaction time was prolonged to
12 h, compound 3i was immediately and completely trans-
formed into the unexpected quaternary salt 3j [20]. The
structures of all target compounds were characterized by
*Corresponding authors: Lei Tang and Yong Li, College of Pharmacy,
State Key Laboratory of Functions and Applications of Medicinal
Plants, Guizhou Provincial Engineering Technology Research
Center for Chemical Drug R & D, Guizhou Medical University,
Guiyang 550004, P.R. China, Tel./Fax: +86-0851-86908318,
E-mail: tlei1974@hotmail.com (L. Tang); liyong19851016@126.com
(Y. Li)
Lingling Fan, Bilan Luo, Zhongfu Luo, Li Zhang and Judi Fan: College
of Pharmacy, State Key Laboratory of Functions and Applications
of Medicinal Plants, Guizhou Provincial Engineering Technology
Research Center for Chemical Drug R & D, Guizhou Medical
University, Guiyang 550004, P.R. China
Wei Xue: Key Laboratory of Green Pesticide and Agricultural
Bioengineering, Ministry of Education, Guizhou University, Guiyang
550025, P.R. China
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ꢀꢀꢀꢁ
2ꢀ
ꢀL. Fan et al.: Synthesis and antifungal activity of phthalides
OH
O
O
CH3
OH
O
OH
O
O
HO2C
O
O
O
H3CO
S
(CH2)5CH3
Corollosporine
( )-Chrycolide
HO
CH3
3-n-butylphthalide (NBP)
Mycophenolic acid (MPA)
Fig. 1:ꢀSelected biologically important compounds containing a phthalide scaffold.
Scheme 1:ꢀSynthetic route of the preparation of phthalide derivatives 3a–j and 4a–m.
O
O
O
O
O
OH
N
O
O
K2CO3, actone
r. t., N2, 12h
K2CO3, actone
r. t., N2
O
O
O
O
O
N+
O
Br
Br
O
H3C
Br−
N
H3C
O
3i
2
5
3j
Scheme 2:ꢀThe conversion of compound 3i–j.
1H nuclear magnetic resonance (NMR), 13C NMR and high- berengriana f. sp. Piricola (BP), Curvularia lunata (CL),
resolution mass spectrometry. Fusarium oxysporum schlecht. f. sp. C. maxima (FM), Fusar-
The antifungal activities of 3-substituted phthalide ium graminearum (FG), Alternaria alternata (AA), Pyricu-
derivatives 3a–j and 4a–m against nine phytopatho- laria oryzae (PO), Fusarium oxysporum f. sp. Vasinfectum
genic fungi [i.e. Fusarium solani (FS), Botryosphaeria (FV), and Alternaria brassicae (AB)] were investigated at a
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ꢂ3
L. Fan et al.: Synthesis and antifungal activity of phthalidesꢂ
−1
Table 1:ꢀAntifungal activities of compounds at 50 μg mL .
Compoundsꢁ
ꢁ
Antifungal activities (inhibition %ꢂ ꢂSE)a
FSꢁ
FVꢁ
FMꢁ
FGꢁ
CLꢁ
BPꢁ
AAꢁ
POꢁ
AB
3a
3b
3c
3d
3e
3f
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
5 ( 1)ꢃ
45 ( 2)ꢃ
43 ( 3)ꢃ
14 ( 1)ꢃ
12 ( 3)ꢃ
58 ( 1)ꢃ
46 ( 2)ꢃ
2 ( 2)ꢃ
53 ( 1)ꢃ
34 ( 1)ꢃ
10 ( 2)ꢃ
17 ( 1)ꢃ
44 ( 2)ꢃ
2 ( 2)ꢃ
1 ( 1)ꢃ
17 ( 1)ꢃ
4 ( 1)ꢃ
15 ( 2)ꢃ
29 ( 2)ꢃ
52 ( 2)ꢃ
51 ( 1)ꢃ
23 ( 2)ꢃ
31 ( 2)ꢃ
42 ( 3)ꢃ
9 ( 1)ꢃ
38 ( 2)ꢃ
34 ( 2)ꢃ
27 ( 1)ꢃ
29 ( 1)ꢃ
31 ( 1)ꢃ
34 ( 1)ꢃ
15 ( 3)ꢃ
37 ( 2)ꢃ
43 ( 1)ꢃ
25 ( 1)ꢃ
9 ( 1)ꢃ
38 ( 2)ꢃ
10 ( 2)ꢃ
13 ( 1)ꢃ
18 ( 1)ꢃ
15 ( 1)ꢃ
8 ( 4)ꢃ
8 ( 3)ꢃ
28 ( 1)ꢃ
47 ( 2)ꢃ
27 ( 2)ꢃ
33 ( 1)ꢃ
30 ( 1)ꢃ
32 ( 1)ꢃ
39 ( 2)ꢃ
36 ( 2)ꢃ
44 ( 1)ꢃ
29 ( 1)ꢃ
12 ( 1)ꢃ
35 ( 1)ꢃ
10 ( 1)ꢃ
17 ( 1)ꢃ
30 ( 1)ꢃ
18 ( 2)ꢃ
21 ( 3)ꢃ
24 ( 1)ꢃ
50 ( 1)ꢃ
47 ( 2)ꢃ
18 ( 1)ꢃ
43 ( 1)ꢃ
51 ( 1)ꢃ
10 ( 1)ꢃ
48 ( 1)ꢃ
49 ( 2)ꢃ
40 ( 1)ꢃ
62 ( 2)ꢃ
52 ( 1)ꢃ
22 ( 1)ꢃ
33 ( 1)ꢃ
19 ( 1)ꢃ
43 ( 1)ꢃ
44 ( 3)ꢃ
1 ( 1)ꢃ
39 ( 1)ꢃ
–ꢃ
8 ( 1)ꢃ
16 ( 3)ꢃ
9 ( 1)ꢃ
5 ( 2)ꢃ
–ꢃ
38 ( 1)ꢃ
48 ( 4)ꢃ
29 ( 1)ꢃ
35 ( 3)ꢃ
32 ( 1)ꢃ
41 ( 2)ꢃ
22 ( 2)ꢃ
28 ( 1)ꢃ
43 ( 1)ꢃ
30 ( 1)ꢃ
22 ( 2)ꢃ
56 ( 2)ꢃ
20 ( 1)ꢃ
33 ( 1)ꢃ
30 ( 1)ꢃ
25 ( 1)ꢃ
33 ( 1)ꢃ
33 ( 1)ꢃ
55 ( 1)ꢃ
61 ( 1)ꢃ
31 ( 1)ꢃ
42 ( 1)ꢃ
40 ( 3)ꢃ
9 ( 1)ꢃ
42 ( 1)ꢃ
48 ( 4)ꢃ
34 ( 1)ꢃ
43 ( 2)ꢃ
53 ( 2)ꢃ
52 ( 2)ꢃ
19 ( 2)ꢃ
45 ( 1)ꢃ
41 ( 2)ꢃ
44 ( 1)ꢃ
28 ( 1)ꢃ
41 ( 1)ꢃ
14 ( 2)ꢃ
13 ( 2)ꢃ
13 ( 2)ꢃ
20 ( 2)ꢃ
–ꢃ
6 ( 1)ꢃ
31 ( 2)ꢃ
43 ( 1)ꢃ
26 ( 1)ꢃ
26 ( 2)ꢃ
38 ( 1)ꢃ
24 ( 3)ꢃ
15 ( 2)ꢃ
54 ( 1)ꢃ
20 ( 3)ꢃ
28 ( 1)ꢃ
5 ( 1)ꢃ
16 ( 1)ꢃ
22 ( 1)ꢃ
41 ( 1)ꢃ
18 ( 3)ꢃ
29 ( 3)ꢃ
37 ( 1)ꢃ
21 ( 4)ꢃ
7 ( 1)ꢃ
44 ( 1)ꢃ
23 ( 3)ꢃ
27 ( 1)ꢃ
22 ( 1)ꢃ
45 ( 1)ꢃ
18 ( 3)ꢃ
13 ( 3)ꢃ
24 ( 1)ꢃ
17 ( 1)ꢃ
20 ( 4)ꢃ
22 ( 3)ꢃ
45 ( 1)ꢃ
50 ( 4)ꢃ
19 ( 1)ꢃ
30 ( 1)ꢃ
69 ( 3)ꢃ
12 ( 1)
29 ( 2)
47 ( 1)
20 ( 1)
30 ( 1)
32 ( 1)
38 ( 1)
24 ( 1)
32 ( 2)
35 ( 1)
29 ( 1)
15 ( 1)
50 ( 2)
13 ( 2)
16 ( 1)
22 ( 1)
29 ( 6)
22 ( 1)
31 ( 1)
45 ( 1)
47 ( 1)
21 ( 2)
36 ( 2)
53 ( 1)
3g
3h
3i
3j
4a
4b
4c
4d
4e
4f
50 ( 1)ꢃ
19 ( 2)ꢃ
8 ( 1)ꢃ
23 ( 1)ꢃ
23 ( 2)ꢃ
20 ( 1)ꢃ
19 ( 1)ꢃ
43 ( 1)ꢃ
42 ( 1)ꢃ
11 ( 2)ꢃ
33 ( 1)ꢃ
69 ( 1)ꢃ
4g
4h
4i
25 ( 1)ꢃ
37 ( 1)ꢃ
39 ( 1)ꢃ
17 ( 3)ꢃ
39 ( 1)ꢃ
37 ( 1)ꢃ
33 ( 1)ꢃ
39 ( 1)ꢃ
43 ( 1)ꢃ
26 ( 4)ꢃ
44 ( 1)ꢃ
52 ( 1)ꢃ
22 ( 2)ꢃ
50 ( 3)ꢃ
33 ( 1)ꢃ
20 ( 2)ꢃ
27 ( 1)ꢃ
31 ( 1)ꢃ
4j
4k
4l
4m
Hymb
aValues are the meanꢁ ꢁSE of three replicates. bHym, hymexazol.
concentration of 50 μg mL−1 in vitro by the poisoned food 43, 38, 37, 39, 39%, respectively) displayed slightly higher
technique [21]. Hymexazol, a commercially available agri- inhibition rates than hymexazol (37%). Toward FG strains,
cultural fungicide, was used as a positive control at the the introduction of two nitrogen dioxide (-NO2) group or
same concentration (50 μg mL−1).
-OH group on the benzene ring give the compounds 3e
As is shown in Table 1, the results revealed that most (62%) and 3f (52%), which show better activities than
of derivatives displayed certain inhibitory effects on the hymexazol (52%). For CL strains, seven compounds 3c
growth of the tested phytopathogenic fungi. Among all (48%), 3g (41%), 3j (43%), 4c (56%), 4j (55%), 4k (61%),
the synthesized compounds, ten derivatives 3b, 3c, 3e, 3f, and 4m (42%) display more potent antifungal activi-
3g, 3i, 3j, 4a, 4c, and 4j (42, 48, 43, 53, 52, 45, 41, 44, 41, ties than hymexazol (40%). In addition, all compounds
50%, respectively) generally exhibited more pronounced showed poor fungicidal activities against the four tested
antifungal activity against BP than hymexazol (31%). fungi (FM, AA, PO, and AB) except compounds 3c, 3i, 4c,
This finding indicated that the synthesized 3-substituted 4j, and 4k. Based on these results compounds 3c, 4c, 4j,
phthalide derivatives could represent a new structure and 4k provide broad-spectrum antifungal activities to
skeleton for inhibiting BP. Compounds 3b, 3c, 3f, 3g, 3i, the tested fungi and could be taken under consideration
4c, 4j, and 4k (45, 43, 58, 46, 53, 44, 52, 51%, respectively) for further research.
showed relatively higher activity against FS than hymexa-
zol (42%). Preliminary structure-activity relationships
(SARs) presumed that introduction electron-donating
groups -OH and -NH2 on the benzene ring could enhance 3 Conclusion
their antifungal activity against FS, probably because they
form a hydrogen bond with the active site of the enzyme In conclusion, 24 3-substituted phthalide derivatives were
in the fungus leading to metabolic system disorder [22]. designed and synthesized via reduction, bromine substitu-
For FV strains, compounds 3b, 3j, 4c, 4j, 4k, and 4m (38, tion and Williams etherification, and evaluated in vitro for
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ꢀꢀꢀꢁ
4ꢀ ꢀL. Fan et al.: Synthesis and antifungal activity of phthalides
their antifungal activities against nine phytopathogenic dry carbon tetrachloride (CCl4) (200 mL) and heated to
fungi at the concentration of 50 μg mL−1. Among these deriv- 72°C for 2.5 h. The mixture was cooled to room tempera-
atives, four compounds 3c, 4c, 4j, and 4k generally exhibit ture overnight, filtered, and the residue was washed with
broad-spectrum antifungal activities as compared with the petroleum ether. The filtrate was concentrated in vacuo to
commercially available agricultural fungicide hymexazol. provide the crude product, which was recrystallized from
This clearly demonstrates that the introduction of appropri- cyclohexane to give 2 (8.6 g, 81.8%) as a light brown solid;
1
ate thioether and oxyether substituents on the 3-position of m. p. 79–82°C (lit. [24]: 76–78°C). – H NMR (600 MHz,
phthalide leads to more potent antifungal derivatives.
CDCl3): δꢀ=ꢀ7.65 (d, 1H, Jꢀ=ꢀ7.2 Hz), 7.80–7.77 (m, 1H), 7.64–7.61
(m, 2H), 7.41 (s, 1H). – 13C NMR (150 MHz, CDCl3): δꢀ=ꢀ167.3,
148.8, 135.2, 130.9, 125.9, 124.0, 123.5, 74.6.
4 Experimental section
4.2 General procedure for the synthesis of
compounds 3a–j and 4a–m
4.1 General information
In a 50 mL round-bottom flask containing 5 mL acetone,
anhydrous K2CO3 (0.5 mmol), compound 2 (0.5 mmol) and
substituted phenol or benzenethiol (0.5 mmol) were added
and reacted at room temperature under N2. When the reac-
tion was complete (TLC control), the organic solvent was
removed, followed by addition of water (20 mL). The solu-
tion was extracted with ethyl acetate (EtOAc) (3ꢀ×ꢀ30 mL).
Finally, the resulting organic phases was washed with
brine, dried over anhydrous Na2SO4 and evaporated under
reduced pressure. The crude material was purified by
silica gel column chromatography to give desired products
3a–j and 4a–m, which were characterized by 1H NMR, 13C
NMR and HRMS.
All reagents and solvents were of reagent grade or puri-
fied according to standard methods before use. Thin-
layer chromatography (TLC) and preparative thin-layer
chromatography (PTLC) were used with silica gel 60
GF254 (Qingdao Haiyang Chemical Co., Ltd., China).
Melting points (m. p.) were determined on a digital m.p.
1
apparatus and were uncorrected. H NMR and 13C NMR
spectra were recorded on a Bruker Avance NEO 600 MHz
and 150 MHz instruments, respectively, using TMS as the
internal standard and CDCl3 or DMSO-d6 as the solvent.
High-resolution mass spectra (HRMS) were carried out
with an APEX II Bruker 4.7T AS instrument.
4.1.1 Synthesis of isobenzofuran-1(3H)-one (1)
4.2.1 (R/S)-3-(2-nitrophenoxy)isobenzofuran-1(3H)-
one (3a)
Phthalic anhydride (10.0 g, 67.5 mmol) was dissolved in
tetrahydrofuran (THF) (200 mL) then sodium borohy-
dride (NaBH4) (2.6 g, 67.5 mmol) was added in portions
at Tꢀ=ꢀ0–5°C. The resulting mixture was stirred for 13 h
at room temperature. The reaction mixture was acidified
with 3 n HCl to pHꢀ=ꢀ1 and stirred for an additional 10.5 h.
The solvent was removed under reduced pressure and
the residue was extracted with ethyl acetate (2ꢀ×ꢀ250 mL),
which was then washed with 10% K2CO3 aqueous solu-
tion (3ꢀ×ꢀ100 mL), brine (150 mL), and dried over sodium
sulfate (Na2SO4). The solvent was evaporated to dryness
under reduced pressure to give compound 1 (7.4 g, 81.9%)
as a white solid; m. p. 74–75°C (lit. [23]: 72–73°C).
1
Yield: 50.1%, white solid; m. p. 192–194°C. – H NMR
(600 MHz, DMSO-d6): δꢀ=ꢀ8.03–7.93 (m, 3H), 7.89–7.79 (m,
3H), 7.73 (dd, 1H, Jꢀ=ꢀ8.4 Hz, 1.2 Hz), 7.42 (s, 1H), 7.41–7.37
13
(m, 1H). – C NMR (150 MHz, DMSO-d6): δꢀ=ꢀ168.0, 149.0,
144.4, 141.1, 136.0, 135.3, 132.3, 126.1, 125.8, 125.1, 124.6,
119.1, 100.1. – HRMS [(+)-(electrospray ionization [ESI])]:
+
m/zꢀ=ꢀ294.0376 (calcd. 294.0378 for C14H9NO5Na, [Mꢀ+ꢀNa] ).
4.2.2 (R/S)-3-(2-hydroxyphenoxy)isobenzofuran-1(3H)-
one (3b)
1
Yield: 55.6%, white solid; m. p. 128–130°C. – H NMR
(600 MHz, DMSO-d6): δꢀ=ꢀ9.50 (s, 1H, OH), 7.89–7.85 (m,
3H), 7.73–7.29 (m, 1H), 7.69–7.18 (dd, 1H, Jꢀ=ꢀ6.4 Hz, 1.2 Hz),
7.10 (s, 1H), 6.97–6.93 (m, 1H), 6.90 (dd, 1H, Jꢀ=ꢀ8.0 Hz,
4.1.2 Synthesis of 3-bromoisobenzofuran-1(3H)-one (2)
Isobenzofuran-1(3H)-one (6.6 g, 49.6 mmol), NBS (9.7 g, 1.6 Hz), 6.79–6.75 (m, 1H). – 13C NMR (150 MHz, DMSO-
54.5 mmol) and AIBN (0.8 g, 4.9 mmol) were diluted in d6): δꢀ=ꢀ168.5, 148.5, 145.2, 144.5, 135.5, 131.9, 126.7, 125.4,
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ꢂ5
L. Fan et al.: Synthesis and antifungal activity of phthalidesꢂ
125.2, 125.1, 119.7, 119.6, 117.4, 101.2. – HRMS [(+)-(ESI)]: [(+)-(ESI)]: m/zꢀ=ꢀ243.0659 (calcd. 243.0656 for C14H11O4,
+
+
m/zꢀ=ꢀ243.0660 (calcd. 243.0657 for C14H11O4, [Mꢀ+ꢀH] ).
[Mꢀ+ꢀH] ).
4.2.3 (R/S)-3-(4-tert-butyl-2-hydroxyphenoxy)
isobenzofuran-1(3H)-one (3c)
4.2.7 (R/S)-3-(3-aminophenoxy)isobenzofuran-1(3H)-
one (3g)
1
1
Yield: 62.5%, white solid; m. p. 135–139°C. – H NMR Yield: 68.5%, white solid; m. p. 85–87°C. – H NMR
(600 MHz, DMSO-d6): δꢀ=ꢀ9.40 (s, 1H, OH), 7.90–7.89 (m, (600 MHz, DMSO-d6): δꢀ=ꢀ7.90 (d, 1H, Jꢀ=ꢀ7.2 Hz), 7.76 (d,
3H), 7.77–7.73 (m, 1H), 7.15 (d, 1H, Jꢀ=ꢀ7.6 Hz), 7.08 (s, 1H), 6.95 1H, Jꢀ=ꢀ7.2 Hz), 7.71 (d, 1H, Jꢀ=ꢀ7.2 Hz), 7.64 (d, 1H, Jꢀ=ꢀ7.2 Hz),
(d, 1H, Jꢀ=ꢀ6.4 Hz), 6.84 (dd, 1H, Jꢀ=ꢀ8.4 Hz, 2.0 Hz), 1.24 (s, 7.56 (d, 1H, Jꢀ=ꢀ7.2 Hz), 7.05 (t, 1H, Jꢀ=ꢀ7.8 Hz), 6.99 (t, 1H,
13
9H). – 13C NMR (150 MHz, DMSO-d6): δꢀ=ꢀ168.5, 147.9, 147.8, Jꢀ=ꢀ7.8 Hz), 6.92 (s, 1H), 6.87 (d, 1H, Jꢀ=ꢀ7.6 Hz). – C NMR
145.2, 142.3, 135.5, 131.8, 126.7, 125.4, 125.0, 119.3, 116.4, 114.5, (150 MHz, DMSO-d6): δꢀ=ꢀ169.8, 155.7, 142.4, 133.7, 132.8,
101.6, 34.5, 31.7. – HRMS [(+)-(ESI)]: m/zꢀ=ꢀ299.1285 (calcd. 131.2, 130.2, 125.7, 125.1, 124.5, 121.9, 117.0, 109.7, 95.5.
+
299.1283 for C18H19O4, [Mꢀ+ꢀH] ).
– HRMS [(+)-(ESI)]: m/zꢀ=ꢀ242.0819 (calcd. 242.0817 for
+
C14H12NO3, [Mꢀ+ꢀH] ).
4.2.4 (R/S)-N-(4-(3-oxo-1,3-dihydroisobenzofuran-1-
yloxy)phenyl)acetamide (3d)
4.2.8 (R/S)-3-(naphthalen-1-yloxy)isobenzofuran-1(3H)-
one (3h)
1
Yield: 54.8%, white solid; m. p. 194–196°C. – H NMR
1
(600 MHz, DMSO-d6): δꢀ=ꢀ9.99 (s, 1H, NH), 7.95–7.89 (m, Yield: 88.1%, white solid; m. p. 153–155°C. – H NMR
3H), 7.78–7.76 (m, 1H), 7.60 (d, 2H, Jꢀ=ꢀ8.4 Hz), 7.25 (s, 1H), (600 MHz, DMSO-d6): δꢀ=ꢀ8.07 (d, 1H, Jꢀ=ꢀ8.4 Hz), 8.01 (d,
7.17 (d, 2H, Jꢀ=ꢀ8.4 Hz), 2.03 (s, 3H, COCH3). – 13C NMR 2H, Jꢀ=ꢀ8.4 Hz), 7.98 (t, 2H, Jꢀ=ꢀ7.2 Hz), 7.83 (t, 1H, Jꢀ=ꢀ7.2 Hz),
(150 MHz, DMSO-d6): δꢀ=ꢀ168.5, 168.4, 152.0, 145.0, 135.7, 7.73 (d, 1H, Jꢀ=ꢀ7.8 Hz), 7.59–7.53 (m, 3H), 7.50 (d, 1H,
135.6, 132.01, 132.00, 126.4, 125.6, 125.0, 120.8, 117.7, 100.1, Jꢀ=ꢀ7.8 Hz), 7.47 (s, 1H). – 13C NMR (150 MHz, DMSO-d6):
24.4. – HRMS [(+)-(ESI)]: m/zꢀ=ꢀ284.0927 (calcd. 284.0923 δꢀ=ꢀ168.3, 152.3, 145.1, 135.8, 134.6, 132.0, 128.1, 127.2, 126.3,
+
for C16H14NO4, [Mꢀ+ꢀH] ).
125.5, 125.0, 123.4, 121.7, 110.2, 100.1. – HRMS [(+)-(ESI)]:
+
m/zꢀ=ꢀ277.0869 (calcd. 277.0865 for C18H13O3, [Mꢀ+ꢀH] ).
4.2.5 (R/S)-3-(2,4-dinitrophenoxy)isobenzofuran-1(3H)-
one (3e)
4.2.9 (R/S)-3-(5-methylisoxazol-3-yloxy)isobenzofuran-
1(3H)-one (3i)
1
Yield: 58.7%, white solid; m. p. 181–182°C. – H NMR
1
(600 MHz, DMSO-d6): δꢀ=ꢀ8.87 (d, 1H, Jꢀ=ꢀ2.8 Hz), 8.71 (dd, Yield: 20.3%, white solid; m. p. 153–154°C. – H NMR
1H, Jꢀ=ꢀ9.2 Hz, 2.0 Hz), 8.02–7.99 (m, 1H), 7.97–7.93 (m, 2H), (600 MHz, CDCl3): δꢀ=ꢀ7.99 (d, 1H, Jꢀ=ꢀ7.8 Hz), 7.80–7.78 (m,
7.90 (d, 1H, Jꢀ=ꢀ7.6 Hz), 7.85 (td, 1H, Jꢀ=ꢀ8.8 Hz, 0.8 Hz), 7.61 1H), 7.70 (t, 1H, Jꢀ=ꢀ7.8 Hz), 7.63 (d, 1H, Jꢀ=ꢀ7.2 Hz), 7.28 (s, 1H),
(s, 1H). – 13C NMR (150 MHz, DMSO-d6): δꢀ=ꢀ167.7, 153.5, 5.56 (s, 1H), 2.14 (s, 3H, CH3). – 13C NMR (150 MHz, CDCl3):
143.8, 142.3, 140.0, 136.2, 132.6, 130.3, 126.0, 125.8, 125.2, δꢀ=ꢀ174.7, 170.9, 167.9, 142.2, 134.8, 131.1, 127.2, 125.9, 123.2,
121.9, 118.8, 99.2. – HRMS [(+)-(ESI)]: m/zꢀ=ꢀ317.0334 (calcd. 97.9, 82.3, 13.7. – HRMS [(+)-(ESI)]: m/zꢀ=ꢀ232.0612 (calcd.
+
+
317.0332 for C14H9N2O7, [Mꢀ+ꢀH] ).
232.0610 for C12H10NO4, [Mꢀ+ꢀH] ).
4.2.6 (R/S)-3-(4-hydroxyphenoxy)isobenzofuran-1(3H)-
4.2.10 (R/S)-5-methyl-2-(3-oxo-1,3-dihydroisobenzofuran-
1-yl)-3-(3-oxo-1,3-dihydroisobenzofuran-1-yloxy)
isoxazol bromide (3j)
one (3f)
Yield: 83.9%; m. p. 183–185°C. – 1H NMR (600 MHz, DMSO-
1
d6): δꢀ=ꢀ9.28 (s, 1H, OH), 7.92–7.87 (m, 3H), 7.75–7.74 (m, 1H), Yield: 40.2%, white solid; m. p. 161–164°C. – HNMR
7.05 (d, 2H, Jꢀ=ꢀ8.4 Hz), 6.72 (d, 2H, Jꢀ=ꢀ8.4 Hz), 6.56 (s, 1H). (600 MHz, CDCl3): δꢀ=ꢀ8.00–7.99 (m, 1H), 7.95 (d, 1H,
– 13C NMR (150 MHz, DMSO-d6): δꢀ=ꢀ168.4, 154.0, 150.2, 149.0, Jꢀ=ꢀ7.8 Hz), 7.92–7.90 (m, 1H), 7.86–7.80 (m, 4H), 7.77 (t, 1H,
13
145.1, 135.5, 131.8, 126.5, 125.4, 119.1, 116.1, 101.0. – HRMS Jꢀ=ꢀ7.2 Hz), 7.69 (s, 1H), 6.12 (s, 1H), 2.22 (s, 3H). – CNMR
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6ꢀ ꢀL. Fan et al.: Synthesis and antifungal activity of phthalides
(150 MHz, DMSO-d6) δꢀ=ꢀ168.0, 167.2, 166.6, 165.3, 165.0, (150 MHz, DMSO-d6): δꢀ=ꢀ168.9, 145.8, 135.3, 134.4, 132.2,
144.3, 135.8, 133.5, 132.8, 132.1, 131.0, 130.5, 130.5, 129.5, 129.2, 126.2, 125.6, 123.6, 123.3, 86.0. – HRMS [(+)-(ESI)]:
+
125.8, 125.7, 124.8, 107.4, 93.9, 18.7. – HRMS [(+)-(ESI)]: m/zꢀ=ꢀ320.9590 (calcd. 320.9586 for C14H10O2SBr, [Mꢀ+ꢀH] ).
+
+
m/zꢀ=ꢀ364.0846 (calcd. 364.0849 for C20H14NO6 , [M] ).
4.2.15 (R/S)-3-(3-bromophenylthio)isobenzofuran-1(3H)-
4.2.11 (R/S)-3-(2,3-dichlorophenylthio)isobenzofuran-
1(3H)-one (4a)
one (4e)
Yield: 81.0%, white solid; m. p. 110–112°C (lit. [25]:
1
1
Yield: 89.1%, white solid; m. p. 162–163°C. – H NMR 114–116°C). – H NMR (600 MHz, CDCl3): δꢀ=ꢀ7.84 (d, 1H,
(600 MHz, CDCl3): δꢀ=ꢀ7.92 (d, 1H, Jꢀ=ꢀ7.8 Hz), 7.77–7.70 (m, Jꢀ=ꢀ7.2 Hz), 7.73 (t, 1H, Jꢀ=ꢀ7.2 Hz), 7.65–7.64 (m, 2H), 7.56 (t,
3H), 7.62 (t, 1H, Jꢀ=ꢀ7.8 Hz), 7.42 (d, 1H, Jꢀ=ꢀ8.4 Hz), 7.24 (d, 1H, Jꢀ=ꢀ7.2 Hz), 7.49–7.47 (m, 1H), 7.43–7.42 (m, 1H), 7.18 (t,
13
13
1H, Jꢀ=ꢀ7.8 Hz), 6.84 (s, 1H). – C NMR (150 MHz, DMSO- 1H, Jꢀ=ꢀ7.8 Hz), 6.73 (s, 1H). – C NMR (150 MHz, DMSO-
d6): δꢀ=ꢀ168.8, 145.1, 134.6, 134.4, 133.8, 133.1, 130.6, 130.5, d6): δꢀ=ꢀ168.9, 145.6, 135.6, 134.4, 132.8, 131.9, 131.8, 130.4,
130.0, 127.8, 126.1, 125.8, 123.5, 84.9. – HRMS [(+)-(ESI)]: 130.3, 126.2, 125.6, 123.4, 122.6, 86.1. – HRMS [(+)-(ESI)]:
+
+
m/zꢀ=ꢀ310.9702 (calcd. 310.9700 for C14H9Cl2O2S, [Mꢀ+ꢀH] ).
m/zꢀ=ꢀ320.9591 (calcd. 320.9586 for C14H10O2SBr, [Mꢀ+ꢀH] ).
4.2.12 (R/S)-3-(4-chlorophenylthio)isobenzofuran-1(3H)- 4.2.16 (R/S)-3-[(4-Fluorophenyl)thio]isobenzofuran-
one (4b) 1(3H)-one (4f)
1
Yield: 70.5%, white solid; m. p. 116–118°C. – H NMR Yield: 83.2%, white solid; m. p. 103–105°C (lit. [25]:
1
(600 MHz, CDCl3): δꢀ=ꢀ7.83 (d, 1H, Jꢀ=ꢀ7.2 Hz), 7.73 (t, 1H, 112–114°C). – H NMR (600 MHz, CDCl3): δꢀ=ꢀ7.77 (d, 1H,
Jꢀ=ꢀ6.6 Hz), 7.67 (d, 1H, Jꢀ=ꢀ7.8 Hz), 7.56 (t, 1H, Jꢀ=ꢀ7.2 Hz), Jꢀ=ꢀ7.8 Hz), 7.72–7.69 (m, 2H), 7.65 (d, 1H, Jꢀ=ꢀ7.8 Hz), 7.51 (t,
7.45–7.43 (m, 2H), 7.26–7.24 (m, 2H), 6.70 (s, 1H). – 13C NMR 1H, Jꢀ=ꢀ7.2 Hz), 7.46–7.44 (m, 2H), 6.95–6.92 (m, 1H), 6.65 (s,
(150 MHz, DMSO-d6): δꢀ=ꢀ168.9, 145.8, 135.5, 135.2, 134.4, 1H). – 13C NMR (150 MHz, CDCl3): δꢀ=ꢀ168.9, 164.3, 162.6,
130.1, 129.2, 128.4, 126.2, 125.6, 123.3, 86.1. – HRMS [(+)- 146.0, 136.8, 136.7, 134.3, 130.0, 126.2, 125.4, 124.6, 123.3,
(ESI)]: m/zꢀ=ꢀ277.0092 (calcd. 277.0090 for C14H10O2SCl, 116.2, 86.2. – HRMS [(+)-(ESI)]: m/zꢀ=ꢀ261.0390 (calcd.
+
+
[Mꢀ+ꢀH] ).
261.0386 for C14H10O2FS, [Mꢀ+ꢀH] ).
4.2.13 (R/S)-3-(2-chlorophenylthio)isobenzofuran-1(3H)- 4.2.17 (R/S)-3-[(3-Fluorophenyl)thio]isobenzofuran-
one (4c) 1(3H)-one (4g)
1
1
Yield: 65.7%, white solid; m. p. 85–88°C. – H NMR Yield: 72.5%, white solid; m. p. 91–94°C. – H NMR
(600 MHz, CDCl3): δꢀ=ꢀ7.86 (d, 1H, Jꢀ=ꢀ7.8 Hz), 7.77–7.74 (m, (600 MHz, CDCl3): δꢀ=ꢀ7.86 (d, 1H, Jꢀ=ꢀ7.2 Hz), 7.76–7.74 (m,
1H), 7.68 (d, 1H, Jꢀ=ꢀ7.2 Hz), 7.58 (t, 1H, Jꢀ=ꢀ7.2 Hz), 7.53 (s, 1H), 7.68 (d, 1H, Jꢀ=ꢀ7.8 Hz), 7.58 (t, 1H, Jꢀ=ꢀ7.2 Hz), 7.35–7.34
1H), 7.46 (dd, 1H, Jꢀ=ꢀ7.8, 1.2 Hz), 7.30–7.29 (m, 1H), 7.26 (t, (m, 1H), 7.30–7.26 (m, 2H), 7.04–7.00 (m, 1H), 6.77 (s, 1H).
13
1H, Jꢀ=ꢀ7.8 Hz), 6.71 (s, 1H). – 13C NMR (150 MHz, DMSO-d6): – C NMR (150 MHz, CDCl3): δꢀ=ꢀ168.9, 163.2, 161.6, 145.6,
δꢀ=ꢀ168.9, 145.6, 134.7, 134.4, 132.8, 132.6, 131.3, 130.1, 129.0, 134.4, 132.7, 130.4, 128.8, 126.2, 125.6, 123.3, 120.0, 116.0,
126.2, 125.6, 123.4, 86.1. – HRMS [(+)-(ESI)]: m/zꢀ=ꢀ277.0091 86.0. – HRMS [(+)-(ESI)]: m/zꢀ=ꢀ261.0387 (calcd. 261.0386
+
+
(calcd. 277.0090 for C14H10O2SCl, [Mꢀ+ꢀH] ).
for C14H10O2FS, [Mꢀ+ꢀH] ).
4.2.14 (R/S)-3-(4-bromophenylthio)isobenzofuran-
1(3H)-one (4d)
4.2.18 (R/S)-3-(2,6-dimethylphenylthio)isobenzofuran-
1(3H)-one (4h)
1
Yield: 80.6%, white solid; m. p. 139–141°C (lit. [25]: Yield: 85.4%, white solid; m. p. 128–130°C. – H NMR
1
142–144°C). – H NMR (600 MHz, CDCl3): δꢀ=ꢀ7.84 (d, 1H, (600 MHz, CDCl3): δꢀ=ꢀ7.93 (d, 1H, Jꢀ=ꢀ7.2 Hz), 7.76–7.73 (m,
Jꢀ=ꢀ7.8 Hz), 7.75 (t, 1H, Jꢀ=ꢀ7.8 Hz), 7.67 (d, 1H, Jꢀ=ꢀ7.8Hz), 7.56 2H), 7.62–7.59 (m, 1H), 7.24–7.22 (m, 1H), 7.20–7.19 (m, 2H),
13
(t, 1H, Jꢀ=ꢀ7.2 Hz), 7.42–7.37 (m, 4H), 6.71 (s, 1H). C NMR 6.51 (s, 1H), 2.68 (s, 6H). – 13C NMR (150 MHz, CDCl3):
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ꢂ7
L. Fan et al.: Synthesis and antifungal activity of phthalidesꢂ
δꢀ=ꢀ169.2, 146.4, 143.9, 134.3, 130.1, 129.8, 129.8, 128.6, 126.1, 4.2.23 (R/S)-3-(thiophen-2-ylthio)isobenzofuran-1(3H)-
125.6, 123.3, 88.1, 22.4. – HRMS [(+)-(ESI)]: m/zꢀ=ꢀ271.0792
one (4m)
+
(calcd. 271.0790 for C16H15O2S, [Mꢀ+ꢀH] )
1
Yield: 62.3%, white solid; m. p. 99–101°C. – H NMR
(600 MHz, CDCl3): δꢀ=ꢀ7.73–7.69 (m, 2H), 7.65 (dd, 1H,
Jꢀ=ꢀ7.8 Hz, 0.6 Hz), 7.50 (t, 1H, Jꢀ=ꢀ7.2 Hz), 7.32 (dd, 1H,
Jꢀ=ꢀ7.2 Hz, 1.2 Hz), 7.12 (dd, 1H, Jꢀ=ꢀ3.6 Hz, 1.2 Hz), 6.89–6.88
(m, 1H), 6.55 (s, 1H). – 13C NMR (150 MHz, CDCl3) δꢀ=ꢀ168.9,
4.2.19 (R/S)-3-(3-nitrophenylthio)isobenzofuran-1(3H)-
one (4i)
1
Yield: 87.6%, white solid; m. p. 177–178°C. – H NMR 145.8, 137.6, 134.3, 132.2, 130.0, 127.7, 126.2, 125.3, 123.4, 86.2.
(600 MHz, CDCl3): δꢀ=ꢀ8.19 (dd, 2H, Jꢀ=ꢀ7.2 Hz, 2.4 Hz), 7.93 – HRMS [(+)-(ESI)]: m/zꢀ=ꢀ249.0054 (calcd. 249.0049 for
+
(d, 1H, Jꢀ=ꢀ7.8 Hz), 7.80–7.77 (m, 1H), 7.72–7.68 (m, 3H), 7.64 C12H9O2S2, [Mꢀ+ꢀH] ).
(t, 1H, Jꢀ=ꢀ7.8 Hz), 6.89 (s, 1H). – 13C NMR (150 MHz, CDCl3):
δꢀ=ꢀ168.5, 147.3, 145.0, 141.0, 134.7, 131.3, 130.7, 126.1, 126.0,
124.1, 123.3, 84.8. – HRMS [(+)-(ESI)]: m/zꢀ=ꢀ287.0257 (calcd. 4.3 Biological assay
+
287.0253 for C14H10NO4S, [Mꢀ+ꢀH] ).
Twenty-four phthalide derivatives (3a–j, 4a–m) were
screened in vitro for their antifungal activities against nine
phytopathogenic fungi (i.e. FS, BP, CL, FM, FG, AA, PO, FV,
and AB). Potato dextrose agar (PDA) medium was prepared
in the flasks and sterilized. Compounds 3a–j and 4a–m
4.2.20 (R/S)-3-(4-(trifluoromethyl)phenylthio)
isobenzofuran-1(3H)-one (4j)
Yield: 88.2%, white solid; m. p. 112–113°C (lit. [26]: mp were dissolved in acetone before mixing with PDA, and the
114.0–114.6°C). – 1H NMR (600 MHz, CDCl3): δꢀ=ꢀ7.89 (d, 1H, concentration of test compounds in the medium was fixed
Jꢀ=ꢀ7.8 Hz), 7.77 (td, 1H, Jꢀ=ꢀ7.8 Hz, 1.2 Hz), 7.69–7.67 (m, 3H), at 50 μg mL−1. The medium was then poured into sterilized
7.60–7.56 (m, 3H), 6.81 (s, 1H). – 13C NMR (150 MHz, CDCl3): Petri dishes. All types of fungi were incubated in PDA at
δꢀ=ꢀ168.8, 145.5, 136.1, 134.5, 132.4, 130.4, 126.2, 125.9, 125.7, Tꢀ=ꢀ28ꢀ ꢀ1°C for 5 days to get new mycelium for the antifungal
123.3, 85.6. – HRMS [(+)-(ESI)]: m/zꢀ=ꢀ311.0348 (calcd. assays, and a mycelia disk of approximately 5 mm diameter
+
311.0353 for C15H10F3O2S, [Mꢀ+ꢀH] ).
cut from culture medium was picked up with a sterilized
inoculation needle and inoculated in the center of the PDA
Petri dishes. The inoculated Petri dishes were incubated at
28ꢀ ꢀ1°C for 4 days. Acetone without addition of any com-
pound mixed with PDA served as the control. Hymexazol, a
commercially available agricultural fungicide, was used at
4.2.21 (R/S)-3-(naphthalen-2-ylthio)isobenzofuran-
1(3H)-one (4k)
Yield: 68.5%, white solid; m. p. 99–101°C (lit. [26]: 97.5– 50 μg mL−1 as a positive control. For each treatment, three
97.8°C). – 1H NMR (600 MHz, CDCl3): δꢀ=ꢀ8.05 (s, 1H), 7.79– replicates were conducted. The radial growths of the fungal
7.70 (m, 6H), 7.56 (dd, 1H, Jꢀ=ꢀ8.4 Hz, 1.8 Hz), 7.50–7.48 (m, colonies were measured, and the data were statistically
3H), 6.80 (s, 1H). – 13C NMR (150 MHz, CDCl3): δꢀ=ꢀ169.1, analyzed. The inhibitory effects of the test compounds on
146.0, 134.3, 133.4, 133.0, 132.9, 130.1, 130.0, 128.7, 127.9, 127.8, the fungi in vitro were calculated by the formula:
127.7, 126.9, 126.7, 126.2, 125.5, 123.4, 86.7. – HRMS [(+)-(ESI)]:
Inhibition rate (%) =[(C –T)×100]C–1
+
m/zꢀ=ꢀ293.0636 (calcd. 293.0641 for C18H13O2S, [Mꢀ+ꢀH] ).
where C represents the diameter of fungi growth on
4.2.22 (R/S)-3-(1H-benzo[d]imidazol-2-ylthio)
isobenzofuran-1(3H)-one (4l)
untreated PDA, and T represents the diameter of fungi on
treated PDA.
1
Yield: 64.1%, white solid; m. p. 86–88°C. – H NMR Acknowledgments: This research was supported by the
(600 MHz, CDCl3): δꢀ=ꢀ7.94 (d, 1H, Jꢀ=ꢀ7.8 Hz), 7.77–7.74 (m, Guizhou Provincial Engineering Laboratory for Chemi-
1H), 7.71 (d, 1H, Jꢀ=ꢀ8.4 Hz), 7.64–7.61 (m, 3H), 7.31–7.30 (m, cal Drug R&D (No. [2016]5402), Guizhou Province Sci-
2H), 7.23 (s, 1H). – 13C NMR (150 MHz, CDCl3): δꢀ=ꢀ168.7, ence and Technology Fund (No. [2016]2848, [2017]2835
144.9, 144.1, 135.0, 130.8, 125.9, 125.7, 123.5, 123.4, 84.9. and [2019]1269), Guiyang Science and Technology
– HRMS [(+)-(ESI)]: m/zꢀ=ꢀ283.0549 (calcd. 283.0544 for Fund (No. [2017]30-28) and the opening foundation of
+
C15H11N2O2S, [Mꢀ+ꢀH] ).
the key laboratory of green pesticide and agricultural
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8ꢀ ꢀL. Fan et al.: Synthesis and antifungal activity of phthalides
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Z. Naturforsch.ꢂ
ꢂ2019 | Volume x | Issue x(b)
Graphical synopsis
Lingling Fan, Bilan Luo, Zhongfu Luo,
Li Zhang, Judi Fan, Wei Xue, Lei Tang and
Yong Li
Synthesis and antifungal activities of
3-substituted phthalide derivatives
https://doi.org/10.1515/znb-2019-0110
Z. Naturforsch. 2019; x(x)b: xxx–xxx
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