Natural products as sources of new fungicides (II): antiphytopathogenic activity of 2,4-dihydroxyphenyl ethanone derivatives

Article abstract of DOI:10.1080/14786419.2015.1041140

A series of 17 simple 1-(2,4-dihydroxyphenyl) ethanones were synthesised, and their structures characterised by ¹H, ¹³C NMR and ESI-MS. Their in vitro antifungal activities were evaluated against five phytopathogenic fungi including Glomerella cingulate, Botrytis cirerea, Fusarium graminearum, Curvularia lunata and Fusarium oxysporum f. sp. vasinfectum by the mycelial growth inhibition assay. Compounds 2g and 2h exhibited broad-spectrum inhibitory activity against the mycelial growth of the tested pathogens with IC₅₀ values in the range of 16-36 g/mL, and in particular being more active to G. cingulate, with IC₅₀ values of 16.50 and 19.25 g/mL, respectively, than the other pathogens. Preliminary SAR indicated that an α,β-unsaturated ketone unit of the alkyl chain of the compounds is the structure requirement for fungicidal action. The results suggested that 2g and 2h may be promising leads in the development of new antifungal agents.

Full text of DOI:10.1080/14786419.2015.1041140

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Natural products as sources of new
fungicides (II): antiphytopathogenic
activity of 2,4-dihydroxyphenyl
ethanone derivatives
Tseden Nandinsurena, Wei Shia, An-Ling Zhanga, Yu-Bin Baia & Jin-
Ming Gaoa
a Shaanxi Key Laboratory of Natural Products & Chemical Biology,
College of Science, Northwest A&F University, Yangling712100,
ShaanxiP.R. China
Published online: 15 May 2015.
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To cite this article: Tseden Nandinsuren, Wei Shi, An-Ling Zhang, Yu-Bin Bai & Jin-Ming Gao
(2015): Natural products as sources of new fungicides (II): antiphytopathogenic activity of 2,4-
dihydroxyphenyl ethanone derivatives, Natural Product Research: Formerly Natural Product Letters,
DOI: 10.1080/14786419.2015.1041140
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Natural Product Research, 2015
http://dx.doi.org/10.1080/14786419.2015.1041140
SHORT COMMUNICATION
Natural products as sources of new fungicides (II): antiphytopathogenic
activity of 2,4-dihydroxyphenyl ethanone derivatives
Tseden Nandinsuren, Wei Shi, An-Ling Zhang*, Yu-Bin Bai and Jin-Ming Gao*
Shaanxi Key Laboratory of Natural Products & Chemical Biology, College of Science, Northwest A&F
University, Yangling 712100, Shaanxi P.R. China
(Received 13 February 2015; final version received 6 April 2015)
H
O
O
H
O
H
O
CH=CH-R
=
H
O
2
R H
=
g
O
2h
R
H
C
3
inactive
antifungal activity to 5 pathogens
with IC50 = 16-36 ug/mL
A series of 17 simple 1-(2,4-dihydroxyphenyl) ethanones were synthesised, and their
structures characterised by 1H, 13C NMR and ESI-MS. Their in vitro antifungal
activities were evaluated against five phytopathogenic fungi including Glomerella
cingulate, Botrytis cirerea, Fusarium graminearum, Curvularia lunata and Fusarium
oxysporum f. sp. vasinfectum by the mycelial growth inhibition assay. Compounds 2g
and 2h exhibited broad-spectrum inhibitory activity against the mycelial growth of the
tested pathogens with IC50 values in the range of 16–36 mg/mL, and in particular being
more active to G. cingulate, with IC50 values of 16.50 and 19.25 mg/mL, respectively,
than the other pathogens. Preliminary SAR indicated that an a,b-unsaturated ketone
unit of the alkyl chain of the compounds is the structure requirement for fungicidal
action. The results suggested that 2g and 2h may be promising leads in the development
of new antifungal agents.
Keywords: acetophenones; benzophenones; phytopathogenic fungi; antifungal
activity; structure–activity relationship
1. Introduction
Agricultural crops are facing tremendous losses due to pests, diseases and weed damages which
result in direct economic losses including reduction in grain yield and quality (Thind 2012;
Madrid Villegas et al. 2015). Despite the availability of effective synthetic fungicides, new
fungicides with novel chemical structures which have higher potency and broader spectrum of
activity against resistant fungal strains are still needed. Recent studies have demonstrated that
acetophenone and its derivatives can be seen as important intermediates for the synthesis of
some agrochemicals and pharmaceuticals. For example, two antifungal agents 1-(2-hydroxy-
4,6-dimethoxy) acetophenone (xanthoxylin) from a medicinal plant Melicope borbonica
(Simonsen et al. 2004) and 2,4-dihydroxy-5-methylacetophenone from the fungus Polyporus
picipes (Bai et al. 2013; Ma et al. 2013). Based on these antecedents, the aim of this work was to
*Corresponding author. Email: jinminggao@nwsuaf.edu.cn
q 2015 Taylor & Francis

2
T. Nandinsuren et al.
prepare a series of 2,4-dihydroxyphenyl ethanones: 2a–n, 3, 4 and 5, and evaluated in vitro
antifungal activities against several fungal phytopathogens. Herein, we report the interesting
findings of these simple acetophenone derivatives.
2. Results and discussion
The synthetic pathways for the preparation of 2,4-dihydroxyacetophenone analogues 2a–n are
shown in Figure 1. Target compounds 2a–n could be readily obtained in a single step by the
Fries rearrangement of the appropriate phenol esters (method B) or by the Friedel–Crafts
acylation reaction of resorcinol with the proper acyl chlorides in the presence of dry AlCl3 in
good yields (method A). Specifically, as stated in the Experimental Section (Supplementary
Material), benzoylated and some alkanoylated products with a large steric hindrance group, such
as 2c, 2k and 2m, were obtained by increasing reaction temperature and time in order to get a
reasonable yield, and the best result was obtained for 2c at 1008C for 3 h in yield of 82%.
In addition, the preparation of compounds 3 (93 mg, 56%), 4 (139 mg, 90%) and 5 (135 mg,
81%) started with 2a following the conventional methods (Figure 2). The spectroscopic data of
the semi-synthetic compounds are given in Supplementary Material.
H
O
O
.
H
O
H
O
O
O
BF3 Et
2O
+
Method A
R
R
R
O
reflux
H
O
1
2a-f
H
O
O
H
O
H
O
O
AlCl3
R
+
Method B
l
C
R
D M 0¡æ
C
/
H
O
1
2g-n
2a: R = -CH3; 2b: R = -CH2CH3; 2c: R = -CH2CH2CH3; 2d: R = -CH(CH3)2; 2e:
R = -CH2(CH2)2CH3; 2f: R = -C(CH3)3; 2g: R = -CH=CH2; 2h: R = -CH=CCH3;
2i: R = -CH2Cl; 2j: R = -cyclopropyl; 2k: R = -p-NO2Ph; 2l: R = -p-ClPh; 2m: R
= -p-CH3OPh; 2n: R = -Ph
Figure 1. Synthesis of compounds 2a–n.
H
O
O
O
H
O
H
H
O
a
c
H
O
H
O
b
3
5
O
O
O
H
H
4
O
2a
N
H
O
a: MeI, K2CO3 , acetone, reflux; b: NaBH4, MeOH; c: NH2OH·HCl, AcONa, MeOH,
reflux
Figure 2. Synthesis of compounds 3–5.

Natural Product Research
3
Preliminary in vitro screening results of the title compounds for antifungal activities against
five phytopathogenic fungi (Glomerella cingulate, Botrytis cirerea, Fusarium graminearum,
Curvularia lunata and Fusarium oxysporum f. sp. vasinfectum) are listed in Table S1 (Li et al.
2012; Lu et al. 2014). The results indicated that some of the synthetic compounds exhibited
over 65% growth inhibition against mycelial growth of these tested fungi at concentrations of
100 mg/mL. As shown in Table S1, among the semisynthetic derivatives, compounds 2a–d and
2f, with a saturated aliphatic chain C1–C4, showed weak antifungal activities against the
test pathogenic fungi with ,65% inhibition (except B. cinerea), while 2e, with a saturated
aliphatic straight C4 chain exerted strong activities against G. cingulate, B. cinerea,
F. graminearum and C. lunata, with the inhibition of 68.75%, 74.52%, 65.50% and 76.83%,
respectively. This indicated that the alkyl chain length appeared to be required for activity. The
introduction of the unsaturated aliphatic carbon chain into 1 gave compounds 2g and 2h,
producing more increased activity compared to 2a–e and 2j. They almost completely inhibited
the mycelial growth of the pathogens with 92% to 98% inhibition (Table S1). Both 2g and
2h were significantly more active against G. cingulate and C. lunata than a commercial
fungicide thiabendazole as positive control. The results suggested that the presence of a
conjugated (ZCHvCHZCvOZ) unit in the alkyl chain plays an important role in the
activity. In addition, 2i with a chlorine atom in the side chain was better than 2a in activity,
implying that the Cl group is more sensitive to the tested pathogens. Furthermore, the
introduction of mono-substituted aromatic rings decreased activity of benzophenones (2k–m)
with 7% to 58% inhibition, possibly due to a steric hindrance. Also, among the tested
compounds 3–5, 4 and 5 reduced the mycelial growth of B. cinerea up to 73.35% and 75.45%
at 100 mg/mL, respectively, but were inactive to other pathogens tested. The results suggested
that the OH group at C-4 is very sensitive to B. cinerea (3 vs 5).
Compared to other tested compounds, the highest activities with broad antifungal spectra
of 2g and 2h make them good candidates for further evaluation, and their median inhibitory
concentration (IC50) was thus determined (Li et al. 2012). The IC50 values for 2g and 2h
against G. cingulate were 16.50 and 19.25 mg/mL, respectively; a slightly higher IC50 values
(2g, 22.55 mg/mL; 2h, 24.52 mg/mL) were found against F. oxysporum f. sp. Vasinfectum,
whereas F. graminearum Sehw. was found less sensitive (IC50 values of 25.62 and 27.49 mg/
mL, respectively). Moreover, B. cinerea and C. lunata were weak sensitive organisms, with
IC50 values of 32.05 and 35.37 mg/mL for 2g and 2h against B. cinerea and of 34.37 and
36.52 mg/mL against C. lunata. These results confirm that the co-occurrence of acidic
phenolic hydroxyls and lipophilic residues is an important chemical feature for antifungal
activity. Taken together, the order of their antifungal potency is R ¼ allylic group . -
chloromethyl . alkanyl q aromatic group. This suggests that the addition of the aliphatic
side chain increases the lipophilicity of the compound resulting in a greater antifungal
activity, which might be associated with better penetration through the plasmatic membrane
of the fungi.
3. Conclusions
In conclusion, a series of acetophenone derivatives were prepared and their in vitro antifungal
activities against five phytopathogens were evaluated. Among the synthetic derivatives,
compounds 2g and 2h displayed broad-spectrum antifungal activities to various important plant
pathogens and might be promising leads for new agricultural fungicides.
Supplementary material
Supplementary material relating to this article is available online, alongside Table S1.

4
T. Nandinsuren et al.
Disclosure statement
No potential conflict of interest was reported by the authors.
Funding
This work was supported by grants from the Program of Unified Planning Innovation Engineering of
Science & Technology in Shaanxi Province [grant number S2015TQNY0014] and from the National
Natural Science Foundation of China [grant number 30971882].
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