Development of novel pesticides based on phytoalexins: Part 2. Quantitative structure-activity relationships of 2-heteroaryl-4-chromanone derivatives

Article abstract of DOI:10.1002/ps.584

Phytoalexins are low-molecular-weight chemicals that immune systems of plants produce and accumulate in response to infections, especially those of fungal origin. Although their content is not high in plants, yet they have shown unique fungicidal activity

Full text of DOI:10.1002/ps.584

Pest Management Science
Pest Manag Sci 58:1063–1067 (online: 2002)
DOI: 10.1002/ps.584
Development of novel pesticides based
on phytoalexins: Part 2. Quantitative
structure–activity relationships of
2-heteroaryl-4-chromanone derivatives†
Guangfu Yang,1* Xiaohua Jiang1 and Huazheng Yang2
1Institute of Organic Synthesis, Central China Normal University, Wuhan 430079, People’s Republic of China
2National Key Laboratory of Elemento-organic Chemistry, Nankai University, Tianjin 300071, People’s Republic of China
Abstract: Phytoalexins are low-molecular-weight chemicals that immune systems of plants produce
and accumulate in response to infections, especially those of fungal origin. Although their content is
not high in plants, yet they have shown unique fungicidal activity and played an important role in the
defence system of plants. In searching for novel environmentally benign fungicides with high activity,
the structures of flavanone derivatives, one of the most important phytoalexins groups, have been
modified via bioisosteric substitution and a series of 2-heteroaryl-4-chromanones were designed and
synthesized. They showed good fungicidal activities against rice blast disease, Pyricularia grisea
(Sacc). Their IC50 values were tested in vitro and the relationship between structure and fungicidal
activity was analyzed quantitatively using a Hansch–Fujita approach. The results showed that
hydrophobicity was very important for fungicidal activity and there is apparently an optimum
hydrophobic property for the molecules at a log Pow value of about 2.7. In addition, the results indicated
that electronic effects played an important role in binding with the receptor and that the C=O group
was probably a electron-accepting site. The quantitative structure–retention correlative equation of
the title compounds was also established.
# 2002 Society of Chemical Industry
Keywords: 2-heteroaryl-4-chromanones; phytoalexins; bioisosterism substitution; fungicidal activity; QSAR;
molecular design
1
INTRODUCTION
decades,3,4,7–12 but all the modifications have been
concerned with the substituents on the aromatic
moiety rather than the skeletal structure, and all of
structure–activity relationships are of a qualitative
nature.7–11
Phytoalexins are compounds involved in the resistance
of plants to fungal infection.1 They exhibit fungistatic,
fungicidal and, in some cases, antibacterial activity.
However, in comparison with modern synthetic fungi-
cides, phytoalexins are poorly active in vitro (ED50:
10ꢀ4ꢁ10ꢀ5 M) and almost inactive in in vivo tests.2
Therefore, suggestions of the possibility of using them
as models for the synthesis of new fungicides have been
made in the past two decades,3–6 although so far no
commercial fungicide has been obtained.
Bioisosterism is an important approach used by the
medicinal and pesticidal chemist for the rational
modification of lead compounds into more effective
agents.13 We have noted the successful use of the
classical bioisosteres such as replacement of benzene
with thiophene, furane or pyridine, and used the
concept of bioisosterism to develop novel environ-
mentally benign fungicidal structures and also to
improve the hydrophobicity of flavanone phytoalexins
by modifying the skeletal structure of flavanone to give
the title compounds, 2-heteroaryl-4-chromanones (4),
by replacing the benzene ring with thiophene, furane
or pyridine. On the basis of systematically determining
the fungicidal activity against Pyricularia grisea (Sacc),
Flavanones are a group of important phytoalexins
inhibiting several biological processes. A drawback to
the use of these phytoalexins in fungicide studies is
that they are not easily translocated in the plant tissues
due to the existence of polyhydroxyl groups in their
molecular structure. Many studies have been made on
the structural modification and structure–activity
relationships of flavanone derivatives in recent
* Correspondence to: Guangfu Yang, Institute of Organic Synthesis, Central China Normal University, Wuhan 430079, People’s Republic of
China
E-mail: gfyang@ccnu.edu.cn
† Part 1. Yang G, Jiang X, Ding Y and Yang H, Chinese J Chem 19:423–428 (2001)
Contract/grant sponsor: National Natural Science Foundation of China; contract/grant number: 29802002; contract/grant number: 20172017
Contract/grant sponsor: Foundation for University Key Teacher, Ministry of Education of China; contract/grant number: GG-150-10511-1005
Contract/grant sponsor: Dawn Plan of Science and Technology for Young Scientists of Wuhan City
(Received 28 March 2002; revised version received 26 April 2002; accepted 27 June 2002)
# 2002 Society of Chemical Industry. Pest Manag Sci 1526–498X/2002/$30.00
1063

G Yang, X Jiang, H Yang
a quantitative structure–activity relationship of the title
compounds was derived using the Hansch–Fujita
approach.14 To our knowledge, this is the first QSAR
study for phytoalexin analogues.
P grisea was tested in vitro according to the modified
method described previously.16 A set amount of each
sample was dissolved in chloroform to which a drop of
a Tween 20 was added. The solution was then diluted
with water until it reached the concentration required.
Compound-amended agar media were dispersed
aseptically into 9-cm-diameter plastic Petri dishes
(15ml). Inocula consisted of plugs (7mm diameter)
taken from the edges of actively growing colonies and
inverted on the agar (two per dish) with two replicate
plates for each fungus-compound combination. Col-
ony diameters (mm) were measured after 12, 36, and
72h incubation at 28°C in the dark. The data reported
in Table 1 refer to the 72-h results. The molar
concentration of each compound required to inhibit
the mycelial growth to half the length of the control
(I50 value) was evaluated by the probit method.17 The
2
MATERIALS AND METHODS
2.1 Synthesis of the title compounds
2-Heteroaryl-4-chromanones (4) used in this work are
listed in Table 1, and were designed and synthesized
according to the synthetic pathway outlined in Fig 1.
All the products 4 were purified by chromatography
over silica gel and their structures were confirmed by
1H NMR and mass spectroscopy as well as elemental
analyses. In order to enrich the electronic effect in the
title compounds, we have cited three flavanone
derivatives 4x–4z with pI50 values from our previous
study.15
I
50 measurements were repeated for at least three runs
and the pI50 values were averaged over repeats, the
standard deviation being ꢂ0.20. The activity pI50
values of the compounds are listed in Table 1.
2.2 Biological tests
The fungicidal activity of the title compounds against
Table 1. Structure, fungicidal activity and physicochemical parameters of 2-heteroaryl-4-chromanones (4)
Compound
Het a
Parameters
pI50
No
R
log k
clog P CMR EHOMO ELUMO DE FOE 1
FNC4
Obsd Eqn (3)
D c
Eqn (4)
d
4a 6-Br
4b 7-CH3
4c 7-CH3O
A
A
A
A
B
B
B
B
C
C
C
C
C
D
D
D
D
D
D
B
A
B
A
E
0.4579
0.2504
0.0212
3.84 7.19 ꢀ9.36 ꢀ0.68 8.68 1.25 18.28
3.44 6.88 ꢀ9.30 ꢀ0.45 8.85 1.52 29.15
2.96 7.03 ꢀ9.20 ꢀ0.39 8.81 0.86 31.65
5.83
5.90
6.29
5.14
5.40
4.66
5.87
5.66
6.04
5.84
5.84
4.98
5.76
5.09
6.22
6.13
5.87
6.01
6.24
5.44
5.89
5.18
5.73
5.81
5.92
6.28
5.55
5.35
4.83
5.60
5.33
6.02
5.83
6.03
5.24
6.15
5.16
6.13
5.95
5.80
5.98
5.92
5.38
5.98
5.11
5.56
5.81
6.17
6.05
0.02
ꢀ0.02
0.01
5.79
5.91
6.27
5.56
5.30
4.86
5.60
5.34
5.94
5.84
6.08
5.19
6.13
5.23
6.13
6.00
5.81
5.93
5.99
5.38
5.96
5.10
5.59
5.73
6.20
6.10
0.04
ꢀ0.01
0.02
4d
4e 6-Br
4f
H
(ꢀ0.0044)b 2.95 6.41 ꢀ9.37 ꢀ0.47 8.90 1.61 30.03
ꢀ0.41
0.05
ꢀ0.42
0.10
0.2833
3.37 6.59 ꢀ9.45 ꢀ0.76 8.69 0.88 16.27
H
(ꢀ0.1505)b 2.48 5.82 ꢀ9.38 ꢀ0.52 8.86 0.32 27.37
ꢀ0.17
0.27
ꢀ0.20
0.27
4g 7-CH3O
4h 7-CH3
ꢀ0.2366
0.0294
2.49 6.43 ꢀ9.28 ꢀ0.44 8.84 0.77 31.59
2.97 6.28 ꢀ9.35 ꢀ0.51 8.84 0.74 26.63
1.82 7.01 ꢀ9.26 ꢀ0.41 8.85 0.77 32.31
2.55 6.88 ꢀ9.37 ꢀ0.69 8.68 1.26 17.93
2.30 6.86 ꢀ9.19 ꢀ0.45 8.74 1.34 31.07
1.80 6.39 ꢀ9.44 ꢀ0.48 8.96 1.56 28.97
2.70 7.17 ꢀ9.42 ꢀ0.71 8.71 1.20 17.12
0.33
0.32
4i
4j
7-CH3O
6-Cl
ꢀ0.6021
ꢀ0.0132
ꢀ0.1675
ꢀ0.6021
0.0253
0.02
0.10
0.01
0.00
4k 6-CH3
4l
4m 6-Br
4n
ꢀ0.19
ꢀ0.26
ꢀ0.39
ꢀ0.07
0.09
ꢀ0.24
ꢀ0.21
ꢀ0.37
ꢀ0.14
0.09
H
H
(ꢀ0.5120)b 1.80 6.39 ꢀ9.50 ꢀ0.57 8.93 1.55 25.25
4o 6-Br
4p 6-CH3
4q 6-Cl
ꢀ0.0862
ꢀ0.0862
ꢀ0.1612
ꢀ0.3768
2.70 7.17 ꢀ9.48 ꢀ0.79 8.69 1.17 15.83
2.30 6.86 ꢀ9.25 ꢀ0.53 8.72 1.33 26.85
2.55 6.88 ꢀ9.45 ꢀ0.78 8.67 1.22 16.38
2.30 6.86 ꢀ9.48 ꢀ0.45 9.03 1.46 28.27
0.18
0.13
0.07
0.06
4r
4s 7-CH3O
4t 6-CH3
7-CH3
0.03
0.08
(ꢀ0.4769)b 1.82 7.01 ꢀ9.32 ꢀ0.49 8.83 0.75 27.41
(0.0492)b 2.97 6.28 ꢀ9.22 ꢀ0.49 8.73 1.30 29.11
(0.2613)b 3.44 6.88 ꢀ9.14 ꢀ0.44 8.70 1.40 32.03
(0.1737)b 3.22 6.31 ꢀ9.41 ꢀ0.74 8.67 1.10 17.08
(0.3488)b 3.69 6.90 ꢀ9.45 ꢀ0.67 8.78 0.08 16.97
0.32
0.25
0.06
0.06
4u 6-CH3
4v 6-Cl
4w 6-Cl
ꢀ0.09
0.07
ꢀ0.07
0.08
0.17
0.14
4xd
H
0.2201
0.2765
0.3927
3.04 7.21 ꢀ9.68 ꢀ1.20 8.48 1.46 0.0522 5.85
3.54 7.68 ꢀ9.60 ꢀ1.19 8.41 1.34 0.0490 6.23
3.79 7.71 ꢀ9.61 ꢀ1.26 8.35 1.14 0.0783 5.86
0.04
0.12
4yd 7-CH3
4zd 6-Cl
E
0.06
0.03
E
ꢀ0.19
ꢀ0.24
a A: 2-thienyl; B: 2-furanyl; C: 2-pyridinyl; D: 3-pyridinyl; E: 3’-nitrophenyl.
b Calculated according to eqn (2).
c Difference between observed and calculated values.
d Cited from Reference 15.
1064
Pest Manag Sci 58:1063–1067 (online: 2002)

Structure–activity relationships of 2-heteroaryl-4-chromanone derivatives
Figure 1. Synthesis route for compounds
discussed.
2.3 Physicochemical parameters
of this series of compounds in the 1-octanol/water
system by the shaking-flask method is certainly the
most direct method but is tedious, requires a large
amount of pure sample and is therefore impracticable
in most situations. For these reasons, the logarithm of
the retention factor (k) in reversed-phase HPLC was
employed as an alternative hydrophobicity parameter.
The relevancy of logk as a hydrophobicity parameter
has been shown in the literature.20–25 Retention times
(tR) were determined on a HP-1100 HPLC apparatus
equipped with an UV absorbance detector (254nm).
The column was a Description-Eclipse XDB-C8
(5-mm particle size, 150mmꢄ4.6mm), the solvent
methanolþwater (60þ40 by volume) and the flow
rate 1ml minꢀ1. Each compound was injected three
times and mean logk values were calculated from eqn
(1), where t0 represents the elution time of an
unretained peak:
It is difficult to take substituent parameters from the
literature to represent the physicochemical properties
of 2-thienyl, 2-furanyl, 2-pyridinyl and 3-pyridinyl
groups. Therefore, we used clogP and CMR values
calculated by the ClogP and CMR programs on the
SGI workstation. In addition, we carried out quantum
chemical calculations for all compounds. Molecular
models were constructed using the SKETCH program
and optimized based on a Tripos 6.5 force field with
Gasteiger–Huekel charges. All energy calculations and
optimization were implemented by an AM1 semi-
empirical method. Because each molecular structure is
rigid, the minimum energy conformation was selected
as the bioactive conformation. These conformations
were used to calculate electronic parameters such as
HOMO and LUMO energies, FOE1 (approximate elec-
trophilic superdelocalizability of the oxygen atom at
the 1 position), FCN4 (approximate nucleophilic super-
delocalizability of the 4-position carbon atom), etc.18
Approximate nucleophilic superdelocalizability and
approximate electrophilic superdelocalizability are
defined as
log k ¼ log½ðtR ꢀ t0Þ=t0ꢃ
ð1Þ
We determined the logk values of 18 title compounds
as shown in Table 1 and established their quantitative
structure retention relationships as eqn (2) using their
physicochemical and electronic parameters. Using eqn
(2) we evaluated the logk values of another eight
compounds as shown in Table 1.
FN ðiÞ ¼ ½f N ðiÞ= ꢀ ELUMOꢃ ꢄ 100
FEðiÞ ¼ ½f EðiÞ= ꢀ EHOMOꢃ ꢄ 100
log k ¼ 1:0652ðꢂ0:0202Þ þ 0:4345ðꢂ0:0433Þclog P
where f N (i) is the frontier electron density of LUMO
at atom i and ELUMO is the energy of LUMO orbital
(measured in ev), f E (i) is the frontier electron
density of HOMO at atom i and EHOMO is the energy
of HOMO orbital (also measured in EV). f(i)
represents the reactivity of different atoms within a
molecule, while F(i) can represent the reactivity and
the electronic effect relatively among different com-
pounds.18 All computations were done on a Silicon
Graphic O2 workstation with the molecular modeling
software package SYBYL, version 6.5.19
ꢀ 0:2642ðꢂ0:1517ÞDELUMO
ð2Þ
HOMO
n ¼ 18; r ¼ 0:9651; s ¼ 0:0860; F ¼ 101:93
where clogP is the hydrophobicity parameter calcu-
lated from the ClogP program, DELUMO–HOMO is the
interval between ELUMO and EHOMO, n is the number
of compounds, r is the correlation coefficient, and s is
the standard derivation. F is the ratio of regression and
residual variances.
2.4 Determination of partition coefficients by HPLC
Direct determination of the partition coefficient (logP)
3 RESULTS AND DISCUSSION
Variations in the fungicidal activity of 23 title com-
Pest Manag Sci 58:1063–1067 (online: 2002)
1065

G Yang, X Jiang, H Yang
Intercept
CMR
clog P
(clog P)2
FNC4
r
s
F test
0.6736
0.6104
0.7422
0.7639 0.2802 33.63
0.7806 0.2772 17.94
0.8217 0.2583 15.25
0.7990 ꢀ0.1155
ꢀ2.0980
ꢀ4.6590
0.8868
1.1250
1.5033
1.7468
ꢀ0.2946
ꢀ0.3192
0.0208 0.8966 0.2055 21.53
Table 2. Development of QSAR of equation (3)
Table 3. Correlation matrix for variables used to derive
equation (3)
activity, suggesting that the greater the ability of the
carbonyl group to accept electrons from an electron-
rich plant receptor, the higher the activity.
CMR
clog P (clogP)2
FNC4
Replacment of clogP with another hydrophobic
parameter for the whole molecule, logk, yield a similar
correlation equation, eqn (4)
CMR
1.0000
clogP
0.1170 1.0000
(clogP)2 0.1389 0.9877 1.0000
FCN4
0.3605 0.2468 0.2551 1.0000
pI50 ¼ ꢀ2:1307ðꢂ0:0401Þ þ 1:1065ðꢂ0:1208ÞCMR
ꢀ 0:2578ðꢂ0:1862Þ log k
pounds (Table 1) were analyzed using clogP, CMR
and FCN4, giving
2
ꢀ 1:3147ðꢂ0:4494Þðlog kÞ
þ 0:0197ðꢂ0:0057ÞFCN4
ð4Þ
pI50 ¼ ꢀ4:6590ðꢂ0:0403Þ þ 1:1250ðꢂ0:1233ÞCMR
þ 1:7468ðꢂ0:6163Þclog P
n ¼ 26; r ¼ 0:8977; s ¼ 0:2045; F ¼ 21:80
The development of eqn (4) and the interrelation of
variables are shown in Tables 4 and 5, respectively.
Equation (4) is similar to eqn (3) in terms of r, s and F
2
ꢀ 0:3192ðꢂ0:1110Þðclog PÞ
þ 0:0208ðꢂ0:0056ÞFCN4
ð3Þ
values, as well as in the coefficients of CMR and FCN4
,
n ¼ 26; r ¼ 0:8966; s ¼ 0:2055; F ¼ 21:53
which indicates that logk is a suitable parameter to
describe the whole hydrophobicity of molecules. The
negative coefficient of the (logk)2 term indicates that
variations in the activity are parabolically related to the
hydrophobic parameters. The optimum logk value in
eqn (4) is about ꢀ0.0981. The fungicidal activities
calculated by eqns (3) and (4) are listed in Table 1.
There is a growing consensus that, in most systems,
flavonoid phytoalexins exert their toxicity by some
membrane-associated phenomenon, again indicating
the possible importance of lipophilicity for their
activity.3–11 The relative lipophilicities of flavonoid
phytoalexins have been qualitatively compared and the
with the best correlation. In this and the following
equations, n is the number of compounds, r is the
correlation coefficient, and s the standard derivation.
The figures in parentheses accompanying each coeffi-
cient are the 95% confidence intervals of the regres-
sion coefficient. The development of this equation and
the interrelation of variables are shown in Tables 2 and
3, respectively.
Equation (3) indicates that hydrophobicity is the
most important physical property in determining
fungicidal activity. The negative coefficient of the
(clogP)2 term indicates that variations in the activity
are parabolically related to the hydrophobic par-
ameters. The optimum clogP value in eqn (3) is about
2.74. The positive coefficient of CMR term indicates
that the more polarizable the molecule, the higher the
activity. In addition, Table 2 shows that introduction
of the FCN4 term led to a significant improvement in the
correlation. The positive coefficient of FCN4 term
indicates that the higher the approximate nucleophilic
superdelocalizability of the carbon 4, the higher the
Table 5. Correlation matrix for variables used to derive
equation (4)
CMR
log k
(log k)2
FNC4
CMR
1.0000
logk
0.1209 1.0000
(logk)2 0.0090 0.2324 1.0000
FCN4
0.3605 0.2878 0.0110 1.0000
Intercept
CMR
log k
(log k)2
FNC4
s
r
F test
0.6736
0.3005
0.7422
0.7962
0.9004
1.1065
0.7639
0.7785
0.8337
0.8977
0.2802
0.2784
0.2504
0.2045
33.63
17.69
16.72
21.80
ꢀ0.2219
ꢀ0.5145
ꢀ0.2578
ꢀ0.2906
ꢀ2.1307
ꢀ1.3937
ꢀ1.3147
0.0197
Table 4. Development of QSAR of equation (4)
1066
Pest Manag Sci 58:1063–1067 (online: 2002)

Structure–activity relationships of 2-heteroaryl-4-chromanone derivatives
and their mixtures against different fungi occurring on grain.
Pestic Sci 38:347–351 (1993).
relationships between the lipophilicity and fungicidal
activity also been discussed qualitatively.3,4,8,11
Arnoldi et al4 studied the relationships between the
lipophilicity and fungicidal activity of 3-(4,5-disub-
stituted)phenylcoumarins, analogues of the isoflavo-
noids, and pointed out that an increase in lipophilicity
induces a decrease in biological activity both in vitro
and in hypocotyl tests. They also studied the relation-
ship between the lipophilicity and antifungal activity
on Aphanomyces euteiches C Drechsler and Fusarium
solani (Martius) Sacc fsp cucurbitae Snyder & Hansen
of 18 isoflavonoid phytoalexins whose values of logP
ranged from 1.5 to 4.2 as measured by reversed-phase
HPLC and/or calculated by the use of Hansch
hydrophobic parameters.8 The results indicated that,
within groups of compounds of similar structure, an
increase in lipophilicity correlates positively with
increased antifungal activity. Laks and Pruner11
studied the relationship between the lipophilicity and
antifungal activity of two sets of semi-synthetic
flavonoid phytoalexin analogues, epicatechin-4-alkyl-
sulphides and catechin dialkyl ketals, and found that
the plots of the activity against A euteiches and F solani
against the lipophilic parameters (RM) were paraboli-
cal and the most active members of the two sets of
flavonoid derivatives had very similar RM values,
c ꢀ0.1. However, all the above results are qualitative,
and no clear quantitative results have been reported so
far. The results we have obtained have shown that the
variations in the fungicidal activity of 2-heteroaryl-4-
chromanone derivatives are parabolically related to the
hydrophobic parameters and that the optimum clogP
or logk values are about 2.74 or ꢀ0.0981, respectively.
To our knowledge, this is the first quantitative report
on the hydrophobic requirement for phytoalexin
analogues.
6 Weidenborner M and Jha HC, Antifungal spectrum of flavone
and flavanone tested against 34 different fungi. Mycol Res
101:733–736 (1997).
7 Aida Y, Tamogami S, Kodama O and Tsukiboshi T, Synthesis of
7-methoxyapigeninidin and its fungicidal activity against
Gloeocercospora sorghi. Biosci Biotech Biochem 60:1495–1496
(1996).
8 Arnoldi A and Merlini L, Lipophilicity-antifungal activity rela-
tionships for some isoflavonoid phytoalexins. J Agric Food
Chem 38:834–838 (1990).
9 Carter GA, Chamberlain K and Wain RL, Investigations on
fungicides. XX. The fungitoxicity of analogues of the phyto-
alexin
2-(2’-methoxy-4’-hydroxyphenyl)-6-methoxybenzo-
furan (Vignafuran). Ann Appl Biol 19:107–124 (1978).
10 Adesanya SA, O’Neill MJ and Roberts MF, Structure-related
fungitoxicity of isoflavonoids. Physiol Mol Plant Pathol 29:95–
103 (1986).
11 Laks PE and Pruner MS, Flavonoid biocides: structure–activity
relations of flavonoid phytoalexin analogues. Phytochemistry
28:87–91 (1989).
12 Kodama O, Miyakawa J, Tadami T and Kiyosawa S, Sakur-
anetin, a flavanone phytoalexin from ultraviolet-irradiated rice
leaves. Phytochemistry 31:3807–3809 (1992).
13 George AP and Edmond JL, Bioisosterism: a rational approach
in drug design. Chem Rev 96:3147–3176 (1996).
14 Hansch C and Fujita T, r–s–p Analysis. A method for the
correlation of biological activity and chemical structure. J Am
Chem Soc 86:1616–1626 (1964).
15 Ding Y and Yang G, Syntheses and fungicidal activity of B-cycle
substituted flavanone derivatives. Chinese J Appl Chem 18:785–
788 (2001).
16 Yang G, Jiang X, Ding Y and Yang H, Development of pesticides
based on phytoalexins. Part 1: Design and synthesis of
flavanone analogues via bioisosterism substitution. Chinese J
Chem 19:423–428 (2001).
17 Finney DJ, Probit analysis, Cambridge Univ Press, London, p
183 (1952).
18 Karelson M and Lobanov VS, Quantum-chemical descriptors in
QSAR/QSPR studies. Chem Rev 96:1027–1043 (1996).
19 SYBYL Molecular Modeling Software, Tripos Associates, Inc, St
Louis, Missouri, USA.
20 Kim KH, Description of the reversed-phase high-performance
liquid chromatography (RP-HPLC) capacity factors and
octanol–water partition coefficients of 2-pyrazine and 2-pyri-
dine analogues directly from the three-dimensional structures
using comparative molecular field analysis (CoMFA) ap-
proach. Quant Struct Act Relat 14:8–18 (1995).
ACKNOWLEDGEMENTS
This project is supported by the National Natural
Science Foundation of China (29802002, 20172017),
Foundation for University Key Teacher by the
Ministry of Education of China (GG-150-10511-
1005) and the Dawn Plan of Science and Technology
for Young Scientists of Wuhan City.
21 Terada H, Determination of logPoct by high-performance liquid
chromatography, and its application in the study of quantita-
tive structure-activity relationships. Quant Struct Act Relat
5:81–88 (1986).
22 Krikorian SE and Chorn TA, Determination of octanol/water
partition coefficients of certain organophosphorus compounds
using high-performance liquid chromatography. Quant Struct
Act Relat 6:65–69 (1987).
REFERENCES
1 Bailey JA and Mansfield JW, Phytoalexins, Blackie, Glasgow and
London, Chapter 2 (1986).
23 Dorsey JG and Khaledi MG, Hydrophobicity estimations by
reversed-phase liquid chromatography: Implications for bio-
logical partitioning processes. J Chromatogr A 656:485–499
(1993).
2 Rathmell WG and Smith DA, Lack of activity of selected iso-
flavonoid phytoalexins as protectant fungicides. Pestic Sci
11:568–572 (1980).
24 Yamagami C, Yokota M and Takao N, Hydrophobicity par-
ameters determined by reversed-phase liquid chromatography.
IX. Relationship between capacity factor and water-octanol
partition coefficient of monosubstituted pyrimidines. Chem
Pharm Bull 42:907–912 (1994).
3 Arnoldi A, Carughi M, Farina G, Merlini L and Parrino MG,
Synthetic analogues of phytoalexins. Synthesis and antifungal
activity of potential free-radical scavengers. J Agric Food Chem
37:508–512 (1989).
4 Arnoldi A, Farina G, Galli R, Merlini L and Parrino MG, Ana-
logues of phytoalexins. Synthesis of some 3-phenylcoumarins
and their fungicidal activity. J Agric Food Chem 34:185–188
(1986).
25 Baj S and Dawid M, Correlation between the chemical structures
of dialkyl peroxides and their retention in reversed-phses
high-performance liquid chromatography. J Liq Chromatogr
17:3933–3949 (1994).
5 Weidenborner M and Jha HC, Antifungal activity of flavonoids
Pest Manag Sci 58:1063–1067 (online: 2002)
1067