Estimation of the hydrophobicity of 2,4-diphenyl-1,3-oxazoline analogs and QSAR analysis of their ovicidal activity against Tetranycus urticae

Article abstract of DOI:10.1016/j.bmcl.2006.04.089

Partition coefficients of six 2-phenyl-1,3-oxazoline congeners containing 2-I, 2-NO₂, 2-CF₃, 2,6-(CH₃)₂, 2,6-F₂, and 2-F-6-Cl substitutions on the phenyl moiety were measured in a 1-octanol/water syst

Full text of DOI:10.1016/j.bmcl.2006.04.089

Bioorganic & Medicinal Chemistry Letters 16 (2006) 4080–4084
Estimation of the hydrophobicity of 2,4-diphenyl-1,3-oxazoline
analogs and QSAR analysis of their ovicidal activity against
Tetranycus urticae
Chieka Minakuchi,a Junji Suzuki,b Kazuya Toda,b Miki Akamatsuc and
Yoshiaki Nakagawaa,*
aDivision of Applied Life Sciences, Graduate School of Agriculture, Kyoto University, Kyoto 606-8502, Japan
bKyoyu Agri Co., Ltd, Nagano 381-0006, Japan
cDivision of Environmental Science and Technology, Kyoto University, Kyoto 606-8502, Japan
Received 15 March 2006; revised 20 April 2006; accepted 28 April 2006
Available online 22 May 2006
Abstract—Partition coefficients of six 2-phenyl-1,3-oxazoline congeners containing 2-I, 2-NO2, 2-CF3, 2,6-(CH3)2, 2,6-F2, and 2-F-
6-Cl substitutions on the phenyl moiety were measured in a 1-octanol/water system using the flask-shaking method. The effect on the
hydrophobicity (LogP) of substituents on the phenyl moiety of 2-phenyl-1,3-oxazolines linearly correlated with that of benzamide
congeners. logP values of other 2-(substituted phenyl)-1,3-oxazoline analogs were empirically estimated from the corresponding
substituted benzamides. The ovicidal activity of 2-(substituted phenyl)-4-phenyl-1,3-oxazoline analogs against the two-spotted
spider mite Tetranycus urticae was quantitatively analyzed using the classical QSAR (Hansch–Fujita) method. Results showed that
ovicidal activity increases with hydrophobicity. The introduction of inductive electron-withdrawing groups at ortho-positions
increased ovicidal activity, but addition of steric bulk was unfavorable. Substitution at either the meta- or para-position was
detrimental to the acaricidal activity.
Ó 2006 Elsevier Ltd. All rights reserved.
Etoxazole [YI-5301, 4-(4-tert-butyl-2-ethoxyphenyl)-2-
(2,6-difluorophenyl)-1,3-oxazoline, I in Fig. 1] is a
growth inhibitory-type acaricide discovered by Kyoyu
Agri Co., Ltd (formerly Yashima Chemical Industry
Co., Ltd).1,2 This compound has an excellent activity
against eggs, larvae, protonymphs, and deutonymphs
of susceptible mites such as Tetranycus kanzawai and
Panonycus citri, but no activity against adult mites.
Etoxazole also exhibits insecticidal activity against juve-
nile aphids such as Myzus persicae and Aphis gossypii by
inhibiting their molting process. The mode of action of
this compound is thought to be via the inhibition of chi-
tin biosynthesis in mites and insects. Similar growth
inhibitory-type acaricides have also been developed, in
which benzoylphenylurea (BPU) analogs are included.3
F
F
OCH2CH3
t-Bu
N
N
A
B
Xn
O
O
(I)
(II)
Figure 1. Structures of etoxazole (I) and 2-(substituted phenyl)-4-
phenyl-1,3-oxazolines (II).
accelerated the study of chitin synthesis inhibitors,6–8 as
well as other insect growth regulators such as juvenile
hormone mimics and molting hormone agonists.9–11
We have been continuing the quantitative structure–
activity relationship (QSAR) study of benzoylphenylu-
rea12–16 and thiadiazole derivatives17 for the larvicidal
activity against the rice stem borer Chilo suppressalis
Walker and other lepidopteran insects.18 QSAR study
has also been executed for analysis of the inhibition of
chitin synthesis in the cultured integuments.19 In all
QSARs, the molecular hydrophobicity is the common
significant factor, whereas electronic and steric effects
participate to vary the activity depending upon the
insect species and experimental condition.
The discovery of a BPU-type compound, Du19111 [N-
(2,6-dichlorobenzoyl)-N0-(3,4-dichlorophenyl)urea],4,5
Keywords: 2,4-Diphenyl-1,3-oxazoline; Tetranycus urticae; LogP;
QSAR; Ovicidal activity.
*
Corresponding author. Tel.: +81 75 753 6117; fax: +81 75 753
6123; e-mail: naka@kais.kyoto-u.ac.jp
0960-894X/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2006.04.089

C. Minakuchi et al. / Bioorg. Med. Chem. Lett. 16 (2006) 4080–4084
4081
Previously Suzuki and co-workers reported the ovicidal
activity of 2,4-diphenyl-1,3-oxazoline congeners having
various substituents at both phenyl moieties against
mites.20 Introduction of halogens at ortho-position(s)
of A-ring (II in Fig. 1) is favorable to the activity, but
not at meta- and para-positions. Moreover, di-ortho-
substituted compounds were more potent than the
mono ortho-substituted. However, the physicochemical
meaning of this substitution has not yet been analyzed.
Since the hydrophobicity seems to be very important
for the in vivo activity, we attempted to evaluate the
hydrophobicity parameters for the substituents at the
A-ring moiety. The hydrophobic substituent parameter,
p, defined as the difference of logP (P, partition coeffi-
cient between 1-octanol and water) between mono-
substituted benzene and unsubstituted benzene21 is not
valid for the QSAR of certain series of compounds,22
particularly for ortho-substituted analogs.23,24
oxazoline congeners were compared with those of
corresponding methyl benzoates and benzamides as
shown in Eqs. 1 and 2.
log P ¼ 1:005ðꢀ0:319Þ log PðbenzamidesÞ
þ 1:359ðꢀ0:204Þ
n ¼ 6; s ¼ 0:107; r ¼ 0:975; F 1;4 ¼ 76:54: ð1Þ
log P ¼ 0:809ðꢀ0:152Þ log PðbenzoateÞ
ꢁ 0:052ðꢀ1:022Þ
n ¼ 6; s ¼ 0:168; r ¼ 0:936; F 1;4 ¼ 28:49:
ð2Þ
In these and the following correlation equations, n is the
number of compounds included in the analysis, s is the
standard deviation, r is the correlation coefficient, and
F is the value of the ratio between regression and resid-
ual variances. The figures in parentheses after each coef-
ficient are the 95% confidence intervals of the regression
coefficient. Since the correlation in Eq. 1 was improved
relative to Eq. 2, logP values of other substituted com-
pounds were calculated using Eq. 1 from the corre-
sponding benzamides.22–24 LogP values of benzamides
were either obtained from the CLOGP database, or cal-
culated using the CLOGP program (ver. 4.0; BioByte
Corp., Claremont, CA, USA).25 logP values for 2,4-di-
phenyl-1,3-oxazoline analogs were calculated from the
corresponding 2-phenyl-1,3-oxazoline congeners by
adding 1.56 for the phenyl moiety, the difference of logP
values between 2-phenyl-1,3-oxazoline and 2,4-diphen-
yl-1,3-oxazoline, which were calculated from the
CLOGP program. All calculated logP values for 2,4-di-
phenyl-1,3-oxazoline analogs are listed in Table 2.
In this study, we synthesized 2-phenyl-1,3-oxazoline
congeners containing various ortho-substituents and
measured their logP values. Accumulation of the hydro-
phobicity values of such heterocyclic compounds as
phenyloxazolines is very important to enhance the pre-
dictability of the logP calculation program CLOGP,
which is widely used to predict the hydrophobicity of
compounds.25 In further studies the substituent effects
of 2-(substituted phenyl)-4-phenyl-1,3-oxazoline analogs
on the ovicidal activity against the two-spotted spider
mite Tetranycus urticae were quantitatively analyzed
using Hansch–Fujita QSAR method21,26 to find the essen-
tial physicochemical property for the ovicidal activity.
Partition coefficient (P) values of 2-phenyl-1,3-oxazoline
congeners were measured in the 1-octanol/water system
using a conventional flask-shaking method21 as listed in
Table 1. Since five 2-phenyl-1,3-oxazoline congeners
with H, 2-CH3, 2-F, 2-Cl, and 2-Br were labile in the
water/octanol system, their P values were not able to
be determined.
Previously we reported the ovicidal activity against
T. urticae which is expressed in LC50 (ppm) values such
as 0.01–0.1, 0.1–1, 1–10, 10–100, 100–1000, and
>1000 ppm.20 Although these LC50 values were not pre-
cisely determined, they are considered to be 0.05 0.05,
0.5 0.5, 5.0 5.0, 50 50, 500 500, and >1000 ppm,
respectively. Since the difference between concentrations
is 10-fold, they were converted to the free energy-related
index, BA = 5, 4, 3, 2, 1, <0 (logarithmic scale), respec-
tively. The activity of mono ortho-substituted com-
pounds was first quantitatively analyzed to derive Eq.
3, using QREG2.05.27 Since the substituent effect on
the activity is very similar to that of BPU-type insecti-
cides,14 similar parameters were used in the QSAR of
2-phenyl-1,3-oxazolines.
Since the substructure –C(O–)(@N–) of 2-phenyl-1,3-
oxazoline is somewhat similar to [–C(@O)O–] of meth-
ylbenzoate and [–C(@O)NH2] of benzamide,23 the
experimentally measured logP values of 2-phenyl-1,3-
Table 1. Experimentally measured LogP values of 2-(2,6-disubstituted
phenyl)-1,3-oxazolines
X2
N
O
X6
BA ¼ 1:999ðꢀ1:466Þ log P þ 3:123ðꢀ1:674ÞrIo
ꢁ 0:981ðꢀ0:654ÞDBo5 ꢁ 5:134ðꢀ5:180Þ
n ¼ 15; s ¼ 0:794; r ¼ 0:831; F 3;11 ¼ 8:167: ð3Þ
X2
X6
logPa
Calcdb
I
H
2.30 0.01 (4)
1.27 0.02 (8)
2.15 0.03 (8)
2.21 0.05 (8)
1.45 0.01 (8)
1.89 0.02 (8)
2.30
1.22
1.83
2.11
1.52
1.98
NO2
CF3
CH3
F
H
H
CH3
F
In Eq. 3 and the following equation, rI is the electronic
parameter representing the inductive component of the
total electronic effect28 and B5 is the STERIMOL
parameter representing the maximum width of substitu-
ents from the axis connecting an atom of substituents
F
Cl
a Mean standard deviation. Numbers in parentheses are replications.
b Calculated by Eq. 1.

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C. Minakuchi et al. / Bioorg. Med. Chem. Lett. 16 (2006) 4080–4084
Table 2. Ovicidal activity of 2-(substituted phenyl)-4-phenyl-1,3-oxazolines against Tetranycus urticae and physicochemical parameters for QSAR
N
Xn
O
Compound
Substituents (Xn)
Activity
Physicochemical parameters
No.
BAa
Calcdb
logPc
rIo
B5o
Im/p
1
2
H
2
1
2.0
1.3
1.4
1.8
1.1
1.1
1.0
3.1
2.6
2.7
2.6
2.0
1.5
0.7
0.2
1.2
0.7
0.2
1.3
1.6
1.8
1.8
3.5
3.7
3.5
3.56
3.68
3.76
4.22
5.61
3.50
4.04
3.51
3.56
3.69
3.86d
3.71d
2.83d
4.11
3.77
4.44
4.11
3.78
4.48
4.28
4.40
4.40
3.01d
3.45d
3.69
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
1
1
1
1
1
1
1
1
1
0
0
0
2-CH3
2-OCH3
2-OEt
2-OPh
2-SCH3
2-SEt
2-F
ꢁ0.01
0.3
0.28
0
1.04
2.07
2.36
4.89
2.26
2.97
0.35
0.8
0.95
1.15
1.61
1.44
0
3
2
4
<0
1
5
6
1
0.4
0.28
0.54
0.47
0.47
0.4
0.4
0.67
0
7
1
8
2
9
2-Cl
2-Br
3
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
4
2-I
3
2-CF3
2-NO2
3-CH3
3-OCH3
3-Cl
1
1
<0
<0
1
0
0
0
0
4-CH3
4-OCH3
4-Cl
<0
1
0
0
0
0
1
0
0
2,3-Cl2
2,4-Cl2
2,5-Cl2
2,6-F2
2-F-6-Cl
2,6-Cl2
2
0.47
0.47
0.47
1.08
1.01
0.94
0.8
0.8
0.8
0.7
1.15
1.6
2
1
3
5
3
a 0 = >1000 ppm; 1 = 100–1000 ppm, 2 = 10–100 ppm, 3 = 1–10 ppm, 4 = 0.1–1 ppm, 5 = 0.01–0.1 ppm.
b Calculated by Eq. 4.
c Sum of logP values of 2-phenyl-1,3-oxazolines and the fragment value (1.56) for the 4-phenyl moiety of 2,4-diphenyl-1,3-oxazoline.
d Calculated from their observed values listed in Table 1.
and the rest of molecules.29 In this analysis, DB5, the
value relative to that of hydrogen, was utilized. The
superscript ‘o’ means the ortho-position, and values for
meta- and para-positions are zero. The use of CLOGP
instead of logP made the correlation poorer
(s = 0.901, r = 0.775). In further analysis, six compounds
containing meta- and para-substituents (16, 18–22) were
added to the compounds in Eq. 3 to formulate Eq. 4,
with the addition of a new indicator parameter Im/p
which assumes 1 for compounds having meta- or para-
substituents.
are listed in Table 2, and the degree of collinearity of
independent variables used to derive Eq. 4 is summa-
rized in Table 3.
As shown above, significant QSAR equations were
formulated for the ovicidal activity of 2-phenyl-1,3-
oxazoline congeners with various substituents at the
2-phenyl moiety against T. urticae. The hydrophobici-
ty parameter, p, defined for mono-substituted
benzenes is generally used for the QSAR analysis of
substituted benzene analogs. However, since the p val-
ue varies from one solute to another for di-substituted
benzenes with hydrogen-bonders, the corrected p val-
ues are rationally used.14,24 In the di-substituted benz-
enes the electronic interactions between two
substituents exist for meta- and para-substitutions,
and the steric interaction is also recognized for
ortho-substitutions. Therefore, we newly determined
the hydrophobicity parameter for the phenyl substitu-
ents of 2-phenyl-1,3-oxazolines.
BA ¼ 1:591ðꢀ1:187Þ log P þ 2:790ðꢀ1:307ÞrIo
ꢁ 0:857ðꢀ0:550ÞBo5 ꢁ 2:153ðꢀ1:388ÞIm=p
ꢁ 3:663ðꢀ4:144Þ
n ¼ 21; s ¼ 0:743; r ¼ 0:820; F 4;16 ¼ 8:210: ð4Þ
Eqs. 3 and 4 show that activity increases with the induc-
tive electron-withdrawing property, whereas the intro-
duction of the bulkier group at the ortho-position is
unfavorable to the activity. By the introduction of sub-
stituents at either the meta- or para-position, the activity
decreased 100-fold. The addition of the squared term of
logP was not significant in either Eq. 3 or 4. The
predicted activity values by Eq. 4 for all compounds
Table 3. Squared correlation matrix between parameters
logP
rIo
B5o
rIo
0.289
0.149
0.217
B5o
0.000
0.100
Io/m
0.207

C. Minakuchi et al. / Bioorg. Med. Chem. Lett. 16 (2006) 4080–4084
4083
The logP value of 2-(2,6-difluorophenyl)-4-phenyl-1,3-
oxazoline was calculated to be 3.01 by summing the
logP value (1.45) of 2-(2,6-difluorophenyl)-1,3-oxazo-
line and the difference (1.56) of logP values between
2,4-diphenyl-1,3-oxazoline (Xn = H in II, Fig. 1) and
2-phenyl-1,3-oxazoline. According to this rule, the
logP value of etoxazole (I, Fig. 1) is calculated to be
5.37 by the addition of p values of mono-substituted
benzenes, OEt (0.38) and t-Bu (1.98), to that (3.01)
of 2-(2,6-difluorophenyl)-4-phenyl-1,3-oxazoline (Xn =
2,6-F2 in II, Fig. 1). This estimated logP value of
etoxazole is not far from the reported value (5.59).1
Moreover, the logP value of 2-(2,6-difluorophenyl)-4-
(4-hydroxyphenyl)-1,3-oxazoline was measured to be
2.52 (unpublished data). Since the hydrophobicity
parameter for OH group is ꢁ0.67, 2-(2,6-difluorophe-
nyl)-4-phenyl-1,3-oxazoline is calculated to be 3.19,
which is very close to the empirically estimated logP
value (3.01). As a result, the logP value of etoxazole
is estimated to be 5.55, which is very close to the
reported value (5.59).
Haga and co-workers also quantitatively analyzed the
substituent effects of BPUs on the larvicidal activity in
terms of pLC50 (ppm) against Spodoptera litura. They
used chlorfluazuron congeners with various substituents
at the ortho-, meta-, and para-positions of the benzoyl
moiety (IV in Fig. 2).31,32
pLC90 ¼ 0:233Esortho þ 3:15Esmeta þ 2:42Epsara
þ 0:359I þ 0:593
n ¼ 14; r ¼ 0:931; s ¼ 0:597:
ð6Þ
In Eq. 6, I is the indicator variable which takes 1 and 2
for mono- and di-ortho substitution, respectively, and
otherwise 0. Even though the Es parameter was used
for meta- and para-substituents, the variation of substit-
uents at meta- and para-positions is very small. The sub-
stituents at the meta-position are only F and Cl, and
those at the para-position are F, Cl, and CH3, which
seems to be equivalent to the indicator variable Im/p in
Eq. 4.
In conclusion, the molecular hydrophobicity of six 2-
(substituted phenyl)-1,3-oxazoline analogs was experi-
mentally determined. Some compounds were not able
to be determined, because they were labile to the octa-
nol/water partition system. LogP values of labile com-
pounds were able to be estimated from logP values of
corresponding substituted benzamides. Using the exper-
imentally defined hydrophobicity parameter and other
physicochemical parameters, significant QSAR equa-
tions for 2-(substituted phenyl)-1,3-oxazolines were de-
rived. Results showed that ovicidal activity increases
with molecular hydrophobicity. Introduction of induc-
tive electron-withdrawing groups at the ortho-position
was favorable to the activity, but the introduction of
the bulky groups at the ortho-position and the substitu-
tion at the meta- and para-position were detrimental to
the activity. Although the activity index was not as accu-
rate as pLD50 and pLC50, the essential physicochemical
factors to vary the ovicidal activity were disclosed. Inter-
estingly, the factors governing the ovicidal activity were
similar to those found in the QSAR analysis of the lar-
vicidal activity of BPUs. These QSAR results for 2,4-di-
phenyl-1,3-oxazolines will be useful in the future study
regarding the mode of action of chitin synthesis inhibi-
tors including BPUs.
The logP value of etoxazole was calculated by CLOGP
to be 6.56, which is 10 times more hydrophobic than the
observed value. The main reason for this error is
thought to be an incorrect estimation of the hydropho-
bicity change for the 2,6-difluoro substitution. Namely,
the estimation of the hydrophobicity for 2,6-difluoro
substitution is 0.29 higher than the unsubstitution, but
it is lower by 0.55. Therefore, the calculated hydropho-
bicity of etoxazole is 10 times higher in the present
CLOGP version 4.0.
A similar QSAR equation was obtained for the anal-
ysis of the larvicidal activity against C. suppressalis of
benzoylphenylureas (III in Fig. 2) with various substi-
tuted benzoyl moieties as shown in Eq. 5, in which the
p
value is determined from various benzamide
congeners.14
pLD50 ¼ 0:585p þ 0:440r# þ 0:774REso
þ 6:667
n ¼ 20; s ¼ 0:257; r ¼ 0:895:
ð5Þ
In Eq. (5), r# is the mixed electronic parameter which
takes rI values for 2,6-diortho substituted compounds
and r for other compounds. Es is the steric parameter
which was defined by Sotomatsu and co-workers by
measuring the substituent effects on the rate of hydroly-
sis of various substituted benzamides.30 Although the
same parameters were used to analyze the substituent ef-
fects at phenyl moiety of 2-phenyl-1,3-oxazolines, no
significant correlation was derived.
Synthesis of compounds. Eleven 2-phenyl-1,3-oxazoline
congeners with various substituents [H, 2-CH3, 2-F, 2-
Cl, 2-Br, 2-I, 2-CF3, 2-NO2, 2,6-F2, 2-F-6-Cl, and 2,6-
(CH3)2] at the benzene ring were synthesized according
to the conventional method20, from 2-aminoethanol
and substituted benzoyl chloride. The structures of new-
Cl Cl
H
H
H
H
C N C N
Cl
C N C N
O
CF3
Xn
Xn
N
O
O
O
O
Cl
(III)
(IV)
Figure 2. Structures of benzoylphenylurea (III) and chlorfluazuron-type compound (IV).

4084
C. Minakuchi et al. / Bioorg. Med. Chem. Lett. 16 (2006) 4080–4084
1
11. Minakuchi, C.; Riddiford, L. M. J. Pestic. Sci. 2006, 31,
77.
ly synthesized compounds were confirmed by H NMR
and elemental analyses. The analytical values for C, H,
and N of all compounds agreed within 0.3%. 1H
NMR dH (300 MHz, CDCl3) for 2-phenyl-1,3-oxazo-
line: 4.06 (2H, t, J = 9.5 Hz, N–CH2), 4.43 (2H, t,
J = 9.5 Hz, O–CH2), 7.37–7.50 (3H, m, Ar-H), 7.93–
7.97 (2H, m, Ar-H); Anal. Calcd for C9H9NO: C,
73.45; H, 6.16; N, 9.52. Found: C, 73.68; H, 6.20; N,
9.50.
12. Nakagawa, Y.; Kitahara, K.; Nishioka, T.; Iwamura, H.;
Fujita, T. Pestic. Biochem. Physiol. 1984, 21, 309.
13. Nakagawa, Y.; Iwamura, H.; Fujita, T. Pestic. Biochem.
Physiol. 1985, 23, 7.
14. Nakagawa, Y.; Sotomatsu, T.; Irie, K.; Kitahara, K.;
Iwamura, H.; Fujita, T. Pestic. Biochem. Physiol. 1987, 27,
143.
15. Nakagawa, Y.; Akagi, T.; Iwmura, H.; Fujita, T. Pestic.
Biochem. Physiol. 1988, 30, 67.
16. Nakagawa, Y.; Izumi, K.; Oikawa, N.; Kurozumi, A.;
Iwamura, H.; Fujita, T. Pestic. Biochem. Physiol. 1991, 40,
12.
Acknowledgments
17. Nakagawa, Y.; Nishimura, K.; Izumi, K.; Kinoshita, K.;
Kimura, T.; Kurihara, N.; Fujita, T. J. Pestic. Sci. 1996,
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19. Nakagawa, Y.; Matsutani, M.; Kurihara, N.; Nishim-
ura, K.; Fujita, T. Pestic. Biochem. Physiol. 1992, 43,
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20. Suzuki, J.; Ishida, T.; Kikuchi, Y.; Ito, Y.; Morikawa, C.;
Tsukidate, Y.; Tanji, I.; Ota, Y.; Toda, K. J. Pestic. Sci.
2002, 27, 1.
We are thankful to Dr. Craig Wheelock for carefully
reviewing this manuscript. This investigation was
supported, in part, by the 21st century COE program
for Innovative Food and Environmental Studies
Pioneered by Entomomimetic Sciences, from the
Ministry of Education, Culture, Sports, Science and
Technology of Japan. Elemental analyses were
performed at the Microanalytical Center at Kyoto
University.
21. Fujita, T.; Iwasa, J.-i.; Hansch, C. J. Am. Chem. Soc. 1964,
86, 5175.
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