Synthesis and biological activities of hydroxyl-protected fluorine-containing 4,4-dihydroxylmethyl-2-aryl-iminothiazolidines

Article abstract of DOI:10.1016/j.jfluchem.2004.10.007

Eight novel compounds were synthesized by a facile and mild method with high yields, and the structures of all the compounds were characterized by ¹H NMR IR mass and high resolution mass spectroscopy. Their inhibitory activity against insect-flight and trehalase in vitro were screened. Some target compounds have moderate inhibitory activity against trehalase, and show inhibition action to insect-flight.

Full text of DOI:10.1016/j.jfluchem.2004.10.007

Journal of Fluorine Chemistry 126 (2005) 53–58
www.elsevier.com/locate/fluor
Synthesis and biological activities of hydroxyl-protected fluorine-
containing 4,4-dihydroxylmethyl-2-aryl-iminothiazolidines
a
Chuanxiang Liua, Xiaoyong Xua, Zhong Lia,b, , Weidong Chen ,
*
Qingchun Huanga, Xuhong Qianb,
*
aShanghai Key Laboratory of Chemistry Biology, Institute of Pesticides and Pharmaceuticals,
East China University of Science and Technology, P.O. Box 544, Shanghai 200237, PR China
bState Key Laboratory of Fine Chemicals, Dalian University of Technology, Dalian 116012, PR China
Received 20 March 2004; received in revised form 12 October 2004; accepted 16 October 2004
Available online 2 December 2004
Abstract
Eight novel compounds were synthesized by a facile and mild method with high yields, and the structures of all the compounds were
characterized by 1H NMR IR mass and high resolution mass spectroscopy. Their inhibitory activity against insect-flight and trehalase in vitro
were screened. Some target compounds have moderate inhibitory activity against trehalase, and show inhibition action to insect-flight.
# 2004 Elsevier B.V. All rights reserved.
Keywords: Trehalase inhibitors; Insect-flight; Synthesis
1. Introduction
synthetic mimics of trehalase inhibitor, which have
relatively simple structure and can be prepared easily.
It was reported that the bridgehead nitrogen in trehazolin
and the carbonyl group in trehalase played important role in
the formation of trehazolin–trehalase complex [9,10]. Based
on the structural features of trehazolin, fluorine-containing
and non-fluorine-containing 4,4-dihydroxylmethyl-2-aryli-
minothiazo (oxazo) lidines derivatives were designed and
synthesized in our previous study [11]. Comparing our
fluorine-containing compounds with non-fluorine-contain-
ing compounds against insect-flight inhibition (the
inhibitory activity of 2-(4-fluorophenylimino)-4,4-dihy-
droxymethyl-thiazolidine is 37.2%, 2-phenylimino-4,4-
dihydroxymethyl-thiazolidine is 8.1%), we found it was
important that fluorine atom was introduced into phenyl ring
owing to fluorine atom’s unique properties, such as high
thermal stability and lipophilicity. Fluorine-containing 4,4-
dihydroxylmethyl-2-aryliminothiazo (oxazo) lidines deri-
vatives showed moderate inhibitory activity against treha-
lase in vitro and insect-flight in vivo, and the result was
reported [12]. Comparing the effect of sulfur-containing
heterocycle with oxygen-containing heterocycle, it was
found that fluorine-containing 4,4-dihydroxylmethyl-2-
Trehalase is a very specific enzyme that hydrolyses
trehalose to two glucose units [1], and is widely distributed
in microorganisms, insects, plants and animals [2]. In
insects, trehalose is a principal blood sugar and is used to
support various energy-requiring functions, especially for
insect-flight [3]. Therefore, the development of specific and
potent inhibitors of trehalase, which mimic the trehalose
scaffold [4], is of great interest for the control of insect-
flight.
Some trehalase inhibitors have been isolated from natural
sources, and trehazolin (Fig. 1) is the most potent one, which
has strong inhibitory activity against silkworm trehalase in
vitro (IC50: 4.9 Â 10À8 M). Several total syntheses and
modification of trehazolin have been reported since the
seminal work of Shiozaki and Ogawa [5–8]. However, it is
extremely difficult to make trehazolin and its derivatives be
commercialized because of the rather involved synthetic
route. Thus we concentrated on the development of artificial
* Corresponding authors. Tel.: +86 21 64252945; fax: +86 21 64252603.
E-mail address: lizhong@ecust.edu.cn (Z. Li).
0022-1139/$ – see front matter # 2004 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2004.10.007

54
C. Liu et al. / Journal of Fluorine Chemistry 126 (2005) 53–58
Fig. 1. Trehazolin and 4,4-dihydroxylmethyl-2-aryliminothiazo (oxazo) lidines.
aryliminothiazolidine showed higher inhibitory activities
against insect-flight than the fluorine-containing 4,4-
dihydroxylmethyl-2-aryliminooxazolidines, although the
latter had higher activity against trehalase in vitro, however,
they do not show notable activity against insect-flight in vivo
probably due to two hydrophilic hydroxyl groups in their
structures. In view of the particular interest on enhancing the
activity of inhibiting insect-flight in vivo, we concentrated
our efforts on the further structural modification of sulfur-
containing compounds above and the hydroxy was protected
to enhance the lipophilicity of the compound.
substituted derivatives because of the benzene ring’s larger
steric hindrance, only mono-substituted compounds Lcx4,
Lcx5 and Lcx7 were obtained. Accordingly, for halogen
or acetyl substitution, it is easy to obtain the double-
substituted derivatives to enhance compounds’ lipophili-
city.
2.2. Biological activity
The inhibitory activity against trehalase in vitro was
tested according to the standard method [12,14]. Con-
sidering of the excellent solubility of the synthesis
compounds, the standard method was improved by
decreasing the amount of DMSO1 from 20 ml to 2 ml to
minimize the influence of organic solvent to trehalase. And
also, the trehalase inhibition data were obtained only at
10À4 M concentration.
In this paper, a series of hydroxyl-protected fluorine-
containing 4,4-dihydroxylmethyl-2-aryl-iminothiazolidines
were synthesized by a facile method, and their inhibitory
activities against insect-flight action in vivo and trehalase in
vitro were screened. Lcx1 and Lcx4 show moderate
inhibitory activity against trehalase in vitro, which reach
to 77.2% and 72.4% at 10À4 M, respectively, and Lcx8 has
53% inhibitory activity against the flight of musca domestica
vicina Linnaeus at 200 ppm.
In our previous report [12], the inhibition experiment of
insect-flight was evaluated with fruitfly Drosophila
melanogaster, but its flight ability is so weak that it often
brought larger experimental error. Herein, musca domes-
tica vicina Linnaeus, which has stronger flight ability, was
chosen as test insect. It has been reported that, in first two-
minute, the energy of insect-flight was mostly supplied by
the hydrolysing of trehalose, which means trehalase is
involved in the process [3]. Thus, we selected the 2 min
insect-flight distance to reflect the inhibitory ability of our
compounds to trehalase. All the test results are listed in
Table 1.
2. Results and discussion
2.1. Synthesis
The designed compounds were prepared as shown in
Scheme 1. The aryl isothiocyanates were commonly
prepared according to our reported procedure [13]. Carbon
disulfide in NaOH aqueous was stirred for 1 h at 2–5 8C,
and then 4-fluoroaniline was added dropwise into the
reactant liquid to give the intermediate dithiocarbamates.
After adding ethyl chloroformate at 35–40 8C, 4-fluoro-
phenyl isothiocyanates 1 was obtained. Compound 2 was
synthesized by the reaction that 2-amino-2-hydroxyl-
methyl-propane-1,3-diol and 1 were refluxed in ethyl
From the data listed in Table 1, the compounds that the
hydroxymethyl group was protected or replaced by methyl
group have not any activity against trehalase in vitro except
for Lcx4. The inhibition of Lcx8 against insect-flight was
53%, which is the highest in our prepared compound against
musca domestica vicina Linnaeus. It seems reasonable to
assume that the effectiveness with appropriate hydrophile–
lipophile balance and easily leaving groups at hydroxy-
methyl of thiazolines is essential. In addition, there was not
directly relationship between the inhibition to trehalase in
vitro and the inhibition to 2 min insect-flight in vivo, maybe
the action mechanism of flight inhibition was not according
to our presume. Therefore, it need further research to modify
the lead structure in order to control insect-flight and explore
the action mechanism.
acetate. Lcx2 was obtained by the heating
2 in
concentrated hydrochloric acid at 90 8C. Compound
Lcx1 was prepared from 4-chloroaniline in the same
manner, and Lcx3 was obtained by the reaction of 1 with 2-
amino-2-methyl-propan-1-ol, followed by treatment of 2
with concentrated hydrochloric acid. Lcx4–8 were also
obtained by reaction of Lcx2 reacted with SOCl2, benzoyl
chloride, benzenesulfonyl chloride, and acetyl chloride in
THF or pyridine, respectively. For R = benzenesulfonyl,
2,4-dichloro-5-fluoro-benzoyl or 2,4,6-trimethyl-benzoyl,
it is difficult for synthesis the hydroxyl-protected double-
1
The inhibition to trehalase (20 ml DMSO: 10.3%; 2 ml DMSO: 0.7%,
but no effect to the bioactivity test).

C. Liu et al. / Journal of Fluorine Chemistry 126 (2005) 53–58
55
Scheme 1. Synthesis of hydroxyl-protected fluorine-containing 4,4-dihydroxylmethyl-2-aryliminothiazolidines.
Table 1
Flight-inhibition activities and trehalase inhibitory activity of compounds Lcx1–8
Compound
Structure
Flight inhibition (200 ppm, %)
17.8 (2 min)
Trehalase inhibition (10À4 M, %)
77.24
Lcx1
21 (2 min)
0a
Lcx2
Lcx3
23.5 (2 min)
25.8 (2 min)
0.5
72.41
Lcx4
7.37 (2 min)
0
Lcx5
Lcx6
32.4 (2 min)
6.13 (2 min)
0
0
Lcx7
53 (2 min)
0
Lcx8
a
Trehalase inhibition of Lcx2 at 10À4 M is 5.0% calculated by the equation [12].

56
C. Liu et al. / Journal of Fluorine Chemistry 126 (2005) 53–58
3. Experimental
cooled to room temperature, the obtained mixture was
neutralized by 10 M aqueous NaOH solution in ice bath. The
resulting precipitate was filtered and recrystallized from
absolute ethanol to give the desired products.
Melting points were taken on a micro-melting point
1
apparatus made in Beijing and were uncorrected. H NMR
spectra were recorded with a Bruker WP-500SY (500 MHz)
spectrometer with CDCl3 as the solvent and TMS as the
internal standard. Infrared spectra were measured on KBr
disks using a Nicolet FT-IR-20SX instrument. High Resolu-
tion Mass spectra were obtained on a MicroMass GCT CA
055 spectrometers. Combustion analyses for elemental
composition were made with an Italian MOD 1106 analyzer.
Analytical thin-layer chromatography (TLC) was carried out
on precoated plated (silica gel 60F254), and spots were
visualized with ultraviolet light. All chemicals or reagents
were purchased from standard commercial suppliers.
3.2.1. [2-(4-Chlorophenylimino)-4-hydroxymethyl-
thiazolidin-4-yl] methanol (Lcx1)
1.44 g, yield 62%; obtained as white powder crystals; mp
230 8C; IR (KBr); v 3300, 3100, 2880, 1640, 1580, 1490,
1
1050, 840 cmÀ1. H NMR (500 MHz, CD3COCD3): d 3.35
(2H, s, SCH2), 3.70 (4H, m, CH2OH), 7.25 (2H, d,
J = 8.71 Hz, ArH), 7.55 (2H, d, ArH). EIMS, 5.00 ev, m/z
(relative intensity): 274 [M + 2]+ (2.23), 272 [M]+ (5.83),
243 (21.92), 241 (87.95), 223 (24.44), 211 (22.21), 168
(11.23), 152 (100), 127 (33.64), 110 (22.46), 90 (15.53), 75
(24.08), 63 (15.49), 39 (23.09). HRMS Calcd. for
C11H13N2O2SCl: 274.0357; Found: 274.0352.
3.1. Preparation of 4-phenyl isothiocyanate
To a stirred mixture of carbon disulfide (45.6 g,
0.60 mol), sodium hydroxide (16.0 g, 0.40 mol) and water
(80 ml) at 2–5 8C was added dropwise the 4-fluoro (or 4-
chloro) phenylamine (0.40 mol) over a period of 30 min.
After stirring at 40–45 8C for 24 h, the lower layer of carbon
disulfide was removed and the upper aqueous layer contain-
ing intermediate was washed with benzene (3 Â 100 ml). To
this aqueous solution was added dropwise ethyl chloro-
formate (0.4 mol) at 35–40 8C and the resulting mixture
was stirred for about 40 min at the same temperature. Then
the lower organic phase was separated, washed with water
(3 Â 50 ml), dried over anhydrous magnesium sulfate and
distilled in vacuo to give pure 4-fluoro (or 4-chloro)
phenylisothiocyanate.
3.2.2. [2-(4-Fluorophenylimino)-4-hydroxymethyl-
thiazolidin-4-yl] methanol (Lcx2)
1.36 g, yield 56%; obtained as white powdery crystals;
mp 202–203 8C; Rf = 0.40 (ethyl acetate); IR (KBr); v 3300,
1
3100, 2880, 1620, 1500, 1200, 1050, 840 cmÀ1. H NMR
(500 MHz, CDCl3): d 3.29 (2H, s, SCH2), 3.66 and 3.69 (4H,
m, J = 11.0 Hz, CH2OH), 7.00 (2H, t, J = 8.9 Hz, ArH), 7.36
(2H, m, ArH). Anal. Calcd. (%) for C11H13FN2O2S: C,
51.56; H, 5.08; N, 10.94. Found: C, 51.34; H, 4.97; N, 11.09.
3.2.3. (4,4-Dimethyl-thiazolidin-2-ylidene)-(4-
fluorophenyl) amine (Lcx3)
1.54 g, yield 61%; obtained as white powdery crystals;
mp 209–210 8C; IR (KBr); v 3100, 2950, 2825, 1630, 1590,
1500, 1320, 1210, 1190, 1170, 850, 760, 650 cmÀ1. 1H NMR
(500 MHz, CD3COCD3): d 1.39 (6H, s, CH3), 3.18 (2H, s,
SCH2), 7.00 (2H, t, J = 8.5 Hz, ArH). EIMS, 4.53 ev, m/z
(relative intensity): 225 [M]+ (23.84), 224 (45.53), 209
(100), 137 (11.80), 136 (27.87), 88 (12.72). HRMS Calcd.
for C11H13FN2S: 224.0783. Found: 224.0788.
3.1.1. 4-Fluoropheny isothiocyanate
44.06 g, yield 72%; obtained as colorless liquid; bp 95–
97 8C/8 Torr. Rf = 0.85 (petroleum ether). IR (KBr); n 2040,
1590, 1504 cmÀ1. GC–MS m/z 153 (M+).
3.1.2. 4-Chlorophenyl isothiocyanate
The 38 g, yield 68%; obtained as white solid; Rf = 0.85
(petroleum ether). IR (KBr); n 2040, 1790, 1490,
1095 cmÀ1. GC–MS m/z 169 (M+).
3.3. General procedure for preparation of Lcx4–8
To the mixture of Lcx2 0.256 g (0.001 mol) and THF
7 ml (or pyridine 7 ml) in ice bath was added dropwise RCl
(substituted benzoyl chloride or benzenesulfonyl chloride,
acetyl chloride) (0.001 mol) and THF (or pyridine) 3 ml.
After stirring for 3 h, the mixture was neutralized with
NaHCO3, extracted with dichloromethane, washed with
water (3 Â 10 ml), dried over MgSO4 and the solvent
removed in vacuo. The residue was chromatographed on a
silica gel column using a 2:1 mixture of ethyl acetate and
petroleum ether as eluent to give a white solid.
3.2. General procedure for preparation of Lcx1–3
A mixture of 4-fluoro (or 4-chloro) phenylisothiocyanate
(0.02 mol), tri(hydroxylmethyl)methyl amine (2.662 g,
0.022 mol), and ethyl acetate (30 ml) was refluxed for
12 h. After cooling, it was concentrated under reduced
pressure to give the crude products, which were dissolved in
water (20 ml), stirred for 30 min, extracted with ethyl
acetate (3 Â 20 ml) and dried over anhydrous magnesium
sulfate. The resulting colorless liquid was concentrated
under reduced pressure to give the desired intermediate, and
then it was dissolved by concentrated HCl (10 ml). The
reaction mixture was stirred for 45 min at 90 8C. After
3.3.1. Benzenesulfonic acid 2-(4-fluorophenylimino)-4-
hydroxymethyl-thiazolidin-4-ylmethyl ester (Lcx4)
Yield 95%, mp 197 8C; Rf = 0.6 (ethyl acetate); IR (KBr);
v 3300, 3070, 2900, 1630, 1510, 1470, 1180, 1050, 980, 730,

C. Liu et al. / Journal of Fluorine Chemistry 126 (2005) 53–58
57
690 cmÀ1. 1H NMR(500 MHz, CDCl3): d 3.18 (2H, s, CH2S),
1700, 1630, 1500, 1450, 1370, 1250, 1050, 830, 600 cmÀ1
.
1H NMR (500 MHz, CDCl3): d 2.1 (6H, m, CH3), 3.25 (2H,
s, SCH2), 4.2 (4H, m, CH2O), 6.99 (2H, m, ArH-F), 7.16
(2H, m, ArH-F). EIMS, 4.15 ev, m/z (relative intensity): 340
(13.17, M+), 309 (6.06), 267 (27.60), 249 (7.92), 207 (100),
43 (8.97). HRMS Calcd. for C15H17FN2O4S: 340.0893.
Found: 340.0872.
3.62 (4H, m, CH2OH), 7.125 (2H, dd, J1 = 8.31 Hz,
J2 = 8.48 Hz, ArH), 7.30 (2H, multi, J = 4.78, 3.99, 4.72,
7.67 Hz, ArH), 7.56 (2H, dd, J1 = 7.77 Hz, J2 = 7.69 Hz
ArH), 7.69 (1H, dd, J1 = 7.41 Hz, J2 = 7.48 Hz ArH), 7.95
(2H, d, J = 7.66 Hz, ArH). EIMS, 4.86 ev, m/z (relative
intensity):396[M]+ (0.12), 365(100), 335(11.59), 251(7.37),
224 (84.95), 195 (41.51), 153 (8.65), 136 (9.48), 122 (13.13),
110 (15.04), 95 (11.37), 77 (24.85), 51 (6.31). HRMS Calcd.
for C17H17FN2O4S2: 396.0614. Found: 396.0652.
3.4. The method of trehalase inhibition in vitro
was as follows
3.3.2. 2,4-Dichloro-5-fluoro-benzoicacid2- (4-
fluorophenylimino)-4-hydroxymethyl-thiazolidin-4-
ylmethyl ester (Lcx5)
Yield 52%, mp 140 8C; Rf = 0.8 (ethyl acetate); IR (KBr);
v 3300, 2920, 2850, 1700, 1690, 1600, 1500, 1470, 1390,
1300, 1210, 1100, 900, 720 cmÀ1 1H NMR (500 MHz,
.
To a solution of 1.08 mg of porcine trehalase (Sigma) in
20 ml of 50 nM phosphate buffer (pH 5.5) was added 2 ml of
DMSO containing the compound, then the mixture was
incubated at 37 8C for 15 min. To the mixture was added
80 ml of trehalose solution (3 nM in the same buffer). After
the reaction mixture was incubated at 37 8C for 30 min, then
boiled for 5 min, and then the mixture was centrifuged for
5 min. To the resulting supernatant solution containing
glucose was added 1 ml color-producing reagent of
containing 10 units of glucose oxidase from Aspergillus
spp., 0.8 units of peroxidase from horseradish, and 1 mg of
ABTS. After the mixture was left standing at 37 8C for
20 min, the absorbance at 660 nm was measured, and the
amount of glucose in the solution was determined on the
basis of the standard glucose-absorbance curve. The
inhibition of trehalase was calculated by the following
equation: inhibition of trehalase (%) = [1 - A/B] Â 100,
where A and B indicate the amount of glucose in the
solution with and without compound, respectively. The
concentration is defined as mole of compound per liter of
solution.
CDCl3): d 3.25 (2H, s, CH2S), 3.5 (2H, d, J = 10.95 Hz,
CH2OH), 3.6 (2H, d, J = 10.96 Hz, CH2O), 7.07 (1H, m,
ArH), 7.26 (3H, m, J = 4.79, 3.33, 5.26 Hz ArH), 7.37 (1H,
d, J = 6.23 Hz, ArH). EIMS, 3.09 ev, m/z (relative intensity):
446 [M]+ (1.25), 414 (28.72), 398 (3.64), 309 (1.44), 292
(4.39), 238 (2.07), 225 (11.31), 207 (12.99), 190 (74.03),
162 (21.89), 127 (7.25), 111 (5.76), 83 (3.74). HRMS Calcd.
for C18H14Cl2F2N2O3S: 446.0070. Found: 446.0069.
3.3.3. (4,4-Bis-chloromethyl-thiazolidin-2-ylidene)-
(4-fluorophenyl) amine (Lcx6)
Yield 81%, mp 139 8C; Rf = 0.8 (ethyl acetate); IR (KBr);
v 3100, 2820, 1720, 1640, 1500, 1200, 1180, 850, 790 cmÀ1
.
1HNMR (500 MHz, CDCl3): d 2.81 (4H, d, CH2Cl,
J = 2.15 Hz), 3.43 (2H, s, SCH2), 7.00 (2H, t, ArH), 7.25
(2H, m, ArH-F). EIMS, 3.64 ev, m/z (relative intensity): 295
[M]+ (1.11), 243 (100), 221 (9.84), 207 (9.52), 190 (4.52),
153 (12.26), 136 (28.22), 121 (11.54), 109 (14.12), 95
(16.44), 75 (12.09), 57 (5.04), 35 (16.42). HRMS Calcd. for
C11H11FN2SCl2: 295.9945. Found: 295.9990.
Acknowledgements
This work was supported by Minister of Science and
Technology (2003CB114405; 2001AA235011) and Shang-
hai Education Committee. We are grateful to key Laboratory
of Organofluorine Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences.
3.3.4. 2,4,6-Trimethyl-benzoic acid 2-(4-fluoro-
phenylimino)-4-hydroxymethyl-thiazolidin-4-yl-methyl
ester (Lcx7)
Yield 61%, mp 160 8C; Rf = 0.8 (ethyl acetate); IR (KBr);
v 3300, 2920, 2850, 1690, 1600, 1500, 1310, 1280, 1000,
1
820 cmÀ1. H NMR (500 MHz, CDCl3): d 2.25 (9H, m,
References
CH3), 3.25 (2H, s, SCH2), 3.5 (2H, d, J = 10.95 Hz,
CH2OH), 3.68 (2H, d, J = 9.96 Hz, CH2O), 7.18 (2H, s,
ArH), 6.86 (2H, s, ArH-F), 7.38 (2H, d, J = ;6.02 Hz, ArH-
F). EIMS, 3.38 ev, m/z (relative intensity): 403 (1.92, M+),
388 (4.08), 387 (18.65), 371 (2.48), 225 (2.29), 195 (1.90),
147 (100), 119 (18.70). HRMS Calcd. for C21H23FN2O3S:
402.1413. Found: 402.1415.
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