Synthesis and anticoccidial activity of ethyl 6-substitutedbenzyloxy-7- alkoxy-4-hydroxyquinoline-3-carboxylates

Article abstract of DOI:10.3184/030823409X439726

A series of novel ethyl 6-substitutedbenzyloxy-7-alkoxy-4-hydroxyquinoline- 3-carboxylates have been designed and synthesised from 4-nitro-2-alkoxyphenol. Their structures have been characterised by 1H NMR, HRMS and IR spectra. Anticoccidial activities of

Full text of DOI:10.3184/030823409X439726

252 RESEARCH PAPER
APRIL, 252–254
JOURNAL OF CHEMICAL RESEARCH 2009
Synthesis and anticoccidial activity of ethyl 6-substitutedbenzyloxy-
7-alkoxy-4-hydroxyquinoline-3-carboxylates
Yan Zoua, Chun-Rong Yanb, Ya-Biao Wengc, Juan Lic, Kai-Qun Wub*,Yu-Liang Wangb and
Yu-Zhong Wanga,b
aDepartment of Chemical Engineering, Sichuan University, Chengdu, Sichuan 610064, P.R. China
bDepartment of Chemistry, Sichuan University, Chengdu, Sichuan 610064, P.R. China
cDepartment of Veterinary Medicine, South China Agricultural University, Guangzhou, Guangdong 510642, P.R. China
A series of novel ethyl 6-substitutedbenzyloxy-7-alkoxy-4-hydroxyquinoline-3-carboxylates have been designed and
synthesised from 4-nitro-2-alkoxyphenol. Their structures have been characterised by 1H NMR, HRMS and IR spectra.
Anticoccidial activities of these compounds were evaluated according to the ACI (the anticoccidial index) method.
The results indicated that three of the tested compounds exhibited anticoccidial activities against Eimeria tenella in
chicken feed with a dose of 27 mg/kg.
Keywords: anticoccidial activities, ACI method, Eimeria tenella, ethyl 6-substitutedbenzyloxy-7-alkoxy-4-hydroxyquinoline-3-
carboxylate
OH
Coccidiosis is an intestinal infection caused by protozoan
parasites of the genus Eimeria and could result in intestinal
lesions, diarrhoea, enteritis and death.1 It is a devastating
disease and occurs all over the world which causes serious
economic loss in the poultry industry.2 Many drugs have
contributed to the prevention and treatment of coccidiosis
in fowl, but coccidian inevitably develop a resistance to
them. This drug resistance has developed in almost to all of
the anticoccidial drugs introduced so far, and is therefore a
very serious problem, which hinders the effective control of
coccidiosis.3,4 Monensin, the main anticoccidial drug at one
time, might be abandoned in the future, because its sensitivity
to coccidia has decreased with the ACI 111.4,5 Therefore, to
solve the problem of drug resistance, it is necessary to search
and develop new drugs.
4-Hydroxyquinoline-3-carboxylates with general structure
(Fig. 1, compound 1) have a good biological activity against
coccidiosis in chicken and little toxicity to humans.6,7 Among
them, decoquinate (Fig. 1, compound 2) has high anticoccidial
activity when added to chicken feed with a 27 mg kg-1, and
play an important role in controlling coccidiosis.8-10
OH
5
8
4
R2
R1
CH3(CH2)8CH2O
CH3CH2O
6
7
3
2
CO2CH2CH3
CO2CH2CH3
N
N
1
1
2
OH
R2CH2O
R1O
CO2CH2CH3
N
R1 = CH3 or CH3CH2; R2 = substituted phenyl.
3
Fig. 1 The structures of compounds 1, 2 and 3.
effective candidates to coccidiosis, and those candidates might
be alternately used with other drugs to slow the rate of the
drug resistance development. In this paper, 10 novel ethyl 4-
hydroxyquinoline-3-carboxylateswithgeneralstructure(Fig.1,
compound 3) were designed and synthesised according to the
routes described in Scheme 1, and their anticoccidial activities
were also evaluated according to the ACI (the anticoccidial
index) method.
Our team has been working with structure-activity
UHODWLRQVKLSꢀ DQGꢀ WKHꢀ LQÀXHQFHꢀ DERXWꢀ WKHꢀ VXEVWLWXWHGꢀ JURXSVꢀ
on the activity about the substituted 4-hydroxyquinoline-3-
FDUER[\ODWHꢁꢀ:HꢀKRSHꢀWRꢀ¿QGꢀVRPHꢀUXOHVꢀZKLFKꢀKHOSꢀWRꢀ¿QGꢀ
Results and discussion
Starting compound 4-nitro-2-alkoxyphenol (compound 4)
was reduced by Pd/C in ethyl acetate at the experimental
CO2CH2CH3
HO
HO
HO
5% Pd/C, H2
NO2
C
CO2CH2CH3
R1O
R1O
R1O
NH2
NH
5
4
6
(1)KOH,CH3CH2OH
(2)R2CH2Cl,TBAB
CO2CH2CH3
OH
R2CH2O
R1O
R2CH2O
R1O
CO2CH2CH3
C
CO2CH2CH3
N
NH
3
7
3a: R1 = CH3, R2 = 2-chlorophenyl;
3b: R1 = CH3CH2, R2 = 2-chlorophenyl;
3c: R1 = CH3, R2 =4-chlorophenyl;
3d: R1 = CH3CH2, R2 = 4-chlorophenyl;
1
: R = CH3, R2 = 2,4-dichlorophenyl;
: R1 = CH3CH2, R2 = R2 = 2,4-dichlorophenyl;
3f
3e
3g
: R1 = CH3, R2 =4-methoxyphenyl;
: R1 = CH3CH2, R2 =4-methoxyphenyl;
3j: R1 = CH3CH2, R2 = 2,4,6-trifluorophenyl.
3h
3i: R1 = CH3, R2 = 2,4,6-trif luorophenyl;
Scheme 1 Synthesis route for compounds 3a–j.
* Correspondent. E-mail: chemwang2000@163.com

JOURNAL OF CHEMICAL RESEARCH 2009 253
Table 1 Data for anticoccidial activities of compounds 3a–j and the compound decoquinate against Eimeria tenella
Test
groups
Test
Rate of relative
body weight
gain/%
Survival
rate/%
Caecal lesion
Caecal oocyst
ACIa
compounds
/mg kg-1
Lesion
Lesion
value
Oocyst
Oocyst
value
scores
counts u 106
1
3a (27)
3b (27)
48.5
84.8
70.6
68.2
125.8
56.8
76.2
20.55
74.36
88.4
100
95
80
3.8
3.2
1.8
3
2.8
3.2
2.6
3.8
1
2.6
1.0
3.4
0
38
32
18
30
28
32
26
38
10
26
1
5.544
14.039
9.12
11.6
4.2
4.767
20.52
9.01
9.57
7.37
0.12
12.34
0
30
40
30
40
20
20
40
40
30
30
1
73.3
92.8
115.9
91.5
147.8
89.8
110.2
5.85
134.36
132.4
198
2
3
3c (27)
93.3
93.3
70
4
3d (27)
5
3e (27)
6
3f (27)
85
7
3g (27)
100
53.3
100
100
100
86.7
100
8
3h (27)
9
3i (27)
10
11
12
13
3j (27)
Decoquinate (27)
INGb
37
34
0
40
0
49.7
200
NNGc
100
aAnticoccidial activity index.
bInfected non-medicated group.
cNon-infected non-medicated group.
visualised with UV light. Purity of all the compounds was determined
by TLC method, and the target compounds 3a–j was determined by
+3/&±'$'ꢁ
value of pressure to obtain 4-amino-2-alkoxyphenol.
Then EMME (ethoxymethylenemalonic diethyl ester) was
added directly without further processing and the compounds
6a–j were obtained. The intermediates 7a–j were synthesised
by condensing the compounds 6a–j and substituting benzyl
chloride in the presence of KOH. Finally, the compounds
ZHUHꢀ UHÀX[HGꢀ LQꢀ GLSKHQ\Oꢀ HWKHUꢀ IRUꢀ ꢂ±ꢃꢀ PLQXWHVꢀ WRꢀ JHWꢀ WKHꢀ
target compounds. In this step, the temperature and time
of the reaction were critical, and the pure and well dried
intermediate 7a–j was also necessary. Otherwise, many
E\ꢄSURGXFWVꢀZRXOGꢀEHꢀIRUPHGꢀDQGꢀWKHꢀSXUL¿FDWLRQꢀSURFHVVꢀRIꢀ
SURGXFWꢀZRXOGꢀEHFRPHꢀYHU\ꢀGLI¿FXOWꢀRUꢀHYHQꢀZRUVHꢅꢀWKHꢀF\FOHꢄ
closing reaction might not take place and no product could be
obtained.
General procedure for preparation of 5a–j and 6a–j
A sample of 4-nitro-2-alkoxyphenol (compound 4) (18.2 mmol)
was reduced by 5% Pd/C (1.6 g) catalysed hydrogenation in ethyl
acetate (150 mL) at the experimental value of pressure. The reaction
¿QLVKHGꢀ DIWHUꢀ ꢂ±ꢎꢀ Kꢁꢀ 7KHꢀ VROXWLRQꢀ ZDVꢀ GLUHFWO\ꢀ XVHGꢀ IRUꢀ WKHꢀ QH[Wꢀ
step without further processing. The equiv. amount of EMME
(ethoxymethylenemalonic diethyl ester) was then added dropwise,
DQGꢀWKHꢀPL[WXUHꢀZDVꢀKHDWHGꢀXQGHUꢀUHÀX[ꢀIRUꢀꢏꢀKꢁꢀ$IWHUꢀWKHꢀPL[WXUHꢀ
ZDVꢀ FRROHGꢀ GRZQꢀ DQGꢀ ¿OWHUHGꢅꢀ WKHꢀ ¿OWUDWHꢀ ZDVꢀ FRQFHQWUDWHGꢀ XQGHUꢀ
reduced pressure to from a solid. The crude solid was recrystallised
in ethanol, and vacuum-dried to obtain 6a–jꢀLQꢀꢐꢊ±ꢃꢑꢒꢀ\LHOGꢁ
General procedure for preparation of 7a–j
A solution of KOH (1.09 g, 19.5 mmol) in anhydrous ethanol
(20 ml) was added dropwise to a solution of compounds 6a–j
(19.5 mmol) in anhydrous ethanol (20 ml) at 40°C. The mixture was
then stirred for 30 minutes and evaporated under reduced pressure
until it was dry. After the addition of substituted benzyl chlorides
(19.5 mmol), TBAB (tetrabutylammonium bromide) (0.3 g) and
DMF (N,N-dimethylformamide) (20 ml), the resulting mixture was
VWLUUHGꢀDQGꢀUHÀX[HGꢀIRUꢀꢉꢀKꢁꢀ&RROHGꢀGRZQꢀWRꢀWKHꢀURRPꢀWHPSHUDWXUHꢅꢀ
water was then added and the mixture was extracted with diethyl
ether (3 u 30 ml). The combined organic layer was washed with 5%
NaOH aqueous solution and water, and dried over anhydrous MgSO4.
$IWHUꢀ¿OWUDWLRQꢅꢀWKHꢀVROXWLRQꢀZDVꢀUHPRYHGꢀXQGHUꢀUHGXFHGꢀSUHVVXUHꢀDQGꢀ
the resulting residues were recrystallised from ethanol to afford pure
intermediates 7a–jꢀLQꢀꢐꢑ±ꢎꢑꢒꢀ\LHOGꢁ
Biological activities
The anticoccidial activities were evaluated according to the
ACI (the anticoccidial index) method,11-13 ACI = (relative
UDWHꢀRIꢀZHLJKWꢀJDLQꢀꢆꢀUDWHꢀRIꢀVXUYLYDOꢇꢀ±ꢀꢈOHVLRQꢀYDOXHꢀꢆꢀRRF\VWꢀ
value). The data on anticoccidial activities of the compounds
3a–j against Eimeria tenella in chicken feed with a dose of
27 mg kg-1 were shown in Table 1, using decoquinate as a
reference drug.
The ACI indicated that compounds 3e (ACI = 147.8),
3i (ACI = 134.36) and 3j (ACI = 132.4) exhibited certain
anticoccidial activity. This may be due to more halogen
groups, because the three compounds all have no less than
two halogen groups. It is possible that these three compounds
could be developed as available mild anticoccidial drugs.
The data were obtained when chickens were fed the basal
diet with the compounds with a dose at 27 mg kg-1 which was
choosed optionally. Given the adjustments of concentration,
all the activity parameter might be improved.
General procedure for preparation of 3a–j
Diphenyl ether (10 mL) was heated to 260°C and compound 7a–j
ꢈꢏꢀJꢇꢀZDVꢀDGGHGꢁꢀ7KHꢀUHDFWLRQꢀPL[WXUHꢀZDVꢀVWLUUHGꢀIRUꢀꢂ±ꢃꢀPLQXWHVꢀ
at a temperature about 255°C, and then cooled down to the room
temperature. Petroleum ether (50 mL) was added to precipitate the
VROLGꢁꢀ$IWHUꢀ¿OWUDWLRQꢅꢀZDVKHGꢀZLWKꢀSHWUROHXPꢀHWKHUꢀDQGꢀGULHGꢀWRꢀJLYHꢀ
compounds 3a–jꢁꢀ7KHꢀ\LHOGVꢀZHUHꢀꢊꢑ±ꢂꢊꢒꢁ
Ethyl
6-(2-chlorobenzyloxy)-4-hydroxy-7-methoxyquinoline-3-
Experimental
carboxylate (3aꢇꢋꢀ ,YRU\ꢄZKLWHꢀ VROLGꢅꢀ \LHOGꢋꢀ ꢂꢓꢒꢅꢀ PꢁSꢁꢀ ꢓꢏꢃ±ꢓꢊꢉ°C;
1H NMR spectrum (400 MHz; d6-DMSO): G 12.11 (s, 1H, OH),
ꢎꢁꢏꢊꢃꢀꢈVꢅꢀꢉ+ꢅꢀTXLQROLQHꢄꢓꢄ+ꢇꢅꢀꢐꢁꢊꢃꢃꢀꢈVꢅꢀꢉ+ꢅꢀTXLQROLQH+ꢇꢅꢀꢐꢁꢂꢉꢉ±ꢐꢁꢊꢎꢎꢀ
ꢈPꢅꢀ ꢉ+ꢅꢀ 3K+ꢇꢅꢀ ꢐꢁꢊꢊꢏ±ꢐꢁꢊꢌꢉꢀ ꢈPꢅꢀ ꢉ+ꢅꢀ 3K+ꢇꢅꢀ ꢐꢁꢏꢉꢃ±ꢐꢁꢌꢃꢎꢀ ꢈPꢅꢀ ꢓ+ꢅꢀ
PhH), 7.102 (s, 1H, quinolineH), 5.243 (s, 2H, PhCH2), 4.193 (t, 2H,
J = 7.2 Hz, CO2CH2CH3), 3.901 (s, 3H, OCH3), 1.269 (q, 3H,
J = 7.2 Hz, CO2CH2CH3); IR (KBr, cm-1) 3428(br), 3137, 3093, 2976,
1700, 1622, 1560, 1497, 1376, 1270, 1094, 799, 756, 617; HRMS
(ESI) Calcd for C20H19ClNO5 [M + H]+:388.0952. Found 388.0942.
All solvents and reagents used in this study were obtained from
FRPPHUFLDOꢀ VRXUFHVꢀ DQGꢀ ZDVꢀ XVHGꢀ ZLWKRXWꢀ IXUWKHUꢀ SXUL¿FDWLRQꢁꢀ
Melting point was recorded on XRC-1 apparatus and the thermometer
was uncorrected. Proton NMR spectra were recorded on a Varian
Unity Inova-400 spectrometer in d6-DMSO with TMS as the internal
standard, and mass spectra on Agilent 6210 Series Time of Flight LC/
MS using the ESI source. IR spectra were recorded with Perkin-Elmer
ꢉꢂ3&ꢄ)7ꢀLQVWUXPHQWꢁꢀ7KHꢀ +3/&±'$'ꢀ DQDO\VLVꢀ ZDVꢀ FRQGXFWHGꢀ RQꢀ
Agilent 1100 series diode array and multiple wavelength detectors at
265 nm with the Agilent 1100 control module. A ZORBAX SB-C18
column (2.1 u 30 mm, 3.5Pm) was used at 35°C temperature. Water
containing 0.1% formic acid/CH3&1ꢀ ꢈꢂꢊꢋꢌꢊꢅꢀ YꢍYꢇꢀ ZLWKꢀ Dꢀ ÀRZꢀ UDWHꢀ
of 0.3 mL min-1 was used as the mobile phase. Analytical TLC was
carried out on precoated plates (silica gel GF254), and all spots were
Ethyl
6-(2-chlorobenzyloxy)-7-ethoxy-4-hydroxyquinoline-3-
carboxylate (3bꢇꢋꢀ <HOORZꢀ VROLGꢅꢀ \LHOGꢋꢀ ꢂꢊꢒꢅꢀ PꢁSꢁꢀ ꢓꢊꢓ±ꢓꢊꢏ°C;
1H NMR spectrum (400 MHz; d6-DMSO): G 12.083 (s, 1H, OH),
ꢎꢁꢏꢊꢑꢀꢈVꢅꢀꢉ+ꢅꢀTXLQROLQHꢄꢓꢄ+ꢇꢅꢀꢐꢁꢊꢃꢃꢀꢈVꢅꢀꢉ+ꢅꢀTXLQROLQH+ꢇꢅꢀꢐꢁꢊꢃꢃ±ꢐꢁꢊꢐꢎꢀ
ꢈPꢅꢀ ꢉ+ꢅꢀ 3K+ꢇꢅꢀ ꢐꢁꢊꢊꢑ±ꢐꢁꢊꢓꢐꢀ ꢈPꢅꢀ ꢉ+ꢅꢀ 3K+ꢇꢅꢀ ꢐꢁꢏꢉꢉ±ꢐꢁꢌꢎꢎꢀ ꢈPꢅꢀ ꢓ+ꢅꢀ
PhH), 7.093 (s, 1H, quinolineH), 5.258 (s, 2H, PhCH2), 4.189 (t, 2H,

254 JOURNAL OF CHEMICAL RESEARCH 2009
J = 7.2 Hz, CO2CH2CH3), 4.158 (t, 2H, J = 7.2 Hz, OCH2CH3),
1.412 (q, 3H, J = 7.2 Hz, OCH2CH3), 1.266 (q, 3H, J = 7.2 Hz,
CO2CH2CH3); IR (KBr, cm-1) 3429(br), 3173, 3139, 3095, 2981,
1700, 1622, 1562, 1499, 1377, 1267, 1094, 798, 753, 617; HRMS
(ESI) Calcd for C21H21ClNO5 [M + H]+: 402.1108. Found 402.1099.
IR (KBr, cm-1) 3433, 2978, 1699, 1625, 1585, 1498, 1269, 799,
619; HRMS (ESI) Calcd for C22H24NO6[M + H]+: 398.1604. Found
398.1596.
(WK\Oꢀ ꢁꢂK\GUR[\ꢂꢃꢂPHWKR[\ꢂꢄꢂꢅꢆꢇꢁꢇꢄꢂWULÀXRUREHQ]\OR[\ꢈTXLQROLQHꢂ
3-carboxylate (3iꢇꢋꢀ <HOORZꢀ VROLGꢅꢀ \LHOGꢋꢀ ꢊꢑꢒꢅꢀ PꢁSꢁꢀ ꢓꢌꢎ±ꢓꢏꢑ°C;
1H NMR spectrum (400 MHz; d6-DMSO): G 12.106 (d, 1H, J = 6.8 Hz,
OH), 8.458 (d, 1H, Jꢀ ꢀ ꢂꢁꢎꢀ +]ꢅꢀ TXLQROLQHꢄꢓꢄ+ꢇꢅꢀ ꢐꢁꢐꢓꢃ±ꢐꢁꢂꢓꢉꢀ ꢈPꢅꢀ
2H, PhH), 7.638 (s, 1H, quinolineH), 7.092 (s, 1H, quinolineH),
5.172 (s, 2H, PhCH2), 4.199 (t, 2H, J = 7.2 Hz, CO2CH2CH3), 3.884
(s, 1H, CH3O), 1.275 (q, 3H, J = 7.2 Hz, CO2CH2CH3); IR (KBr, cm-1)
3429, 2928, 1697, 1625, 1587, 1498, 1274, 804, 737, 619; HRMS
(ESI) Calcd for C20H17F3NO5 [M + H]+: 408.1059. Found 408.1050.
(WK\Oꢀ ꢃꢂHWKR[\ꢂꢁꢂK\GUR[\ꢂꢄꢂꢅꢆꢇꢁꢇꢄꢂWULÀXRUREHQ]\OR[\ꢈTXLQROLQHꢂꢉꢂ
carboxylate (3jꢇꢋꢀ<HOORZꢀVROLGꢅꢀ\LHOGꢋꢀꢊꢌꢒꢅꢀPꢁSꢁꢀꢓꢏꢉ±ꢓꢏꢌ°C. 1H NMR
spectrum (400 MHz; d6-DMSO) G: 12.068 (d, 1H, J = 6.4 Hz, OH),
8.452 (d, 1H, Jꢀ ꢀ ꢂꢁꢏꢀ +]ꢅꢀ TXLQROLQHꢄꢓꢄ+ꢇꢅꢀ ꢐꢁꢂꢎꢏ±ꢐꢁꢂꢌꢉꢀ ꢈPꢅꢀ ꢓ+ꢅꢀ
PhH), 7.631 (s, 1H, quinolineH), 7.084 (s, 1H, quinolineH), 5.187
(s, 2H, PhCH2), 4.197 (t, 2H, J = 7.2 Hz, CO2CH2CH3), 4.128 (t, 2H,
J = 7.2 Hz, CO2CH2CH3), 1.395 (q, 3H, J = 7.2 Hz, OCH2CH3),
1.273 (q, 3H, J = 7.2 Hz, CO2CH2CH3); IR (KBr, cm-1) 3431, 2980,
1702, 1626, 1587, 1499, 1273, 804, 738, 620; HRMS (ESI) Calcd for
C21H19F3NO5 [M + H]+: 422.1215. Found 422.1207.
Ethyl
6-(4-chlorobenzyloxy)-4-hydroxy-7-methoxyquinoline-
3-carboxylate (3cꢇꢋꢀ <HOORZꢀ VROLGꢅꢀ \LHOGꢋꢀ ꢊꢎꢒꢅꢀ PꢁSꢁꢀ ꢓꢏꢊ±ꢓꢏꢎ°C;
1H NMR spectrum (400 MHz; d6-DMSO): G 12.088 (d, 1H, J = 6.4 Hz,
OH), 8.442 (d, 1H, J = 6.4 Hz, quinoline-2-H), 7.592 (s, 1H,
quinolineH), 7.507 (d, 2H, J = 8.0 Hz, PhH), 7.475 (d, 2H, J = 8.0 Hz,
PhH), 7.086 (s, 1H, quinolineH), 5.191 (s, 2H, PhCH2), 4.193 (t, 2H,
J=7.2Hz,CO2CH2CH3),3.887(s,3H,OCH3),1.271(q,3H,J=7.2Hz,
CO2CH2CH3); IR (KBr, cm-1) 3431, 2925, 1708, 1627, 1585, 1499,
1274, 800, 619; HRMS (ESI) Calcd for C20H19ClNO5 [M + H]+:
388.0952. Found 388.0942.
Ethyl
6-(4-chlorobenzyloxy)-7-ethoxy-4-hydroxyquinoline-3-
carboxylate (3dꢇꢋꢀ <HOORZꢀ VROLGꢅꢀ \LHOGꢋꢀ ꢂꢌꢒꢅꢀ PꢁSꢁꢓꢏꢊ±ꢓꢏꢎ°C; 1H
NMR spectrum (400 MHz; d6-DMSO): G 12.045 (d, 1H, J = 6.8
Hz, OH), 8.432 (d, 1H, J = 6.8 Hz, quinoline-2-H), 7.572 (s, 1H,
quinolineH), 7.498 (d, 2H, J = 8.8 Hz, PhH), 7.466 (d, 2H, J = 8.8 Hz,
PhH), 7.071 (s, 1H, quinolineH), 5.200 (s, 2H, PhCH2), 4.184 (t, 2H,
J = 7.2 Hz, CO2CH2CH3), 4.147 (t, 2H, J = 7.2 Hz, OCH2CH3),
1.408 (q, 3H, J = 7.2 Hz, OCH2CH3), 1.263 (q, 3H, J = 7.2 Hz,
CO2CH2CH3); IR (KBr, cm-1) 3429, 2971, 1709, 1627, 1584, 1499,
1274, 802, 736, 698, 621; HRMS (ESI) Calcd for C21H21ClNO5 [M +
H]+: 402.1108. Found 402.1100.
Conclusion
In conclusion, a series of novel ethyl 6-substitutedbenzyloxy-
7-alkoxy-4-hydroxyquinoline-3-carboxylates were designed
and synthesised as anticoccidial drugs. The results indicate
that compounds 3e, 3i and 3j which are of certain anticoccidial
activity against E. tenella at a dose of 27 mg kg-1 and might
be developed as anticoccidial drugs. The three compounds
all have no less than two halogen groups. Further structural
optimisation and anticoccidial activities regarding the
4-hydroxyquinoline-3-carboxylate analogues are still in
progress.
Ethyl 6-(2,4-dichlorobenzyloxy)-4-hydroxy-7-methoxyquinoline-
3-carboxylate (3eꢇꢋꢀ <HOORZꢄEODQNꢀ VROLGꢅꢀ \LHOGꢋꢀ ꢂꢑꢒꢅꢀ PꢁSꢁꢀ ꢓꢊꢎ±
1
260°C; H NMR spectrum (400 MHz; d6-DMSO): G 12.122 (d, 1H,
J = 6.4 Hz, OH), 8.458 (d, 1H, J = 6.4 Hz, quinoline-2-H), 7.727
(d, 1H, J = 2.0 Hz, PhH), 7.615 (d, 1H, J = 8.4 Hz, PhH), 7.586 (s,
1H, quinolineH), 7.508 (dd, 1H, J1 = 2.0 Hz, J2 = 8.4 Hz, PhH),
7.102 (s, quinolineH), 5.230 (s, 2H, PhCH2), 4.193 (t, 2H, J = 6.8
Hz, CO2CH2CH3), 3.899 (s, 3H, OCH3), 1.269 (q, 3H, J = 7.2 Hz,
CO2CH2CH3); IR (KBr, cm-1) 3431(br), 3072, 2975, 1710, 1627,
1587, 1498, 1378, 1276, 1113, 853, 803, 616; HRMS (ESI) Calcd for
C
20H18Cl2NO5 [M + H]+: 422.0562. Found 422.0554.
Ethyl 6-(2,4-dichlorobenzyloxy)-7-ethoxy-4-hydroxyquinoline-3-
7KHꢀ DXWKRUVꢀ DSSUHFLDWHꢀ WKHꢀ ¿QDQFLDOꢀ VXSSRUWꢀ IURPꢀ WKHꢀ
National Science Foundation of China (No. 20372052)
and 1H NMR analysis by Sichuan University Analytical &
Testing Centre.
carboxylate (3f): *UD\ꢀVROLGꢅꢀ\LHOGꢋꢀꢂꢊꢒꢅꢀPꢁSꢁꢀꢓꢂꢊ±ꢓꢂꢎ°C; 1H NMR
spectrum (400 MHz; d6-DMSO): G 12.077 (s, 1H, OH), 8.457 (s, 1H,
quinoline-2-H), 7.725(d, 1H, J = 2.0Hz, PhH), 7.596 (d, 1H, J = 8.4Hz,
PhH), 7.564 (s, 1H, quinolineH), 7.505 (dd, 1H, J1 = 2.0 Hz,
J2 = 8.4 Hz, Ph H), 7.093 (s, quinolineH), 5.243 (s, 2H, PhCH2),
4.173 (t, 2H, J = 7.2 Hz, OCH2CH3), 4.141 (t, 2H, J = 7.2 Hz,
CO2CH2CH3), 1.409 (q, 3H, J = 7.2 Hz, OCH2CH3), 1.266 (q, 3H,
J = 7.2 Hz, CO2CH2CH3); IR (KBr, cm-1) 3430(br), 2974, 2926,
1701, 1626, 1589, 1498, 1272, 1115, 858, 802, 619; HRMS (ESI)
Calcd for C21H20Cl2NO5 [M + H]+: 436.0718. Found 436.0709.
Received 5 January 2009; accepted 24 February 2009
Paper 09/0377 doi: 10.3184/030823409X439726
Published online: 29 April 2009
Ethyl
3-carboxylate (3gꢇꢋꢀ <HOORZꢀ VROLGꢅꢀ \LHOGꢋꢀ ꢊꢂꢒꢅꢀ PꢁSꢁꢀ ꢓꢊꢂ±ꢓꢊꢎ°C;
1H NMR spectrum (400 MHz; d6-DMSO):
12.075 (d, 1H,
4-hydroxy-7-methoxy-6-(4-methoxybenzyloxy)quinoline-
References
1
2
3
4
C.F. Duffy, G.F. Mathis and R.F. Power, Vet Para., 2005, 130, 185.
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H.D. Chapman, Avian Pathol., 1997, 26, 221.
G
J = 6.4 Hz, OH), 8.438 (d, 1H, J = 6.4 Hz, quinoline-2-H), 7.609
(s, 1H, quinolineH), 7.400 (d, 2H, J = 7.2 Hz, PhH), 7.067 (s, 1H,
quinolineH), 6.960 (d, 2H, J = 7.2 Hz, PhH), 5.093 (s, 2H, PhCH2),
4.195 (t, 2H, J = 7.2 Hz, CO2CH2CH3), 3.878 (s, 3H, OCH3), 1.41 (q,
3H, J = 6.8 Hz, CH3CH2O), 1.273 (q, 3H, J = 6.8 Hz, CO2CH2CH3);
IR (KBr, cm-1) 3430, 2981, 1697, 1623, 1585, 1497, 1267, 802, 737,
696, 620; HRMS (ESI) Calcd for C21H22NO6 [M + H]+: 384.1447.
Found 384.1438.
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Ethyl
7-ethoxy-4-hydroxy-6-(4-methoxybenzyloxy)quinoline-3-
carboxylate (3hꢇꢋꢀ<HOORZꢀVROLGꢅꢀ\LHOGꢀꢊꢓꢒꢅꢀPꢁSꢁꢀꢓꢊꢑ±ꢓꢊꢌ°C; 1H NMR
spectrum (400 MHz; d6-DMSO): G 12.038 (d, 1H, J = 6.4 Hz, OH),
8.431 (d, 1H, J = 6.4 Hz, quinoline-2-H), 7.599 (s, 1H, quinolineH),
7.399 (d, 2H, J = 7.2 Hz, PhH), 7.059 (s, 1H, quinolineH), 6.959 (d,
2H, J = 7.2 Hz, PhH), 5.106 (s, 2H, PhCH2), 4.192 (t, 2H, J = 6.8 Hz,
OCH2CH3), 4.137 (t, 2H, J = 6.8 Hz, CO2CH2CH3), 1.399 (q, 3H,
J = 6.8 Hz, CH3CH2O), 1.270 (q, 3H, J = 6.8 Hz, CO2CH2CH3);
10 J.N. Hodgson, Br. Vet F., 1968, 124, 209.
11 T. Tomio, T. Yoshikazu, H. Masa; N. Hiroshi and S. Kiyoshi, US Pat.,
5215981, 1990.
12 G.Q. Li, S. Kanu, F.Y. Xiang, S.M. Xiao, L. Zhang, H.W. Chen and
H.J. Ye, Vet Para., 2004, 119, 261.
13 S.D. Folz, B.L. Lee, L.H. Nowakowski, D.L. Rector and B.M. Folz,
J. Para., 1989, 75, 696.