Synthesis and biological evaluation of ethyl 6-alkoxy-7-phenyl-4-hydroxy-3-quinolinecarboxylates against Eimeria tenella

Article abstract of DOI:10.1016/j.cclet.2009.12.006

A series of ethyl 6-alkoxy-7-phenyl-4-hydroxy-3-quinolinecarboxylates were designed and synthesized. Their structures were confirmed by ¹H NMR, ¹³C NMR, IR and HRMS. The biological activities were primarily evaluated against Eimeria

Full text of DOI:10.1016/j.cclet.2009.12.006

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Chinese Chemical Letters 21 (2010) 426–428
www.elsevier.com/locate/cclet
Synthesis and biological evaluation of ethyl
6-alkoxy-7-phenyl-4-hydroxy-3-quinolinecarboxylates
against Eimeria tenella
Yuan Yuan Zhang a, Xing Yan Zeng b, Kui Nie b, Zhi Cheng Zhong c,
a,c
Yu Liang Wang a,c, , Yu Zhong Wang
*
a Department of Chemical Engineering, Sichuan University, Chengdu 610065, China
b College of Animal Science and Technology, Southwest University, Chongqing 400715, China
c Department of Chemistry, Sichuan University, Chengdu 610064, China
Received 24 August 2009
Abstract
A series of ethyl 6-alkoxy-7-phenyl-4-hydroxy-3-quinolinecarboxylates were designed and synthesized. Their structures were
1
confirmed by H NMR, 13C NMR, IR and HRMS. The biological activities were primarily evaluated against Eimeria tenella
according to Anticoccidial Index (ACI) method in vivo. The results showed that compounds 5e, 5f and 5i exhibited anticoccidial
activities against E. tenella at 27 mg kgÀ1
.
# 2009 Yu Liang Wang. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: Ethyl 6-alkoxy-7-phenyl-4-hydroxy-3-quinolinecarboxylate; Synthesis; Anticoccidial activity; Eimeria tenella
Coccidiosis is an infection of intestinal epithelium caused by protozoan parasite of the genus Eimeria, which
induces production losses, high morbidity (due to acute, bloody enteritis) and mortality rates [1,2]. Anticoccidiostats
were used to control this disease, but after using for a period of time, the coccidia were inevitably to develop resistance
to the drugs [3]. Nowadays, drug resistance has extended to all of the anticoccidiostats that have been introduced [4]. It
was reported that some anticoccidiostats such as Salinomycin, Dinitolmide, Maduramicin and Amprolium had lost
anticoccidial activities against many strains in many areas of China [5]. Thus, it is necessary to search and develop new
anticoccidial drugs.
Quinolinecarboxylate anticoccidiostats such as buquinolate, nequinate and decoquinate (Fig. 1), possessing 6-
alkoxy/alkyl and 7-alkoxy in the structure of quinoline ring, exhibited good anticoccidial activities for chickens in one
time. However, the effects of these drugs have been reported to decline because of drug resistance [4]. These current
quinolinecarboxylate anticoccidiostats would be certainly invalid one day.
In order to search new anticoccidial compounds, a series of ethyl 6-alkoxy-7-phenyl-4-hydroxy-3-
quinolinecarboxylates were designed and synthesized. In the new object molecules, 7-phenyl group was introduced
* Corresponding author at: Department of Chemistry, Sichuan University, Chengdu 610064, China.
E-mail address: chemwang2000@163.com (Y.L. Wang).
1001-8417/$ – see front matter # 2009 Yu Liang Wang. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
doi:10.1016/j.cclet.2009.12.006

Y.Y. Zhang et al. / Chinese Chemical Letters 21 (2010) 426–428
427
Fig. 1. The structure of buquinolate, nequinate and decoquinate.
Scheme 1. The synthetic route of target compounds. (a) H2, Pd/C, EtOAc, 45 8C, 6 h; (b) EMME, reflux, 4 h, 75%; (c) R-Br, K2CO3, TBAB, DMF,
80 8C, 2–3 h, 70–80%; (d) diphenyl ether, reflux, 10–20 min, 67–78%.
to the quinoline rine and the molecular structures were different from the former quinolinecarboxylate
anticoccidiostats. Therefore the drug-resistant strains might be sensitive to the new compounds.
Compounds 5a–i were prepared as shown in Scheme 1. Compound 1 [6] was reduced by Pd/C catalyzed
hydrogenation in EtOAc at normal pressure for 6 h. The obtained mixture was directly used to react with proper
amount of diethylethoxymethylenemalonate (EMME) for 4 h to form 3, which was purified through recrystallization
in ethanol. Then, 3 was treated with bromoalkane (R-Br), TBAB and potassium carbonate in DMF for 2–3 h to give
compounds 4a–i. Target compounds 5a–i were obtained by cyclization reaction in diphenyl ether for 10–20 min, and
purified by washing with petroleum ether and EtOAc. The data of yields, melting points, 1H NMR, 13C NMR, IR and
HRMS spectra of the target compounds were shown in Ref. [8].
The anticoccidial activities of 5c–5i were evaluated according to ACI method [7] in vivo, using diclazuril as
reference drug (Table 1). Compared with Infected-untreated group (ACI 60.9), 5e, 5f and 5i showed obvious
anticoccidial activities against Eimeria tenella, with ACI 122.4, 138.5 and 133.3, respectively. At the same time, 5f
and 5i showed better anticoccidial activities than diclazuril (ACI 127) against the tested E. tenella strain.
Table 1
Anticoccidial activity of target compounds 5c–5i against Eimeria tenella at 27 mg kgÀ1
.
Group Test compounds
No. of chicken Relative rate of weight gain (%) Rate of survival (%) Lesion value Oocyst value ACI
1
2
5c
5d
10
10
10
10
10
10
10
10
10
73.9
65.7
68.8
87.6
47.9
62.1
85.1
87
80
90
90
90
70
70
90
90
60
100
38
40
30
20
20
40
30
20
20
40
0
75.9
100.7
122.4
138.5
44.9
25
3
5e
16.4
19.1
33
4
5f
5g
5
6
5h
5i
24
78.1
7
21.8
30
133.3
127
8
Diclazurila
Infected-untreated
9
78.9
38
60.9
10
Uninfected-untreated 10
100
0
200
a
The concentration of diclazuril is 1 mg kgÀ1, which is the standard concentration of this drug for chickens.

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Y.Y. Zhang et al. / Chinese Chemical Letters 21 (2010) 426–428
From the results of 5c–5h, it was clear that the number of carbon atoms in 6-alkyoxy played an important role in
determining the activities. Anticoccidial activity was exhibited by the introduction of decyloxy (C10) or dodecyloxy
(C12) group in 6-position, while compounds with more or less number of carbon atoms displayed no anticoccidial
activity. 5i with 6-benzyloxy also showed anticoccidial activity against E. tenella.
In summary, nine ethyl 6-alkoxy-7-phenyl-4-hydroxy-3-quinolinecarboxylates were designed and synthesized.
Evaluation of the anticoccidial activity of new compounds revealed that compounds 5e, 5f and 5i had anticoccidial
activities against E. tenella at 27 mg kgÀ1
.
Acknowledgments
We appreciate the financial support from the National Science Foundation of China (No. 20372052) and NMR
analysis by Sichuan University Analytical & Testing Center.
References
[1] R.B. Williams, Int. J. Parasitol. 29 (1999) 1209.
[2] C.F. Duffy, G.F. Mathis, Vet. Parasitol. 130 (2005) 185.
[3] G. Greif, B. Stephan, Parasitol. Res. 8 (1996) 706.
[4] H.D. Chapman, Avian Pathol. 26 (1997) 221.
[5] J.J. Xu, J.P. Tao, J.B. Peng, Anim. Husbandry Vet. Med. 40 (2008) 18.
[6] M. Novak, J.S. Helmick, N. Oberlies, J. Org. Chem. 58 (1993) 863.
[7] S.D. Folz, B.L. Lee, L.H. Nowakowski, Int. J. Parasitol. 75 (1989) 696.
[8] The data for representative compounds: 5a: yellow solid; yield: 72%; melting point: 252–254 8C; 1H NMR (400 MHz, DMSO-d6): d 12.29 (s,
1H), 8.53 (s, 1H), 7.67 (s, 1H), 7.58 (d, 2H, J = 7.2 Hz), 7.55 (s, 1H), 7.48 (t, 2H, J = 7.2 Hz, J = 7.6 Hz), 7.42–7.40 (m, 1H), 4.22 (q, 2H,
J = 7.2 Hz), 4.14 (q, 2H, J = 6.8 Hz), 1.32 (t, 3H, J = 6.8 Hz), 1.29 (t, 3H, J = 6.8 Hz); 13C NMR (400 MHz, DMSO-d6): d 173.84, 167.83,
152.86, 151.58, 145.02, 138.25, 133.86, 129.45, 129.16, 128.74, 128.08, 127.17, 105.83, 63.88, 58.44, 14.68; IR (KBr, cmÀ1): 3440, 2979, 2930,
1700, 1613, 1582, 1502, 1469, 1443, 1188; HRMS(ESI): Calcd. for C20H19NO4: 337.1314; Found: 338.1351 (M+H+), 360.1204 (M+Na+); 5b:
yellow solid; yield: 75%; melting point: 248–250 8C; 1H NMR (400 MHz, DMSO-d6): d 12.26 (d, 1H, J = 6.0 Hz), 8.51 (d, 1H, J = 6.4 Hz), 7.65
(s, 1H), 7.54 (d, 2H, J = 8.0 Hz), 7.52 (s, 1H), 7.45 (t, 2H, J = 7.2 Hz, J = 8.0 Hz), 7.40–7.38 (m, 1H), 4.20 (q, 2H, J = 7.2 Hz), 4.06 (t, 2H,
J = 6.4 Hz), 1.66 (m, 2H), 1.37 (m, 2H), 1.27 (t, 3H, J = 7.2 Hz), 0.89 (t, 3H, J = 7.2 Hz); 13C NMR (400 MHz, DMSO-d6): d 173.99, 167.82,
152.80, 151.79, 144.95, 138.19, 133.75, 129.44, 129.08, 128.72, 128.01, 127.20, 105.54, 67.69, 58.47, 30.62, 18.91, 14.85, 13.71; IR (KBr,
cmÀ1: 3417, 2958, 2926, 2871, 1698, 1614,1581, 1501, 1444, 1384, 1185; HRMS(ESI): Calcd. for C22H23NO4: 365.1627; Found: 366.1709
(M+H+), 388.1724 (M+Na+); 5c: yellow solid; yield: 75%; melting point: 244–245 8C; 1H NMR (400 MHz, DMSO-d6): d 12.47 (s, 1H), 8.51 (d,
1H, J = 4.8 Hz), 7.67 (s, 1H), 7.56 (d, 2H, J = 8.0 Hz), 7.55 (s, 1H), 7.47 (t, 2H, J = 6.8 Hz, J = 7.2 Hz), 7.42–7.40 (m, 1H), 4.22 (q, 2H,
J = 7.2 Hz), 4.07 (t, 2H, J = 6.4 Hz), 1.68 (m, 2H), 1.37 (m, 2H), 1.28 (m, 7H), 0.84 (t, 3H, J = 6.4 Hz); 13C NMR (400 MHz, DMSO-d6): d
173.99, 167.82, 152.83, 151.79, 145.01, 138.22, 133.70, 129.49, 129.11, 128.96, 127.97, 127.17, 105.52, 67.96, 58.43, 30.84, 28.88, 25.33,
22.12, 14.86, 13.91; IR (KBr, cmÀ1): 3422, 2930, 2861, 1697, 1614, 1580, 1502, 1465, 1444, 1383, 1186, 720; HRMS(ESI): Calcd. for
C24H27NO4: 393.1940; Found: 394.2016 (M+H+), 416.1632 (M+Na+); 5d: white solid; yield: 78%; melting point: 236–238 8C; 1H NMR
(400 MHz, DMSO-d6): d 12.25 (d, 1H, J = 6.4 Hz), 8.51 (d, 1H, J = 7.2 Hz), 7.65 (s, 1H), 7.54 (d, 2H, J = 8.0 Hz), 7.56 (s, 1H), 7.45–7.41 (m,
3H), 4.20 (q, 2H, J = 7.2 Hz), 4.06 (t, 2H, J = 6.4 Hz), 1.67 (m, 2H), 1.35 (m, 2H), 1.26 (m, 11H), 0.84 (t, 3H, J = 6.4 Hz); 13C NMR (400 MHz,
DMSO-d6): d 174.03, 167.88, 152.68, 151.83, 145.03, 138.24, 133.78, 129.51, 129.14, 128.97, 128.02, 127.23, 105.57, 68.01, 58.52, 31.27,
28.75, 25.71, 22.21, 14.71, 14.09; IR (KBr, cmÀ1): 3424, 2960, 2945, 2855, 1698, 1614, 1581, 1502, 1467, 1444, 1384, 1186, 724; HRMS(ESI):
Calcd. for C26H31NO4: 421.2253; Found: 422.2290 (M+H+), 444.2105 (M+Na+); 5e: white solid; yield: 75%; melting point: 237–239 8C; 1H
NMR (400 MHz, DMSO-d6): d 12.27 (d, 1H, J = 6.4 Hz), 8.53 (d, 1H, J = 6.8 Hz), 7.67 (s, 1H), 7.57 (d, 2H, J = 8.0 Hz), 7.56 (s, 1H), 7.49 (t,
2H, J = 6.8 Hz, J = 6.8 Hz), 7.42–7.40 (m, 1H), 4.22 (q, 2H, J = 7.2 Hz), 4.07 (t, 2H, J = 6.4 Hz), 1.66 (m, 2H), 1.32 (m, 2H), 1.26 (m, 15H), 0.86
(t, 3H, J = 6.4 Hz); 13C NMR (400 MHz, DMSO-d6): d 173.84, 167.83, 152.86, 151.54, 145.07, 138.28, 133.86, 129.49, 129.12, 128.74, 128.08,
127.17, 105.86, 63.86, 58.44, 31.33, 29.10, 28.68, 25.75, 22.12, 18.48, 14.88, 14.01; IR (KBr, cmÀ1): 3434, 2957, 2925, 2854, 1700, 1614, 1581,
1502, 1467, 1444, 1383, 1186, 725; HRMS(ESI): Calcd. for C28H35NO4: 449.2566; Found: 450.2599 (M+H+), 472.2419 (M+Na+). The data left
were conserved by the editorial department of Chinese Chemical letters.