Synthesis, anticonvulsant and antihypertensive activities of 8-substituted quinoline derivatives

Article abstract of DOI:10.1248/bpb.27.1683

A series of 8-substituted quinolines were synthesized and tested against seizures induced by maximal electro shock (MES), pentylenetetrazole (scMet) and antihypertensive activities. Neurologic deficit was evaluated by the rotarod test. Among the newly syn

Full text of DOI:10.1248/bpb.27.1683

October 2004
Notes
Biol. Pharm. Bull. 27(10) 1683—1687 (2004)
1683
Synthesis, Anticonvulsant and Antihypertensive Activities of
8-Substituted Quinoline Derivatives
Nithyanantham MURUGANANTHAM,a Ramaiah SIVAKUMAR,a Navaneetharaman ANBALAGAN,b
Vedachalam GUNASEKARAN,a and Joseph Thomas LEONARD*,a
a Department of Pharmaceutical Chemistry and Pharmacology, Vel’s College of Pharmacy; Old Pallavaram, Chennai-600
117, India: and b Department of Pharmaceutical Chemistry, C. L. Baid Metha College of Pharmacy; Thorapakkam,
Chennai-600 096, India. Received March 1, 2004; accepted May 7, 2004
A series of 8-substituted quinolines were synthesized and tested against seizures induced by maximal electro
shock (MES), pentylenetetrazole (scMet) and antihypertensive activities. Neurologic deficit was evaluated by the
rotarod test. Among the newly synthesized derivatives, several compounds with a 2-hydroxypropyloxyquinoline
moiety displayed excellent anticonvulsant and antihypertensive activities. Compound 20 (8-(3ꢀ-(4ꢁ-phenylpiper-
azino)-2ꢀ-hydroxypropyloxy)quinoline) was potent in both series as an anticonvulsive agent. 13 (8-(3ꢀ-piper-
azino)-2ꢀ-hydroxypropyloxyquinoline) and 14 (8-(3ꢀ-imidazolo)-2ꢀ-hydroxypropyloxyquinoline) showed very good
anticonvulsant activities in the propanol series of compound, whereas in the ethane series, 1 (8-(2ꢀ-piperazino-
ethanoxy)quinoline) and 2 (8-(2ꢀ-imidazolo-ethanoxy)quinoline) were the most active as anticonvulsive agents.
Compounds 20 (8-(3ꢀ-(4ꢁ-phenylpiperazino)-2ꢀ-hydroxypropyloxy)quinoline), 13 (8-(3ꢀ-piperazino)-2ꢀ-hydroxy-
propyloxyquinoline) and 19 (8-(3ꢀ-(4ꢁ-ethylpiperazino)-2ꢀ-hydroxypropyloxy)quinoline) have shown excellent an-
tihypertensive activity. They have significantly antagonized the pressor response elicited by adrenaline. These
pharmacological results suggest that their anticonvulsant and antihypertensive effects may be correlated to the
presence of b-blocking properties, and that those properties depend on the presence of aryloxypropanolamine.
Key words anticonvulsant; antihypertensive; aryloxypropanolamine; quinoline
Quinolines were reported to possess antibacterial,1) anti-
were consistent with the assigned structures.
fungal,2) immunosuppressive,3) analgesic,4) vasorelaxing,5)
antiplasmodial,6) anticancer7,8) and PDE4 inhibitory9) activi-
ties. Aryloxypropanolamines were reported to be associated
with b-adrenergic blocking,10,11) CNS depressant12) and hy-
potensive13) activities. In view of this potential nature of
these moieties, it was thought worthwhile to study the effects
of two pharmacophoric moieties such as quinoline and
propanolamines/aminoethane in a single molecule. We have
already reported the potential anticonvulsant activity and the
b-blocking activity of propanolamine, aminopropane and
aminoethane from our laboratory.14—20) To explore the het-
eroaryl and propanolamine/aminoethane combination, it was
envisaged that chemical entities with both quinoline and aryl-
oxypropanolamine/aminoethane moieties would result in
compounds with interesting biological activities.
Synthesis of 8-(2ꢀ-Chloroethanoxy)quinoline 8-Hy-
droxy quinoline was reacted with 1,2-dichloroethane, as re-
ported by us earlier.15) A mixture of 8-hydroxy quinoline
(0.13 mol), 1,2-dichloro ethane (0.167 mol) and anhydrous
potassium carbonate (0.195 mol) was refluxed in dry acetone
(420 ml) for 40 h. The reaction mixture was filtered, and the
filtrate on concentration yielded the product. The product
was filtered, dried under vacuum and recrystallized by using
chloroform–ether (1 : 1). Yieldꢂ52%, mp 68—70 °C. 1H-
NMR (CDCl3) d: 8.05—7.86 (m, 6H, 2, 3, 4, 5, 6, 7H),
3.82—4.13 (s, 4H, CH2–CH2). IR (KBr) cmꢃ1: 1425 (C–H),
1126 (C–O), 756, 744 (Ar–H). Anal. Calcd for C11H10NOCl:
C, 66.83; H, 5.06; N, 7.08. Found C, 66.51; H, 5.23; N, 7.31.
General Method of Synthesis for 1 to 12 A mixture of
8-(2ꢀ-chloroethanoxy)quinoline
(0.01 mol),
amine
(0.012 mol), anhydrous sodium carbonate (0.007 mol) and
sodium iodide (0.0034 mol) was refluxed in dry acetone
(40 ml) for 65 h. The reaction mixture was filtered, and the
filtrate on concentration yielded the product. The product
was filtered, dried under vacuum and recrystallized using
1 : 1 acetone–diethyl ether (3, 5, 8), 1 : 1 ethanol–diethyl
ether (1, 6, 9, 11), 1 : 1 chloroform–diethyl ether (7, 10) and
1 : 1 methanol–diethyl ether (2, 4, 12).
In the present study, we report the synthesis, the anticon-
vulsant and antihypertensive activities, and the structure–
activity relationship of 2-(3ꢀ-substituted-2ꢀ-hydroxy-propyl-
oxy/2ꢀ-substituted-ethanoxy)-quinoline. The compounds
were characterized by IR, H-NMR spectral and elemental
analysis. The compounds were investigated for anticonvul-
sant and antihypertensive activities.
1
8-(2ꢀ-Piperazino-ethanoxy)quinoline 1: Yieldꢂ49%, mp
140 °C, H-NMR (CDCl3) d: 7.97—8.23 (m, 6H, 2, 3, 4, 5,
CHEMISTRY
1
6, 7H), 5.25—5.45 (m, 1H, NH), 4.34—4.59 (m, 4H, 2CH2),
2.49—2.73 (m, 8H, 2ꢄ, 3ꢄ, 5ꢄ, 6ꢄ-CH2). IR (KBr) cmꢃ1: 1434
(C–H), 1345 (C–N), 1112 (C–O), 845, 787 (Ar–H). Anal.
Calcd for C15H19N3O: C, 70.03; H, 7.39; N, 16.34. Found: C,
70.32; H, 7.13; N, 16.06.
Melting points were determined in open capillary tubes
and are uncorrected. IR spectra were recorded (in KBr) on a
Bomen FT-IR spectrophotometer M.B Seriel II. H-NMR
1
spectra were recorded on a 300 MHz Bruker DPX 200. The
chemical shifts are reported as parts per million downfield
from tetramethylsilane (Me4Si). Microanalysis for C, H, and
N were performed in an Heraeus CHN Rapid Analyzer.
Analyses indicated by the symbols of the elements are within
8-(2ꢀ-Imidazoyl-ethanoxy)quinoline 2: Yieldꢂ47%, mp
1
235 °C. H-NMR (CDCl3) d: 8.13—8.34 (m, 6H, 2, 3, 4, 5,
6, 7H), 5.34—5.49 (m, 1H, 2ꢀCH), 5.02—5.24 (m, 1H, 4ꢄ, 5ꢄ
(–CH)), 3.88—4.05 (m, 4H, 2CH2). IR (KBr) cmꢃ1: 1445
1
ꢁ0.4% of the theoretical values. H-NMR and IR spectra
* To whom correspondence should be addressed. e-mail: alabarae@yahoo.com
© 2004 Pharmaceutical Society of Japan

1684
Vol. 27, No. 10
(C–H), 1398 (C–N), 1167 (C–O), 881, 798 (Ar–H). Anal.
Calcd for C14H13N3O: C, 70.29; H, 5.43; N, 17.57. Found: C, Yieldꢂ36%, mp 129 °C. H-NMR (CDCl3) d: 7.67—7.83
70.63; H, 5.69; N, 17.75.
8-(2ꢀ-(4ꢄ-Ethylpiperazinyl)-ethanoxy)quinoline 11:
1
(m, 6H, 2, 3, 4, 5, 6, 7H), 4.51—4.65 (m, 4H, 2CH2), 2.23—
8-(2ꢀ-Diphenylamino-ethanoxy)quinoline 3: Yieldꢂ49%, 2.4 (m, 8H, 2ꢄ, 3ꢄ, 5ꢄ, 6ꢄ-CH2), 2.15—2.23 (s, 5H, C2H5). IR
1
mp 58 °C. H-NMR (CDCl3) d: 8.18—8.27 (m, 6H, 2, 3, 4, (KBr) cmꢃ1: 1447 (C–H), 1344 (C–N), 1147 (C–O), 868,
5, 6, 7H), 6.11—6.23 (m, 10H, (C6H5)2), 4.42—4.65 (m, 4H, 753 (Ar–H). Anal. Calcd for C17H23N3O: C, 71.57; H, 8.07;
2CH2). IR (KBr) cmꢃ1: 3112 (C–H), 1423 (C–N), 1373 N, 14.73. Found: C, 71.22; H, 7.78; N, 15.06.
(N–H), 1148 (C–O), 879, 792 (Ar–H). Anal. Calcd for
C23H20N2O: C, 81.17; H, 5.88; N, 8.23. Found: C, 81.43; H, Yieldꢂ41%, mp 143 °C. 1H-NMR (CDCl3) d: 7.3—7.44 (m,
5.53; N, 8.45.
6H, 2, 3, 4, 5, 6, 7H), 6.12—6.23 (s, 4H, C6H4), 4.53—4.68
8-(2ꢀ-(4ꢄ-Phenylpiperazinyl)-ethanoxy)quinoline 12:
8-(2ꢀ-Diethanolamino-ethanoxy)quinoline 4: Yieldꢂ59%, (m, 4H, 2CH2), 2.46—2.57 (m, 8H, 2ꢄ, 3ꢄ, 5ꢄ, 6ꢄ-CH2). IR
mp 147 °C. 1H-NMR (CDCl3) d: 7.92—8.14 (m, 6H, 2, 3, 4, (KBr) cmꢃ1: 1414 (C–H), 1363 (C–N), 1171 (C–O), 834,
5, 6, 7H), 4.19—4.37 (m, 4H, 2CH2), 3.27—3.41 (s, 2H, 736 (Ar–H). Anal. Calcd for C21H23N3O: C, 75.67; H, 6.9; N,
2ꢄ(–OH)2), 2.76—2.93 (m, 8H, (C2H4)2). IR (KBr) cmꢃ1: 12.61. Found: C, 75.36; H, 7.25, N, 12.36.
3339 (O–H), 3119 (C–H), 1446 (C–N), 1127 (C–O), 891,
789 (Ar–H). Anal. Calcd for C15H20N2O3: C, 65.21; H, 7.24; droxyquinoline was reacted with epichlorohydrin, as reported
N, 10.14. Found: C, 64.93; H, 7.56; N, 10.43.
by us earlier.15) A mixture of 8-hydroxyquinoline (0.13 mol),
Synthesis of 2-(2ꢀ,3ꢀ-Epoxypropyloxy)quinoline 8-Hy-
8-(2ꢀ-Phenylamino-ethanoxy)quinoline 5: Yieldꢂ64%, mp epichlorohydrin (0.167 mol) and anhydrous potassium car-
1
205 °C. H-NMR (CDCl3) d: 7.98—8.23 (m, 6H, 2, 3, 4, 5, bonate (0.195 mol) was refluxed in dry acetone (420 ml) for
6, 7H), 5.35—5.59 (m, 1H, NH), 5.02—5.28 (m, 5H, C6H5), 40 h. The reaction mixture was filtered, and the filtrate on
4.21—4.39 (m, 4H, 2CH2). IR (KBr) cmꢃ1: 1426 (C–N), concentration yielded the product. The product was filtered,
1310 (N–H), 1156 (C–O), 849, 790 (Ar–H). Anal. Calcd for dried under vacuum and recrystallized using ethanol–ether
1
C17H16N2O: C, 77.27; H, 6.06; N, 10.6. Found: C, 77.58; H, (1 : 1). Yieldꢂ43%, mp 234 °C. H-NMR (CDCl3) d: 8.13—
6.35; N, 10.89.
8.28 (m, 6H, 2, 3, 4, 5, 6, 7H), 3.43—3.61 (d, Jꢂ4.2 Hz, 2H,
8-(2ꢀ-(4ꢄ-Nitrophenylamino)-ethanoxy)quinoline 6: 3ꢀ-CH2), 3.28—3.4 (d, Jꢂ4.9 Hz, 2H, 1ꢀ-CH2), 2.25—2.39
Yieldꢂ39%, mp 64 °C. 1H-NMR (CDCl3) d: 8.11—8.34 (m, (m, 1H, 2ꢀ-CH). IR (KBr) cmꢃ1: 1453 (C–H), 1235 (epoxide
6H, 2, 3, 4, 5, 6, 7H), 5.19—5.35 (m, 1H, NH), 4.92—5.05 C–O), 1124 (ether C–O), 842, 787, (Ar–H). Anal. Calcd for
(m, 4H, C6H4), 4.32—4.51 (m, 4H, 2CH2). IR (KBr) cmꢃ1: C12H11NO3: C, 66.35; H, 5.06; N, 6.45. Found: C, 66.66; H,
1417 (C–N), 1319 (N–H), 1128 (C–O), 882, 795 (Ar–H). 5.37; N, 6.77.
Anal. Calcd for C17H15N3O3: C, 66.01; H, 4.85; N, 13.59.
Found: C, 65.79; H, 4.98; N, 13.25.
General Method of Synthesis for 13 to 20 A mixture of
8-(2ꢀ,3ꢀ-epoxypropyloxy)quinoline (0.01 mol), amine
8-(2ꢀ-(4ꢄ-Hydroxyphenylamino)-ethanoxy)quinoline 7: (0.012 mol), anhydrous sodium carbonate (0.007 mol) and
Yieldꢂ55%, mp 70 °C. 1H-NMR (CDCl3) d: 8.03—8.12 (m, sodium iodide (0.0034 mol) was refluxed in dry acetone
6H, 2, 3, 4, 5, 6, 7H), 6.23—6.41 (m, 1H, OH), 5.69—5.81 (40 ml) for 65 h. The reaction mixture was filtered, and the
(m, 1H, NH), 5.35—5.49 (m, 4H, C6H4), 4.21—4.39 (m, 4H, filtrate on concentration yielded the product. The product
2CH2). IR (KBr) cmꢃ1: 3415 (O–H), 3212 (C–H), 1421 was filtered, dried under vacuum and recrystallized using
(C–N), 1383 (N–H), 1151 (C–O), 881, 796 (Ar–H). Anal. 1 : 1 acetone–diethyl ether (13, 17), 1 : 1 ethanol–diethyl
Calcd for C17H16N2O2: C, 72.85; H, 5.71; N, 10.0. Found: C, ether (15, 18, 19), 1 : 1 chloroform–diethyl ether (14, 20),
72.67; H, 5.97; N, 10.32.
and 1 : 1 methanol–diethyl ether (16).
8-(2ꢀ-(4ꢄ-Bromophenylamino)-ethanoxy)quinoline 8:
8-(3ꢀ-Piperazinyl-2ꢀ-hydroxypropyloxy)quinoline 13:
1
Yieldꢂ39%, mp 118 °C. H-NMR (CDCl3) d: 7.92—8.14 Yieldꢂ49%, mp 78 °C. 1H-NMR (CDCl3) d: 7.28—7.46 (m,
(m, 6H, 2, 3, 4, 5, 6, 7H), 5.74—5.89 (m, 1H, NH), 5.15— 6H, 2, 3, 4, 5, 6, 7H), 6.68—6.89 (s, 1H, –NH), 3.81—3.98
5.39 (m, 4H, C6H4), 4.18—4.36 (m, 4H, 2CH2). IR (KBr) (m, 4H, 1ꢀ, 3ꢀ-CH2), 3.53—3.7 (s, 1H, 2ꢀ-OH), 2.65—2.82
cmꢃ1: 1412 (C–H), 1372 (C–N), 1132 (C–O), 889, 792 (m, 8H, 2ꢄ, 3ꢄ, 5ꢄ, 6ꢄ-CH2), 1.42—1.56 (m, 1H, 2ꢀ-CH). IR
(Ar–H). Anal. Calcd for C17H15N2OBr: C, 59.49; H, 4.37; N, (KBr) cmꢃ1: 1434 (C–H), 1378 (C–N), 1154, 1063 (C–O)
8.16. Found: C, 59.23; H, 4.14; N, 8.47.
836, 785 (Ar–H). Anal. Calcd for C16H21N3O2: C, 66.89; H,
8-(2ꢀ-(2ꢄ-Aminophenylamino)-ethanoxy)quinoline 9: 7.31; N, 14.63. Found: C, 66.68; H, 7.59; N, 14.95.
1
Yieldꢂ63%, mp 260 °C. H-NMR (CDCl3) d: 7.76—7.92
8-(3ꢀ-Imidazolyl-2ꢀ-hydroxypropyloxy)quinoline 14:
1
(m, 6H, 2, 3, 4, 5, 6, 7H), 6.34—6.12 (m, 1H, NH), 5.81— Yieldꢂ57%, mp 149 °C. H-NMR (CDCl3) d: 7.46—7.69
5.96 (m, 2H, NH2), 5.56—5.79 (m, 4H, C6H4), 4.21—4.39 (m, 6H, 2, 3, 4, 5, 6, 7H), 6.61—6.82 (m, 2H, 2ꢄ-CH),
(m, 4H, 2CH2). IR (KBr) cmꢃ1: 1434 (C–H), 1392 (C–N), 6.15—6.34 (m, 2H, 4ꢄ, 5ꢄ-CH), 3.76—3.91 (m, 4H, 1ꢀ, 3ꢀ-
1181 (C–O), 882, 795 (Ar–H). Anal. Calcd for C17H17N3O: CH2), 3.47—3.65 (s, 1H, 2ꢀ-OH), 1.77—1.93 (m, 1H, 2ꢀ-
C, 73.11; H, 6.09; N, 15.05. Found: C, 73.45 H, 6.31; N, CH). IR (KBr) cmꢃ1: 1423 (C–H), 1376 (C–N), 1174, 1074
15.37.
(C–O) 857, 775 (Ar–H). Anal. Calcd for C15H15N3O2: C,
8-(2ꢀ-(4ꢄ-Methylpiperazinyl)-ethanoxy)quinoline 10: 66.91; H, 5.57; N, 15.61. Found: C, 66.62; H, 5.35; N, 15.29.
1
Yieldꢂ52%, mp 112 °C. H-NMR (CDCl3) d: 7.85—7.97
8-(3ꢀ-Diphenylamino-2ꢀ-hydroxypropyloxy)quinoline 15:
(m, 6H, 2, 3, 4, 5, 6, 7H), 4.02—4.21 (m, 4H, 2CH2), 2.47— Yieldꢂ53%, mp 170 °C. 1H-NMR (CDCl3) d: 7.57—7.8 (m,
2.61 (m, 8H, 2ꢄ, 3ꢄ, 5ꢄ, 6ꢄ-CH2), 2.24—2.35 (s, 3H, CH3). IR 6H, 2, 3, 4, 5, 6, 7H), 6.45—6.59 (s, 1H, –NH), 6.12—6.27
(KBr) cmꢃ1: 1442 (C–H), 1376 (C–N), 1151 (C–O), 875, (m, 10H, (C6H5)2), 3.65—3.92 (m, 4H, 1ꢀ, 3ꢀ-CH2), 3.23—
784 (Ar–H). Anal. Calcd for C16H21N3O: C, 70.84; H, 7.74; 3.41 (s, 1H, 2ꢀ-OH), 1.44—1.57 (m, 1H, 2ꢀ-CH). IR (KBr)
N, 15.49. Found: C, 70.52; H, 7.97; N, 15.16.
cmꢃ1: 1457 (C–H), 1346 (C–N), 1175 (C–O), 865, 778

October 2004
1685
5ꢄ, 6ꢄCH2), 2.37—2.51 (s, 3H, CH3), 1.57—1.72 (m, 1H, 2ꢀ-
CH). IR (KBr) cmꢃ1: 1423 (C–H), 1365 (C–N), 1145, 1035
(C–O) 823, 7423 (Ar–H). Anal. Calcd for C18H25N3O2: C,
68.57; H, 7.93; N, 13.33. Found: C, 68.28; H, 7.57; N, 13.68.
8-(3ꢀ-(4ꢄ-Phenylpiperazino)-2ꢀ-hydroxypropyloxy)quino-
line 20: Yieldꢂ41%, mp 197 °C. 1H-NMR (CDCl3) d:
7.54—7.69 (m, 6H, 2, 3, 4, 5, 6, 7H), 6.27—6.39 (m, 4H,
C6H4), 3.65—3.78 (m, 4H, 1ꢀ, 3ꢀ-CH2), 3.32—3.45 (s, 1H,
2ꢀ-OH), 2.75—2.91 (m, 8H, 2ꢄ, 3ꢄ, 5ꢄ, 6ꢄ-CH2), 1.73—1.89
(m, 1H, 2ꢀ-CH). IR (KBr) cmꢃ1: 1454 (C–H), 1353 (C–N),
1135 (C–O) 864, 778 (Ar–H). Anal. Calcd for C22H25N3O2:
C, 72.72; H, 6.88; N, 11.57. Found: C, 72.48; H, 6.56; N,
11.84.
PHARMACOLOGY
The experiments were carried out on Wistar albino mice
(18—25 g) and Wistar rats (180—250 g). The animals were
kept in colony cages at 25ꢁ2 °C, relative humidity 45—55%
under a 12 h light and dark cycle. All the animals were accli-
matized for a week before use. The animals had free access
to standard pellet diet and water. Control and experimental
groups consisted of 6—8 animals each. The protection of-
fered by the synthesized compounds against clonic and tonic
convulsions in Wistar albino mice was screened at the dose
levels of 30, 100 and 300 mg kgꢃ1. Antihypertensive activity
of the compounds was determined in normotensive anes-
thetized rats.
Fig. 1. Synthetic Scheme
Anticonvulsant Activity The compounds were tested
for anticonvulsant activity using the procedures described
previously.21,22) All compounds were tested for anticonvulsant
activity with Wistar albino mice. Each compound was ad-
ministered intraperitoneally at three dose levels (30, 100,
300 mg kgꢃ1). The compounds were made into a solution
with water for injection.
Maximal electroshock seizures (MES) were induced
30 min after drug treatment by application of a 50 mA cur-
rent for 0.2 s via corneal electrodes into the eyes. The protec-
tion was defined as the abolition of the hind leg and tonic
maximal extension component of the seizure. The subcuta-
neous pentylenetetrazole (Metrozol) seizure threshold test
(sc-Met) was carried out by the subcutaneous administration
of pentylenetetrazole (85 mg kgꢃ1). Animals were observed
for over 30 min. Failure to observe the generalized clonic
seizure is defined as protection.
Minimal neurotoxicity (TD50) was measured by the rotarod
test (Tox). Mice were placed in 1-in. diameter knurled plastic
rod rotating 6 rpm after administration of the drug, and their
ability to maintain their balance was tested. Neurological
deficit was indicated by the inability of the animal to main-
tain equilibrium for 1 min on the rotating rod in each of three
trials. The results are tabulated in Tables 1 and 2.
(Ar–H). Anal. Calcd for C24H22N2O2: C, 77.83; H, 5.94; N,
7.56. Found: C, 77.57; H, 6.21; N, 7.23.
8-(3ꢀ-Diethylamino-2ꢀ-hydroxypropyloxy)quinoline 16:
1
Yieldꢂ44%, mp 139 °C. H-NMR (CDCl3) d: 7.23—7.51
(m, 6H, 2, 3, 4, 5, 6, 7H), 3.67—3.88 (m, 4H, 1ꢀ, 3ꢀ-CH2),
3.33—3.47 (s, 1H, 2ꢀ-OH), 2.32—2.48 (m, 4H, 2ꢄ, 3ꢄ, 5ꢄ,
6ꢄH), 1.56—1.71 (m, 1H, 2ꢀ-CH). IR (KBr) cmꢃ1: 1436
(C–H), 1343 (C–N), 1164 (C–O), 853, 758 (Ar–H). Anal.
Calcd for C16H22N2O4: C, 62.74; H, 7.18; N, 9.15. Found: C,
62.4; H, 7.45; N, 9.39.
8-(3ꢀ-(4ꢄ-Hydroxyphenylamino)-2ꢀ-hydroxypropyloxy)-
1
quinoline 17: Yieldꢂ46%, mp 175 °C. H-NMR (CDCl3) d:
7.68—7.84 (m, 6H, 2, 3, 4, 5, 6, 7H), 6.64—6.72 (s, 1H,
–OH), 6.37—6.49 (s, 1H, –NH), 5.45—5.63 (m, 4H, C6H4),
3.72—3.81 (m, 4H, 1ꢀ, 3ꢀ-CH2), 3.49—3.63 (s, 1H, 2ꢀ-OH),
1.54—1.66 (m, 1H, 2ꢀ-CH). IR (KBr) cmꢃ1: 1455 (C–H),
1379 (C–N), 1164 (C–O), 873, 745 (Ar–H). Anal. Calcd for
C18H18N2O3: C, 69.67; H, 5.8; N, 9.03. Found: C, 69.32; H,
5.65; N, 9.33.
8-(3ꢀ-Methylamino-2ꢀ-hydroxypropyloxy)quinoline 18:
Yieldꢂ54%, mp 90 °C. 1H-NMR (CDCl3) d: 7.34—7.56 (m,
6H, 2, 3, 4, 5, 6, 7H), 4.12—4.26 (m, 4H, 1ꢀ, 3ꢀ-CH2),
3.23—3.31 (s, 1H, 2ꢀ-OH), 1.47—1.59 (m, 1H, 2ꢀ-CH),
1.15—1.32 (s, 3H, CH3). IR (KBr) cmꢃ1: 1442 (C–H), 1363
(C–N), 1136 (C–O), 835, 765 (Ar–H). Anal. Calcd for
C13H16N2O2: C, 67.24; H, 6.89; N, 12.06. Found: C, 67.52;
H, 6.59; N, 12.41.
Antihypertensive Activity23) Male Wistar normotensive
rats were anesthetized with thiopental (50—75 mg kgꢃ1) by
intraperitoneal injection. The right carotid artery was cannu-
lated with a polyethylene tube filled with heparin in saline to
facilitate pressure measurements using a Datamax apparatus.
The studied compounds were injected in doses correspond-
ing to IV into the caudal vein, after a 5 min stabilization pe-
riod in a volume equivalent to 1 ml kgꢃ1.
8-(3ꢀ-(4ꢄ-Ethylpiperazino)-2ꢀ-hydroxypropyloxy)quinoline
1
19: Yieldꢂ43%, mp 128 °C. H-NMR (CDCl3) d: 7.12—
7.32 (m, 6H, 2, 3, 4, 5, 6, 7H), 3.85—3.96 (m, 4H, 1ꢀ, 3ꢀ-
CH2), 3.34—3.51 (s, 1H, 2ꢀ-OH), 2.83—2.96 (m, 8H, 2ꢄ, 3ꢄ,
In a separate series of experiments on anesthetized nor-

1686
Vol. 27, No. 10
motensive rats, the effect of test compounds (100 mg kgꢃ1) on
the pressor response to adrenaline (2 mg kgꢃ1), noradrenaline
(3 mg kgꢃ1), and isoprenaline (150 mg kgꢃ1) was investigated.
Pressor responses of adrenaline, noradrenaline and isopre-
naline injected intravenously were obtained before and at
5 min after administration of the test compounds. Results are
presented in Table 4.
regression line and the SE of the slope were then calculated.
These data are shown in Table 2. Some of these derivatives
showed a high degree of protection against MES-induced
seizures. But they were found to be less effective against
scMet-induced seizures. Compound 20 was the best in the
MES test, having an ED50 of 43.6 mg kgꢃ1. In the MES test,
the ED50 of compounds 14 (44.3 mg kgꢃ1), 1 (45.8 mg kgꢃ1),
2 (46.7 mg kgꢃ1) and 13 (51.7 mg kgꢃ1) were compared fa-
vorably with phenytoin.
RESULTS AND DISCUSSION
The following structure–activity relationships were ob-
served. In the ethane series (1—12), compounds 2, 10, 11
and 12 were found to have a high degree of protection
against MES-induced seizures. Among the heterocyclic sub-
stituted compounds, the piperazino and imidazole substitu-
tion at the 2ꢀ position showed more protection than the other
substitutions. Unsubstituted piperazine showed more protec-
tion than the substituted piperazines. The increase in the car-
bon atom number at the 4th position of piperazine influenced
the activity remarkably. In the propanol series (12—20), only
compounds 13, 14, 19 and 20 were found to have a high de-
gree of protection against MES-induced convulsions. 4-
phenylpiperazino substituted compounds at the 3ꢀ position
showed higher protection than the other substitutions at
piperazine compounds. As with the ethane series com-
pounds, an increase in the carbon atom at the 4th position of
the nitrogen of the piperazine greatly influenced the anticon-
vulsant activity.
The initial evaluation (phase I) of anticonvulsant activity
of synthesized compounds is presented in Table 1. The com-
pounds were administered intraperitoneally at three doses
(30, 100, 300 mg kgꢃ1). Three tests were performed for each
compound: maximal electroshock (MES) induced convul-
sions, subcutaneous Metrozol (sc-Met) induced convulsions
and the rotarod neurotoxicity test (Tox).
As a result of preliminary screening, compounds 2, 10, 11,
12, 13, 14, 17, 19 and 20 were considered for the phase II tri-
als. This provides an evaluation of the median effective dose
(ED50) and median neurotoxic dose (TD50). The slope of the
Table 1. Anticonvulsant and Toxicity Screening Data in Mice (i.p.)
MESa,b)
30 min
scMetc)
30 min
Rotarod toxicityd)
Compound
4 h
4 h
30 min
4 h
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
ꢅꢅ
ꢅꢅ
ꢅ
ꢃ
ꢅ
ꢅ
ꢅ
ꢅ
ꢅ
ꢅꢅ
ꢅꢅ
ꢅꢅ
ꢅꢅ
ꢅꢅ
ꢅ
ꢅ
ꢅꢅ
ꢅ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢅ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢅ
ꢃ
ꢅ
ꢅ
ꢅ
ꢅ
ꢃ
ꢅ
ꢅ
ꢃ
ꢅ
ꢃ
ꢅ
ꢅ
ꢅ
ꢅ
ꢅ
ꢅ
ꢃ
ꢃ
ꢅ
ꢃ
ꢅ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢅ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢅ
ꢅ
ꢅ
ꢅ
ꢃ
ꢅ
ꢅꢅ
ꢅ
ꢅꢅ
ꢅ
ꢅ
ꢅ
ꢃ
ꢅ
ꢅ
ꢃ
ꢅ
ꢃ
ꢅ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢅ
ꢃ
ꢅ
ꢃ
Table 2. Quantitative Anticonvulsant Data in Mice (Test Drug Adminis-
tered i.p.)
a)
ED50
Compound
b)
MES
ScMet
TD50
1
2
10
11
12
13
14
17
45.8 (33—52)
46.7 (34.54)
182 (177—253)
ꢆ250
158 (135—186)
214 (182—247)
95 (83—109)
83.5 (69—97)
78.3 (64—83)
64.6 (52—78)
51.7 (41—63)
44.3 (33—51)
74.7 (59—91)
54.2 (40—69)
43.6 (32—52)
9.9 (6.3—13.1)
9.2 (6.9—11.7)
264 (236—297)
220 (203—243)
248 (219—272)
169 (145—199)
204 (182—232)
ꢆ225
193 (167—221)
176 (155—196)
ꢆ150
83 (69—98)
192 (169—218)
186 (168—207)
173 (155—196)
175 (152—206)
230 (199—263)
164 (145—179)
69.8 (57.2—80.7)
74.4 (59.1—87.5)
408 (364—437)
19
20
ꢃ
ꢃ
ꢅꢅ
ꢅꢅ
Phenytoin
Carbamazepine
Valproate
ꢆ300
ꢆ125
157 (133—185)
ꢅ
a) Key: ꢅꢅꢅꢂactivity at 30 mg kgꢃ1, ꢅꢅꢂactivity at 100 mg kgꢃ1, ꢅꢂactivity at
300 mg kgꢃ1, ꢃꢂno activity at 300 mg kgꢃ1
b) Maximal electroshock seizure test.
.
c) Subcutaneous pentylenetetrazole seizure test. d) Neurologic toxicity (rotarod)
a) Doses measured in mg kgꢃ1 at the peak effect. b) Doses (mg kgꢃ1) determined
test.
by rotarod test at the time of peak neurotoxic effect.
Table 3. Hypotensive Activity of Tested Compounds in Anesthetized Normotensive Rats (Mean Arterial Pressure)
Time of observation (min)
Compounda)
Before
10
30
60
120
13
14
15
16
17
18
19
20
113.6ꢁ3.5
115.4ꢁ2.3
115.1ꢁ2.1
108.3ꢁ7.2
121.9ꢁ3.9
110.8ꢁ3.5
118.4ꢁ7.3
117.3ꢁ3.4
78.5ꢁ2.3***
98ꢁ2.6*
71.8ꢁ5.1**
90.8ꢁ5.3*
93.5ꢁ6.3*
88.8ꢁ3.9*
86.5ꢁ5.7***
83.5ꢁ2.3*
92.5ꢁ3.1**
91.5ꢁ5.3*
65.3ꢁ3.4**
87.8ꢁ4.3**
100.8ꢁ7.5*
93.8ꢁ3.7*
88.7ꢁ2.6**
86.2ꢁ1.9*
85ꢁ3.5*
80.7ꢁ4.1*
99.8ꢁ3.7*
111.5ꢁ2.5*
105.9ꢁ4.5**
114.5ꢁ2.5***
99.3ꢁ1.2*
96.2ꢁ3.8**
93.8ꢁ3.1*
99.2ꢁ4.3*
95.5ꢁ3.7*
104.9ꢁ6.9*
103.2ꢁ7.2*
98.9ꢁ3.9*
104.3ꢁ4.4**
84.9ꢁ6.1*
a) Dose in 80 po (mg kgꢃ1). The data were the means of 5—6 experiments S.E.M. * pꢇ0.05; ** pꢇ0.02; *** pꢇ0.01.

October 2004
1687
Table 4. Antihypertensive Activity of Tested Compounds in Anesthetized
Normotensive Rats (Mean Arterial Pressure)
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