Synthesis, Anticonvulsant and Antihypertensive Activities of 8

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Quinolines were reported to possess antibacterial,1) anti- fungal,2) immunosuppressive,3) ... envisaged that chemical entities with both quinoline and aryl-.
October 2004

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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-(3-(4-phenylpiperazino)-2-hydroxypropyloxy)quinoline) was potent in both series as an anticonvulsive agent. 13 (8-(3-piperazino)-2-hydroxypropyloxyquinoline) and 14 (8-(3-imidazolo)-2-hydroxypropyloxyquinoline) showed very good anticonvulsant activities in the propanol series of compound, whereas in the ethane series, 1 (8-(2-piperazinoethanoxy)quinoline) and 2 (8-(2-imidazolo-ethanoxy)quinoline) were the most active as anticonvulsive agents. Compounds 20 (8-(3-(4-phenylpiperazino)-2-hydroxypropyloxy)quinoline), 13 (8-(3-piperazino)-2-hydroxypropyloxyquinoline) and 19 (8-(3-(4-ethylpiperazino)-2-hydroxypropyloxy)quinoline) have shown excellent antihypertensive 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) antifungal,2) immunosuppressive,3) analgesic,4) vasorelaxing,5) antiplasmodial,6) anticancer7,8) and PDE4 inhibitory9) activities. Aryloxypropanolamines were reported to be associated with b -adrenergic blocking,10,11) CNS depressant12) and hypotensive13) 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 heteroaryl and propanolamine/aminoethane combination, it was envisaged that chemical entities with both quinoline and aryloxypropanolamine/aminoethane moieties would result in compounds with interesting biological activities. In the present study, we report the synthesis, the anticonvulsant and antihypertensive activities, and the structure– activity relationship of 2-(3-substituted-2-hydroxy-propyloxy/2-substituted-ethanoxy)-quinoline. The compounds were characterized by IR, 1H-NMR spectral and elemental analysis. The compounds were investigated for anticonvulsant and antihypertensive activities. CHEMISTRY 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. 1H-NMR 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 0.4% of the theoretical values. 1H-NMR and IR spectra * To whom correspondence should be addressed.

were consistent with the assigned structures. Synthesis of 8-(2-Chloroethanoxy)quinoline 8-Hydroxy quinoline was reacted with 1,2-dichloroethane, as reported 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). Yield52%, mp 68—70 °C. 1HNMR (CDCl3) d : 8.05—7.86 (m, 6H, 2, 3, 4, 5, 6, 7H), 3.82—4.13 (s, 4H, CH2–CH2). IR (KBr) cm1: 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-(2-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). 8-(2-Piperazino-ethanoxy)quinoline 1: Yield49%, mp 140 °C, 1H-NMR (CDCl3) d : 7.97—8.23 (m, 6H, 2, 3, 4, 5, 6, 7H), 5.25—5.45 (m, 1H, NH), 4.34—4.59 (m, 4H, 2CH2), 2.49—2.73 (m, 8H, 2, 3, 5, 6-CH2). IR (KBr) cm1: 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. 8-(2-Imidazoyl-ethanoxy)quinoline 2: Yield47%, mp 235 °C. 1H-NMR (CDCl3) d : 8.13—8.34 (m, 6H, 2, 3, 4, 5, 6, 7H), 5.34—5.49 (m, 1H, 2CH), 5.02—5.24 (m, 1H, 4, 5 (–CH)), 3.88—4.05 (m, 4H, 2CH2). IR (KBr) cm1: 1445

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© 2004 Pharmaceutical Society of Japan

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(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, 70.63; H, 5.69; N, 17.75. 8-(2-Diphenylamino-ethanoxy)quinoline 3: Yield49%, mp 58 °C. 1H-NMR (CDCl3) d : 8.18—8.27 (m, 6H, 2, 3, 4, 5, 6, 7H), 6.11—6.23 (m, 10H, (C6H5)2), 4.42—4.65 (m, 4H, 2CH2). IR (KBr) cm1: 3112 (C–H), 1423 (C–N), 1373 (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, 5.53; N, 8.45. 8-(2-Diethanolamino-ethanoxy)quinoline 4: Yield59%, mp 147 °C. 1H-NMR (CDCl3) d : 7.92—8.14 (m, 6H, 2, 3, 4, 5, 6, 7H), 4.19—4.37 (m, 4H, 2CH2), 3.27—3.41 (s, 2H, 2(–OH)2), 2.76—2.93 (m, 8H, (C2H4)2). IR (KBr) cm1: 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; N, 10.14. Found: C, 64.93; H, 7.56; N, 10.43. 8-(2-Phenylamino-ethanoxy)quinoline 5: Yield64%, mp 205 °C. 1H-NMR (CDCl3) d : 7.98—8.23 (m, 6H, 2, 3, 4, 5, 6, 7H), 5.35—5.59 (m, 1H, NH), 5.02—5.28 (m, 5H, C6H5), 4.21—4.39 (m, 4H, 2CH2). IR (KBr) cm1: 1426 (C–N), 1310 (N–H), 1156 (C–O), 849, 790 (Ar–H). Anal. Calcd for C17H16N2O: C, 77.27; H, 6.06; N, 10.6. Found: C, 77.58; H, 6.35; N, 10.89. 8-(2-(4-Nitrophenylamino)-ethanoxy)quinoline 6: Yield39%, mp 64 °C. 1H-NMR (CDCl3) d : 8.11—8.34 (m, 6H, 2, 3, 4, 5, 6, 7H), 5.19—5.35 (m, 1H, NH), 4.92—5.05 (m, 4H, C6H4), 4.32—4.51 (m, 4H, 2CH2). IR (KBr) cm1: 1417 (C–N), 1319 (N–H), 1128 (C–O), 882, 795 (Ar–H). Anal. Calcd for C17H15N3O3: C, 66.01; H, 4.85; N, 13.59. Found: C, 65.79; H, 4.98; N, 13.25. 8-(2-(4-Hydroxyphenylamino)-ethanoxy)quinoline 7: Yield55%, mp 70 °C. 1H-NMR (CDCl3) d : 8.03—8.12 (m, 6H, 2, 3, 4, 5, 6, 7H), 6.23—6.41 (m, 1H, OH), 5.69—5.81 (m, 1H, NH), 5.35—5.49 (m, 4H, C6H4), 4.21—4.39 (m, 4H, 2CH2). IR (KBr) cm1: 3415 (O–H), 3212 (C–H), 1421 (C–N), 1383 (N–H), 1151 (C–O), 881, 796 (Ar–H). Anal. Calcd for C17H16N2O2: C, 72.85; H, 5.71; N, 10.0. Found: C, 72.67; H, 5.97; N, 10.32. 8-(2-(4-Bromophenylamino)-ethanoxy)quinoline 8: Yield39%, mp 118 °C. 1H-NMR (CDCl3) d : 7.92—8.14 (m, 6H, 2, 3, 4, 5, 6, 7H), 5.74—5.89 (m, 1H, NH), 5.15— 5.39 (m, 4H, C6H4), 4.18—4.36 (m, 4H, 2CH2). IR (KBr) cm1: 1412 (C–H), 1372 (C–N), 1132 (C–O), 889, 792 (Ar–H). Anal. Calcd for C17H15N2OBr: C, 59.49; H, 4.37; N, 8.16. Found: C, 59.23; H, 4.14; N, 8.47. 8-(2-(2-Aminophenylamino)-ethanoxy)quinoline 9: Yield63%, mp 260 °C. 1H-NMR (CDCl3) d : 7.76—7.92 (m, 6H, 2, 3, 4, 5, 6, 7H), 6.34—6.12 (m, 1H, NH), 5.81— 5.96 (m, 2H, NH2), 5.56—5.79 (m, 4H, C6H4), 4.21—4.39 (m, 4H, 2CH2). IR (KBr) cm1: 1434 (C–H), 1392 (C–N), 1181 (C–O), 882, 795 (Ar–H). Anal. Calcd for C17H17N3O: C, 73.11; H, 6.09; N, 15.05. Found: C, 73.45 H, 6.31; N, 15.37. 8-(2-(4-Methylpiperazinyl)-ethanoxy)quinoline 10: Yield52%, mp 112 °C. 1H-NMR (CDCl3) d : 7.85—7.97 (m, 6H, 2, 3, 4, 5, 6, 7H), 4.02—4.21 (m, 4H, 2CH2), 2.47— 2.61 (m, 8H, 2, 3, 5, 6-CH2), 2.24—2.35 (s, 3H, CH3). IR (KBr) cm1: 1442 (C–H), 1376 (C–N), 1151 (C–O), 875, 784 (Ar–H). Anal. Calcd for C16H21N3O: C, 70.84; H, 7.74; N, 15.49. Found: C, 70.52; H, 7.97; N, 15.16.

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8-(2-(4-Ethylpiperazinyl)-ethanoxy)quinoline 11: Yield36%, mp 129 °C. 1H-NMR (CDCl3) d : 7.67—7.83 (m, 6H, 2, 3, 4, 5, 6, 7H), 4.51—4.65 (m, 4H, 2CH2), 2.23— 2.4 (m, 8H, 2, 3, 5, 6-CH2), 2.15—2.23 (s, 5H, C2H5). IR (KBr) cm1: 1447 (C–H), 1344 (C–N), 1147 (C–O), 868, 753 (Ar–H). Anal. Calcd for C17H23N3O: C, 71.57; H, 8.07; N, 14.73. Found: C, 71.22; H, 7.78; N, 15.06. 8-(2-(4-Phenylpiperazinyl)-ethanoxy)quinoline 12: Yield41%, mp 143 °C. 1H-NMR (CDCl3) d : 7.3—7.44 (m, 6H, 2, 3, 4, 5, 6, 7H), 6.12—6.23 (s, 4H, C6H4), 4.53—4.68 (m, 4H, 2CH2), 2.46—2.57 (m, 8H, 2, 3, 5, 6-CH2). IR (KBr) cm1: 1414 (C–H), 1363 (C–N), 1171 (C–O), 834, 736 (Ar–H). Anal. Calcd for C21H23N3O: C, 75.67; H, 6.9; N, 12.61. Found: C, 75.36; H, 7.25, N, 12.36. Synthesis of 2-(2,3-Epoxypropyloxy)quinoline 8-Hydroxyquinoline was reacted with epichlorohydrin, as reported by us earlier.15) A mixture of 8-hydroxyquinoline (0.13 mol), epichlorohydrin (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 using ethanol–ether (1 : 1). Yield43%, mp 234 °C. 1H-NMR (CDCl3) d : 8.13— 8.28 (m, 6H, 2, 3, 4, 5, 6, 7H), 3.43—3.61 (d, J4.2 Hz, 2H, 3-CH2), 3.28—3.4 (d, J4.9 Hz, 2H, 1-CH2), 2.25—2.39 (m, 1H, 2-CH). IR (KBr) cm1: 1453 (C–H), 1235 (epoxide C–O), 1124 (ether C–O), 842, 787, (Ar–H). Anal. Calcd for C12H11NO3: C, 66.35; H, 5.06; N, 6.45. Found: C, 66.66; H, 5.37; N, 6.77. General Method of Synthesis for 13 to 20 A mixture of 8-(2,3-epoxypropyloxy)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 (13, 17), 1 : 1 ethanol–diethyl ether (15, 18, 19), 1 : 1 chloroform–diethyl ether (14, 20), and 1 : 1 methanol–diethyl ether (16). 8-(3-Piperazinyl-2-hydroxypropyloxy)quinoline 13: Yield49%, mp 78 °C. 1H-NMR (CDCl3) d : 7.28—7.46 (m, 6H, 2, 3, 4, 5, 6, 7H), 6.68—6.89 (s, 1H, –NH), 3.81—3.98 (m, 4H, 1, 3-CH2), 3.53—3.7 (s, 1H, 2-OH), 2.65—2.82 (m, 8H, 2, 3, 5, 6-CH2), 1.42—1.56 (m, 1H, 2-CH). IR (KBr) cm1: 1434 (C–H), 1378 (C–N), 1154, 1063 (C–O) 836, 785 (Ar–H). Anal. Calcd for C16H21N3O2: C, 66.89; H, 7.31; N, 14.63. Found: C, 66.68; H, 7.59; N, 14.95. 8-(3-Imidazolyl-2-hydroxypropyloxy)quinoline 14: Yield57%, mp 149 °C. 1H-NMR (CDCl3) d : 7.46—7.69 (m, 6H, 2, 3, 4, 5, 6, 7H), 6.61—6.82 (m, 2H, 2-CH), 6.15—6.34 (m, 2H, 4, 5-CH), 3.76—3.91 (m, 4H, 1, 3CH2), 3.47—3.65 (s, 1H, 2-OH), 1.77—1.93 (m, 1H, 2CH). IR (KBr) cm1: 1423 (C–H), 1376 (C–N), 1174, 1074 (C–O) 857, 775 (Ar–H). Anal. Calcd for C15H15N3O2: C, 66.91; H, 5.57; N, 15.61. Found: C, 66.62; H, 5.35; N, 15.29. 8-(3-Diphenylamino-2-hydroxypropyloxy)quinoline 15: Yield53%, mp 170 °C. 1H-NMR (CDCl3) d : 7.57—7.8 (m, 6H, 2, 3, 4, 5, 6, 7H), 6.45—6.59 (s, 1H, –NH), 6.12—6.27 (m, 10H, (C6H5)2), 3.65—3.92 (m, 4H, 1, 3-CH2), 3.23— 3.41 (s, 1H, 2-OH), 1.44—1.57 (m, 1H, 2-CH). IR (KBr) cm1: 1457 (C–H), 1346 (C–N), 1175 (C–O), 865, 778

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5, 6CH2), 2.37—2.51 (s, 3H, CH3), 1.57—1.72 (m, 1H, 2CH). IR (KBr) cm1: 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-(3-(4-Phenylpiperazino)-2-hydroxypropyloxy)quinoline 20: Yield41%, 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, 1, 3-CH2), 3.32—3.45 (s, 1H, 2-OH), 2.75—2.91 (m, 8H, 2, 3, 5, 6-CH2), 1.73—1.89 (m, 1H, 2-CH). IR (KBr) cm1: 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

Fig. 1.

Synthetic Scheme

(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-(3-Diethylamino-2-hydroxypropyloxy)quinoline 16: Yield44%, mp 139 °C. 1H-NMR (CDCl3) d : 7.23—7.51 (m, 6H, 2, 3, 4, 5, 6, 7H), 3.67—3.88 (m, 4H, 1, 3-CH2), 3.33—3.47 (s, 1H, 2-OH), 2.32—2.48 (m, 4H, 2, 3, 5, 6H), 1.56—1.71 (m, 1H, 2-CH). IR (KBr) cm1: 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-(3-(4-Hydroxyphenylamino)-2-hydroxypropyloxy)quinoline 17: Yield46%, mp 175 °C. 1H-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, 1, 3-CH2), 3.49—3.63 (s, 1H, 2-OH), 1.54—1.66 (m, 1H, 2-CH). IR (KBr) cm1: 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-(3-Methylamino-2-hydroxypropyloxy)quinoline 18: Yield54%, 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, 1, 3-CH2), 3.23—3.31 (s, 1H, 2-OH), 1.47—1.59 (m, 1H, 2-CH), 1.15—1.32 (s, 3H, CH3). IR (KBr) cm1: 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. 8-(3-(4-Ethylpiperazino)-2-hydroxypropyloxy)quinoline 19: Yield43%, mp 128 °C. 1H-NMR (CDCl3) d : 7.12— 7.32 (m, 6H, 2, 3, 4, 5, 6, 7H), 3.85—3.96 (m, 4H, 1, 3CH2), 3.34—3.51 (s, 1H, 2-OH), 2.83—2.96 (m, 8H, 2, 3,

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 252 °C, relative humidity 45—55% under a 12 h light and dark cycle. All the animals were acclimatized 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 offered 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 kg1. Antihypertensive activity of the compounds was determined in normotensive anesthetized rats. 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 administered intraperitoneally at three dose levels (30, 100, 300 mg kg1). 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 current for 0.2 s via corneal electrodes into the eyes. The protection was defined as the abolition of the hind leg and tonic maximal extension component of the seizure. The subcutaneous pentylenetetrazole (Metrozol) seizure threshold test (sc-Met) was carried out by the subcutaneous administration of pentylenetetrazole (85 mg kg1). 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 maintain equilibrium for 1 min on the rotating rod in each of three trials. The results are tabulated in Tables 1 and 2. Antihypertensive Activity23) Male Wistar normotensive rats were anesthetized with thiopental (50—75 mg kg1) by intraperitoneal injection. The right carotid artery was cannulated with a polyethylene tube filled with heparin in saline to facilitate pressure measurements using a Datamax apparatus. The studied compounds were injected in doses corresponding to IV into the caudal vein, after a 5 min stabilization period in a volume equivalent to 1 ml kg1. In a separate series of experiments on anesthetized nor-

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motensive rats, the effect of test compounds (100 m g kg1) on the pressor response to adrenaline (2 m g kg1), noradrenaline (3 m g kg1), and isoprenaline (150 m g kg1) was investigated. Pressor responses of adrenaline, noradrenaline and isoprenaline injected intravenously were obtained before and at 5 min after administration of the test compounds. Results are presented in Table 4. RESULTS AND DISCUSSION The initial evaluation (phase I) of anticonvulsant activity of synthesized compounds is presented in Table 1. The compounds were administered intraperitoneally at three doses (30, 100, 300 mg kg1). Three tests were performed for each compound: maximal electroshock (MES) induced convulsions, 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 trials. 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)

scMetc)

Rotarod toxicityd)

Compound 30 min

4h

30 min

4h

30 min

4h

                   

                   

                   

               

                   

                   

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20

 

1

a) Key: activity at 30 mg kg , activity at 100 mg kg1, activity at 300 mg kg1, no activity at 300 mg kg1. b) Maximal electroshock seizure test. c) Subcutaneous pentylenetetrazole seizure test. d) Neurologic toxicity (rotarod) test.

Table 3.

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 kg1. In the MES test, the ED50 of compounds 14 (44.3 mg kg1), 1 (45.8 mg kg1), 2 (46.7 mg kg1) and 13 (51.7 mg kg1) were compared favorably with phenytoin. The following structure–activity relationships were observed. 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 substituted compounds, the piperazino and imidazole substitution at the 2 position showed more protection than the other substitutions. Unsubstituted piperazine showed more protection than the substituted piperazines. The increase in the carbon 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 degree of protection against MES-induced convulsions. 4phenylpiperazino substituted compounds at the 3 position showed higher protection than the other substitutions at piperazine compounds. As with the ethane series compounds, an increase in the carbon atom at the 4th position of the nitrogen of the piperazine greatly influenced the anticonvulsant activity. Table 2. Quantitative Anticonvulsant Data in Mice (Test Drug Administered i.p.) ED50a) Compound ScMet

TD50b)

182 (177—253) 250 220 (203—243) 248 (219—272) 169 (145—199) 204 (182—232) 225 193 (167—221) 176 (155—196) 150 300 125 157 (133—185)

158 (135—186) 214 (182—247) 95 (83—109) 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)

MES 1 45.8 (33—52) 2 46.7 (34.54) 10 83.5 (69—97) 11 78.3 (64—83) 12 64.6 (52—78) 13 51.7 (41—63) 14 44.3 (33—51) 17 74.7 (59—91) 19 54.2 (40—69) 20 43.6 (32—52) Phenytoin 9.9 (6.3—13.1) Carbamazepine 9.2 (6.9—11.7) Valproate 264 (236—297)

a) Doses measured in mg kg1 at the peak effect. b) Doses (mg kg1) determined by rotarod test at the time of peak neurotoxic effect.

Hypotensive Activity of Tested Compounds in Anesthetized Normotensive Rats (Mean Arterial Pressure) Time of observation (min)

Compounda)

Before 10

13 14 15 16 17 18 19 20

113.63.5 115.42.3 115.12.1 108.37.2 121.93.9 110.83.5 118.47.3 117.33.4

78.52.3*** 982.6* 96.23.8** 93.83.1* 99.24.3* 95.53.7* 104.96.9* 103.27.2*

30 71.85.1** 90.85.3* 93.56.3* 88.83.9* 86.55.7*** 83.52.3* 92.53.1** 91.55.3*

a) Dose in 80 po (mg kg1). The data were the means of 5—6 experiments S.E.M. * p0.05; ** p0.02; *** p0.01.

60 65.33.4** 87.84.3** 100.87.5* 93.83.7* 88.72.6** 86.21.9* 853.5* 84.96.1*

120 80.74.1* 99.83.7* 111.52.5* 105.94.5** 114.52.5*** 99.31.2* 98.93.9* 104.34.4**

October 2004

1687

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

1)

D BP (mmHg) a)

Compound

13 14 18 19 20

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Adrenalineb)

Noradrenalinec)

Isoprenalined)

21 10 13 22 27

14 06 10 18 22

10 08 16 15 12

2) 3)

4) 5) 1

The data were the means of 5—6 experiments S.E.M. a) Dose (100 m g kg ). b) The difference between adrenaline induced an increase in BP and test compound induced a decrease in BP. c) The difference between noradrenaline induced an increase in BP and test compound induced a decrease in BP. d) The difference between isoprenaline induced an increase in BP and the test compound induced fall in BP.

b -Blockers and aryloxypropanolamines24) inhibit adenylyl cyclase, which reduces the production of c-AMP (adenosine monophosphate). c-AMP activates the phosphorylation of a hydroxyl group containing amino acids such as tyrosine, serine and threonine, which causes the enzyme to change its shape, which then causes the release of Ca2. Since b -blockers reduce c-AMP, fewer Ca2 ions are released. The propanol series of compounds may be correlated to the presence of a pharmacophore similarity to the chemical functionality present in b -adrenergic blocking agents. It may be hypothesized that the anticonvulsant activity exerted by some of the compounds is caused by blocking Ca2 channels. Calcium influx via voltage-activated Ca2 channels also plays a role in epileptogenesis and neurodegenerative events, raising the possibility that the blockade of Ca2 channels may represent the mechanism of action of these compounds. 13, 14, 18, 19 and 20 exhibited potential hypotensive activity. None of the ethane series compounds were found to be active. Among the propanol series, 4-substituted piperazino compound showed better hypotensive activity than the other heterocyclic compounds, whereas all other compounds were less active than the 4-substituted piperazino compound. Among the 4-substituted piperazino compounds, the methyl and ethyl substituted compounds were more active than the unsubstituted piperazino and phenyl compounds. To examine the mechanism of the hypotensive effects of these compounds (13, 14, 18, 19, 20), we studied their influence on the pressor responses to adrenaline, noradrenaline and isoprenaline (Table 4). Compounds 13, 19 and 20 given intravenously significantly antagonized the pressor response elicited by adrenaline. Compounds 19 and 20 significantly antagonized the pressor response to noradrenaline. 4phenylpiperazine was most active among all the compounds tested.

6)

7)

8)

9)

10) 11) 12) 13) 14) 15) 16) 17) 18) 19) 20) 21) 22)

23) 24)

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