A new class of anticonvulsants possessing 6 Hz activity: 3,4-Dialkyloxy thiophene bishydrazones
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2009
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Abstract
Thirty nine new 3,4-di(substituted)oxy-N2,N5-bis(substituted)thiophene-2,5-dicarbohydrazides were synthesized starting from ethyl thiodiglycolate through multi-step reactions. In the synthetic sequence, 3,4-dihydroxythiophene-2,5-diester (1) was obtained by condensing the ethyl thiodiglycolate with diethyl oxalate. It was derivatized using different alkyl halides to give disubstituted thiophene esters (2-5), which were then converted to corresponding hydrazides (6-9) following usual methods. Finally, these hydrazides, on treatment with various substituted carbonyl compounds underwent smooth condensation to yield target hydrazones (10-13). The new compounds were characterized using FT-IR, 1H NMR and 13C NMR, mass spectral and elemental analyses. The anticonvulsant activity of the title compounds was established after intraperitoneal (ip) administration in three seizure models, which include maximal electroshock (MES), subcutaneous pentylenetetrazole (scPTZ) and 6 Hz screens and their neurotoxicity was also evaluated. Compound 11f has emerged as an active compound with no neurotoxicity in this series. Also, the structure-activity relationship of the tested compounds was discussed. © 2009 Elsevier Masson SAS. All rights reserved.
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3,4 bis(benzyloxy)thiophene 2,5 dicarbohydrazide, 3,4 dibenzyloxy n 2,n 5 bis(3,4,5 trimethoxyphenylmethylene)thiophene 2,5 dicarbohydrazide, 3,4 dibenzyloxy n 2,n 5 bis(4 nitrophenylmethelene)thiophene 2,5 dicarbohydrazide, 3,4 dibenzyloxy n 2,n 5 bis(phenylmethylene)thiophene 2,5 dicarbohydrazide, 3,4 dibenzyloxy n 2,n 5 bis[(n ethyl 9h carbazole 3 yl)methylene]thiophene 2,5 dicarbohydrazide, 3,4 diheptyloxy n 2,n 5 [bis(4 hydroxy 3 methoxyphenyl)methylene]thiophene 2,5 dicarbohydrazide, 3,4 diheptyloxy n 2,n 5 bis(2 oxo 1,2 dihydro 3h indol 3 ylidene)thiophene 2,5 dicarbohydrazide, 3,4 diheptyloxy n 2,n 5 bis(4 nitrophenylmethylene)thiophene 2,5 dicarbohydrazide, 3,4 diheptyloxy n 2,n 5 bis(phenylmethylene)thiophene 2,5 dicarbohydrazide, 3,4 diheptyloxy n 2,n 5 bis[1 (2 thienyl)ethylidene]thiophene 2,5 dicarbohydrazide, 3,4 dipropyloxy n 2,n 5 bis(2 hydroxyphenylmethylene)thiophene 2,5 dicarbohydrazide, 3,4 dipropyloxy n 2,n 5 bis(4 chlorophenylmethylene)thiophene 2,5 dicarbohydrazide, 3,4 dipropyloxy n 2,n 5 bis[(n dodecyl 9h carbazole 3 yl)methylene]thiophene 2,5 dicarbohydrazide, 3,4 dipropyloxy n 2,n 5 bis[1 (3 thienyl)ethylidene]thiophene 2,5 dicarbohydrazide, 3,4 dipropyloxy n 2,n 5 bis[4 (n,n dimethyl)phenylmethylene]thiophene 2,5 dicarbohydrazide, 3,4 dipropyloxy n2,n 5 bis(2 methoxyphenylmethylene)thiophene 2,5 dicarbohydrazide, 3,4 dipropyloxy n2,n5 bis[1 (2 bromo 3 thienyl)ethylidene]thiophene 2,5 dicarbohydrazide, anticonvulsive agent, ethyl 3 [[[3,4 dipropyloxy 5 [[2 (3 ethoxy 1 methyl 3 oxopropylidene)hydrazino] carbonyl] 2 thienyl]carbonyl]hydrazono]butanoate, hydrazone derivative, n 2,n 7 bis[(4 nitrophenyl)methylene] 2,3 dihydrothieno[3,4 b][1,4]dioxine 5,7 dicarbohydrazide, n 5,n 7 bis(3,4,5 trimethoxyphenylmethylene) 2,3 dihydrothieno[3,4 b][1,4]dioxine 5,7 dicarbohydrazide, n 5,n 7 bis(phenylmethylene) 2,3 dihydrothieno[3,4 b][1,4]dioxine 5,7 dicarbohydrazide, pentetrazole, unclassified drug, animal experiment, animal model, anticonvulsant activity, article, carbon nuclear magnetic resonance, controlled study, dose response, drug discrimination, drug synthesis, electric shock, infrared spectroscopy, mass spectrometry, mouse, neurotoxicity, nonhuman, physical chemistry, polymerization, proton nuclear magnetic resonance, seizure, structure activity relation, substitution reaction, Animals, Anticonvulsants, Electroshock, Hydrazones, Male, Mice, Molecular Structure, Motor Activity, Pentylenetetrazole, Seizures, Structure-Activity Relationship, Thiophenes
Citation
European Journal of Medicinal Chemistry, 2009, 44, 11, pp. 4376-4384