Elsevier

Bioorganic & Medicinal Chemistry

Volume 15, Issue 21, 1 November 2007, Pages 6775-6781
Bioorganic & Medicinal Chemistry

Synthesis and anticonvulsant evaluation of 4-(4-alkoxylphenyl)-3-ethyl-4H-1,2,4-triazoles as open-chain analogues of 7-alkoxyl-4,5-dihydro[1,2,4]triazolo[4,3-a]quinolines

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Abstract

A series of 4-(4-alkoxylphenyl)-3-ethyl-4H-1,2,4-triazole derivatives was synthesized as open-chain analogues of 7-alkoxyl-4,5-dihydro[1,2,4]triazolo[4,3-a]quinolines. Their anticonvulsant activities were evaluated by the maximal electroshock test (MES test) and their neurotoxicity was evaluated by the rotarod neurotoxicity test (Tox). MES test showed that 3-ethyl-4-(4-octyloxyphenyl)-4H-1,2,4-triazole 3q was found to be the most potent with ED50 value of 8.3 mg/kg and protective index (PI = TD50/ED50) value of 5.5, but compound 3r, 3-ethyl-4-(4-octyloxyphenyl)-4H-1,2,4-triazole, exhibited better PI value of 9.3, which was much greater than PI value of the prototype drug phenytoin. For explanation of the possible mechanism of action, the compound 3r was tested in pentylenetetrazole test, isoniazid test, thiosemicarbazide test, 3-mercaptopropionic acid and strychnine test.

Graphical abstract

A series of 4-(4-alkoxylphenyl)-3-ethyl-4H-1,2,4-triazole derivatives was synthesized as open-chain analogues of 7-alkoxyl-4,5-dihydro[1,2,4]triazolo[4,3-a]quinolines. Their anticonvulsant activities were evaluated by the maximal electroshock test (MES test) and their neurotoxicity was evaluated by the rotarod neurotoxicity test (Tox).

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Introduction

Epilepsy, a ubiquitous disease characterized by recurrent seizures, inflicts more than 60 million people worldwide according to epidemiological studies.1 For epilepsy treatment, nearly 95% of clinically available drugs were approved before 1985 and they could provide satisfactory seizure control for 60–70% of patients. These drugs, however, also cause notable adverse side effects such as drowsiness, ataxia, gastrointestinal disturbance, hepatotoxicity and megaloblastic anaemia,2, 3, 4 and even life- threatening conditions.5 Research to find more effective and safer antiepileptic drugs is, therefore, imperative and challenging in medicinal chemistry.

In our previous work, a series of derivatives of 6-alkoxy-3,4-dihydro-1H-quinoline-2-ones were first found to have anticonvulsant activities, among which 6-benzyloxy-3,4-dihydro-1H-quinoline-2-one showed the strongest activity with an ED50 value of 29.6 mg/kg in the maximal electroshock test (MES) and a TD50 value greater than 300 mg/kg.6 Introduction of triazole ring to the first and second position of this 6-benzyloxy-3,4-dihydro-1H-quinoline-2-one caused a remarkable increase in the anticonvulsant activity, such as 7-benzyloxyl-4,5-dihydro[1,2,4]triazolo[4,3-a]quinoline (compound 1a), which showed ED50 values of 17.3 and 24 mg/kg in the MES and the sc-PTZ tests, respectively.7 Another derivative in the group of 7-alkoxy-4,5-dihydro[1,2,4]triazolo[4,3-a]quinoline, 7-(4-fluorobenzyloxyl)-4,5-dihydro[1,2,4]triazolo[4,3-a]quinoline (compound 1b), showed ED50 values of 11.1 and 6.7 mg/kg, protective index (PI = TD50/ED50) values of 4.6 and 8.1 in the MES and the pentylenetetrazole tests, respectively, and thus demonstrated comparable anticonvulsant potency to that of phenobarbital in the corresponding tests.8

Analyzing the relationship of anticonvulsant activity and the structure of 7-alkoxyl-4,5-dihydro[1,2,4] triazolo[4,3-a]quinoline (1), it was found that triazole ring C may be the main structure combined with receptor, aromatic ring A and 7-alkoxyl enhanced the hydrophobic ability of target compounds, thus make them more permeable to the blood–brain barrier and enhance anticonvulsant activity. So we thought that the presence of A and C ring was essential structure for the anticonvulsant activity. In this paper, we designed and prepared a series of 4-(4-alkoxylphenyl)-3-ethyl-4H-1,2,4-triazole derivatives with ring B opened and pseudocycles’ structure existing as open-chain analogue of 7-alkoxy-4,5-dihydro[1,2,4]triazolo[4,3-a]quinoline. The hypothesis was that a rotatable triazole ring may have higher affinity for the receptor and enhance their anticonvulsant activity. The new compounds were evaluated as anticonvulsant agents in experimental epilepsy models, i.e., maximal electroshock (MES) induced seizure in mice. The rotarod assay was performed in mice to evaluate the neurotoxicity of the compounds. For explaining the possible mechanism of action, the compound 3-ethyl-4-(4-octyloxyphenyl)-4H-1,2,4-triazole 3q was tested in pentylenetetrazole, isoniazid, thiosemicarbazide, 3-Mercaptopropionic Acid and strychnine induced test.

Section snippets

Synthesis

There are many methods reported to synthesize triazole derivatives. An efficient one-pot, three-component synthesis of substituted-1,2,4-triazoles has been developed by Michael,9 utilizing a wide range of substituted primary amines, acyl hydrazines and dimethylformamide dimethyl acetal. In this paper, intermediate compound 2 was prepared by the Michael method, and then compound 2 reacted with appropriate alkyl halide to produce target compounds 4-(4-alkoxylphenyl)-3-ethyl-4H-1,2,4-triazoles (3a

Conclusions

In conclusion, 4-alkoxyl-3-ethyl-4-H-1,2,4-triazoles, the open-chain analogues of 7-alkoxyl-4,5-dihydro-[1,2,4]triazolo[4,3-a]quinolines, exhibited remarkable anticonvulsant activity and lower neurotoxicity. Especially, compound 3r produced significant antagonism activity against seizures induced by pentylenetetrazole, 3-mercaptopropionic acid, thiosemicarbazide and Isoniazid, suggested that the compound 3r might have effects on GABAergic neurotransmission and activate glutamate decarboxylase

Chemistry

Melting points were determined in open capillary tubes and are uncorrected. IR spectra were recorded (in KBr) on a FT-IR1730. 1H NMR spectra were measured on AV-300 (Bruker, Switzerland), and all chemical shifts were given in ppm relative to tetramethysilane. Mass spectra were measured on an HP1100LC (Agilent Technologies, USA). Elemental analyses were performed on a 204Q CHN (Perkin-Elmer, USA). Microanalyses of C, N, and H were performed using a Heraeus CHN Rapid Analyzer. The major chemicals

Acknowledgments

This work was supported by the National Natural Science Foundation of China (No. 30460151) and Important Item Foundation of Ministry of Education P.R. China (No. 20070422029).

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