Abstract
Two novel series of 3,4-dihydroisoquinolin with heterocycle derivatives (4a–t and 9a–e) were synthesized and evaluated for their anticonvulsant activity using maximal electroshock (MES) test and pentylenetetrazole (PTZ)-induced seizure test. All compounds were characterized by IR, 1H-NMR, 13C-NMR, and mass spectral data. Among them, 9-(exyloxy)-5,6-dihydro-[1,2,4]triazolo[3,4-a]isoquinolin-3(2H)-one (9a) showed significant anticonvulsant activity in MES tests with an ED50 value of 63.31 mg/kg and it showed wide margins of safety with protective index (PI > 7.9). It showed much higher anticonvulsant activity than that of valproate. It also demonstrated potent activity against PTZ-induced seizures. A docking study of compound 9a in the benzodiazepine (BZD)-binding site of γ-aminobutyric acidA (GABAA) receptor confirmed possible binding of compound 9a with the BZD receptors.
Highlights
Epilepsy is the second most common chronic neurological disorder, and can greatly affect the quality of life of patients
We reported that 7-alkoxyl-4,5-dihydro-[1,2,4]triazolo[4,3-a]quinoline derivatives (I) and 7-alkoxy-4,5-dihydro-[1,2,4]triazolo[4,3-a]quinoline-1(2H)-ones (II) exhibited potential anticonvulsant activity (Figure 1)
We believe that its underlying mechanism may be related to GABAA and that in vitro studies are necessary to confirm this
Summary
Epilepsy is the second most common chronic neurological disorder, and can greatly affect the quality of life of patients. Even in a high-income country, such as the US, epilepsy leads to 42,000 deaths every year [3]. We attempted to develop novel efficacious anticonvulsants to improve the quality of life for patients with epilepsy. We reported that 7-alkoxyl-4,5-dihydro-[1,2,4]triazolo[4,3-a]quinoline derivatives (I) and 7-alkoxy-4,5-dihydro-[1,2,4]triazolo[4,3-a]quinoline-1(2H)-ones (II) exhibited potential anticonvulsant activity (Figure 1). In compound series I, compound 7-(4-fluorobenzyloxy)-4,5-dihydrotriazolo[4,3-a]quinoline was found to be the most potent in protecting against MES-induced seizures, with an ED50 value of 11.8 mg/kg. In compound series II, 8-hexyloxy-4,5-dihydro-[1.2.4]triazole quinoline-1-one was the most potent anticonvulsant, with an ED50 value of 17.17 mg/kg in the maximal electroshock (MES) test [7,8].
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