ABSTRACT
A series of 3-(benzo[d]isoxazol-3-yl)-N-substituted pyrrolidine-2, 5-dione (7a-7d, 8a-8d, 9a-9c) have been prepared and evaluated for their anticonvulsant activities. Preliminary anticonvulsant activity was performed using maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) tests after intraperitoneal (ip) injection into mice, which are the most widely employed models for early identification of anticonvulsant candidate. The acute neurological toxicity (NT) was determined applying rotorod test. The quantitative evaluation after oral administration in rats showed that the most active was 3-(benzo[d]isoxazol-3-yl)-1-(4-fluorophenyl) pyrrolidine-2, 5-dione (8a) with ED50 values of 14.90 mg/kg. Similarly the most potent in scPTZ was 3-(benzo[d]isoxazol-3-yl)-1-cyclohexylpyrrolidine-2, 5-dione (7d) with ED50 values of 42.30 mg/kg. These molecules were more potent and less neurotoxic than phenytoin and ethosuximide which were used as reference antiepileptic drugs.
Subject(s)
Anticonvulsants/pharmacology , Drug Design , Isoxazoles/pharmacology , Motor Activity/drug effects , Seizures/drug therapy , Succinimides/pharmacology , Animals , Anticonvulsants/chemical synthesis , Anticonvulsants/chemistry , Dose-Response Relationship, Drug , Electroshock , Isoxazoles/chemical synthesis , Isoxazoles/chemistry , Mice , Molecular Structure , Pentylenetetrazole/administration & dosage , Rats , Rats, Wistar , Structure-Activity Relationship , Succinimides/chemical synthesis , Succinimides/chemistryABSTRACT
A series of thirty indole C-3 substituted 5-amino-6-(5-substituted-2-phenyl-1H-indol-1-yl)-4,5-dihydro-1,2,4-triazine-3(2H)-thione 5a-f, 6a-f, 7a-f, 8a-f and 9a-f were synthesized to explore prospective anticonvulsant agents. The derivative 1-(1-(5-amino-3-thioxo-2,3,4,5-tetrahydro-1,2,4-triazin-6-yl)-5-fluoro-2-phenyl-1H-indol-3-yl)ethanone (6b) had significant activity in maximal electroshock test with minimal duration of limb extension (5.40 ± 0.61 s) and quantitative median dose of 7 mg/kg. In subcutaneous pentylenetetrazole screen 1-(5-amino-3-thioxo-2,3,4,5-tetrahydro-1,2,4-triazin-6-yl)-5-fluoro-2-phenyl-1H-indole-3-sulfonamide (7b) increased the seizure latency to onset of clonus and was effective at a median dose of 35 mg/kg. An in vitro radioligand binding assay on sodium channel and γ-amino butyric acid estimation was also performed on active compounds to perceive the mechanistic procedure responsible for it action.
Subject(s)
Anticonvulsants/chemistry , Anticonvulsants/pharmacology , Triazines/chemistry , Triazines/pharmacology , Animals , Anticonvulsants/adverse effects , Anticonvulsants/chemical synthesis , Brain/drug effects , Brain/metabolism , Chemistry Techniques, Synthetic , Male , Mice , Motor Activity/drug effects , Sodium Channels/metabolism , Triazines/adverse effects , Triazines/chemical synthesis , gamma-Aminobutyric Acid/metabolismABSTRACT
Various 2-[(6-substituted-1,3-benzothiazol-2-yl)amino]-N-[5-substituted-phenyl-1,3,4-thiadiazol-2-yl]acetamides were synthesized with a prospective exploration of "lead hopping", using pharmacophoric elements for in vivo anticonvulsant activity. This yielded three potent candidates (5i, 5t, and 5u) in the preliminary screening employing the maximal electroshock seizure (MES) and the subcutaneous pentylenetetrazole (scPTZ) test, showing minimal neurotoxicity. Their quantitative study indicated an increase of nearly 2-10 times for the MES test and 7- to 67-fold for the scPTZ test in the protective index, the keystone in drug discovery for anticonvulsant activity.
