ABSTRACT
Herewith, we report the design and synthesis of a series of N-(2-oxo-2((4-oxo-2-substituted thiazolidin-3yl)amino)ethyl) benzamide derivatives 7(a-j) under microwave irradiation, based on four component pharmacophoric model to get structural prerequisite indispensable for anticonvulsant activity. The synthesized derivatives were investigated in maximal electroshock seizure (MES), subcutaneous pentylenetetrazole (sc-PTZ) induced seizure and neurotoxicity screening. All the test compounds were administered at a dose of 30, 100 and 300 mg/kg body weight at the time interval of 0.5 h and 4 h. The compounds were also evaluated for behavioral activity and toxicity study. The compound 7 h was found to be most active in MES model. The anticonvulsant screening data shows that 65% of the compounds were found active against MES model when compared to 35% sc-PTZ model. The computational parameter such as docking study, logP determination and ADME prediction were performed to exploit the results.
Subject(s)
Anticonvulsants/chemical synthesis , Benzamides/chemistry , Microwaves , Animals , Anticonvulsants/pharmacology , Anticonvulsants/therapeutic use , Benzamides/pharmacokinetics , Benzamides/therapeutic use , Binding Sites , Disease Models, Animal , Half-Life , Liver/pathology , Mice , Molecular Docking Simulation , Motor Activity/drug effects , Protein Structure, Tertiary , Seizures/drug therapy , Sodium Channels/chemistry , Sodium Channels/metabolism , Thiazolidines/chemistryABSTRACT
Two series of novel indolyl thiazolidin-4-one derivatives 4a-j and 5a-j were obtained by an ecofriendly synthetic protocol by treating a mixture of Schiff's bases (0.01 mol) with thioglycolic acid or thiolactic acid (0.01 mol) and anhydrous zinc chloride in catalytic amount in DMF as solvent under ultrasound irradiation, using an ultrasound synthesizer with a synthetic solid probe. The structures of the synthesized compounds were confirmed by IR, (1) H NMR, (13) C NMR, MS, and elemental analysis. The anticonvulsant activity and neurotoxicity of the newly synthesized compounds were established by MES and sc-PTZ model and by rotarod test, respectively, in vivo using mouse models. The actophotometer was used for the screening of behavioral activity. The compounds exhibited promising anticonvulsant activity; especially, the compounds showed maximum protection in the MES model at a dose of 100 mg/kg. Further, docking studies of the synthesized compounds were performed against the sodium channel receptor and showed good binding interactions with the receptor. A computational study was carried out to highlight the pharmacophore distance mapping, log p determination, and pharmacokinetic parameters.
Subject(s)
Anticonvulsants/chemical synthesis , Anticonvulsants/pharmacology , Drug Design , Indoles/chemical synthesis , Indoles/pharmacology , Seizures/prevention & control , Thiazolidines/chemical synthesis , Thiazolidines/pharmacology , Ultrasonics , Animals , Anticonvulsants/toxicity , Behavior, Animal/drug effects , Disease Models, Animal , Electroshock , Indoles/toxicity , Magnetic Resonance Spectroscopy , Male , Mass Spectrometry , Mice , Molecular Docking Simulation , Molecular Structure , Motor Activity/drug effects , Neurotoxicity Syndromes/etiology , Neurotoxicity Syndromes/psychology , Pentylenetetrazole , Rotarod Performance Test , Seizures/etiology , Seizures/physiopathology , Structure-Activity Relationship , Thiazolidines/toxicity , Time FactorsABSTRACT
A novel series of 2-(4-(2-amino-6-(4-substituted phenyl) pyrimidin-4-yl)-2-substituted phenoxy) acetic acid derivatives were efficiently synthesized. The synthesized compounds were evaluated for their in vivo hypolipidemic activity, using high-fat-diet-induced hyperlipidemia in rats. Some of these compounds showed significant antihyperlipidemic activity.
