ABSTRACT
Acetylcholinesterase (AChE) inhibitors are currently the most widely prescribed drugs for Alzheimer's disease. The high potential of indole compounds in medicinal chemistry led us to discover a novel series of fluoroindole compounds. The synthesis and pharmacological analysis of the difluoropyrido[4,3-b]indoles 11-34 are described. Compounds 11-34 were tested for AChE inhibition activity using a rat brain homogenate. Compounds 25-29 display a promising in vitro profile with an IC50 value range of 46-51.6 nM and show significant protective effect on scopolamine-induced amnesia. The present data indicate that compounds 25-29 may represent attractive potent molecules for the treatment of Alzheimer's disease.
Subject(s)
Acetylcholinesterase/metabolism , Amnesia/drug therapy , Carbolines/pharmacology , Cholinesterase Inhibitors/pharmacology , Animals , CHO Cells , Carbolines/chemical synthesis , Carbolines/chemistry , Cells, Cultured , Cholinesterase Inhibitors/chemical synthesis , Cholinesterase Inhibitors/chemistry , Cricetulus , Dose-Response Relationship, Drug , Humans , Molecular Structure , Structure-Activity RelationshipABSTRACT
A series of novel 1'-[2-(difluoromethoxy)benzyl]-2'H,5'H-spiro[8-azabicyclo[3.2.1]octane-3,4'-imidazolidine]-2',5'-dione substituted hydantoins (5-32) were synthesized using an appropriate synthetic route and characterized by elemental analysis and spectral data. The novel molecules were screened for anticonvulsant activity in mice by maximal electroshock (MES) and subcutaneous pentylenetetrazol (ScPTZ)-induced seizure tests. The neurotoxicity was assessed using the rotarod method. Compounds 9, 10, 18, 30, and 31 exhibited anticonvulsant potency against MES seizure and in the ScPTZ model, with lesser neurotoxicity. Some title compounds showed lesser central nervous system depression compared to phenytoin.
Subject(s)
Anticonvulsants/chemical synthesis , Azabicyclo Compounds/chemical synthesis , Imidazolidines/chemical synthesis , Spiro Compounds/chemical synthesis , Animals , Anticonvulsants/chemistry , Anticonvulsants/therapeutic use , Anticonvulsants/toxicity , Azabicyclo Compounds/chemistry , Azabicyclo Compounds/therapeutic use , Azabicyclo Compounds/toxicity , Behavior, Animal/drug effects , Imidazolidines/chemistry , Imidazolidines/therapeutic use , Imidazolidines/toxicity , Male , Mice , Molecular Structure , Motor Activity/drug effects , Rotarod Performance Test , Seizures/drug therapy , Spiro Compounds/chemistry , Spiro Compounds/therapeutic use , Spiro Compounds/toxicityABSTRACT
New 3-[(2,4-dioxo-1,3,8-triazaspiro[4.6]undec-3-yl)methyl]benzonitrile derivatives 8-37 were synthesized and their pharmacological activities were determined with the objective to better understand their structure-activity relationship (SAR) for anticonvulsant activity. All the compounds were evaluated for their possible anticonvulsant activity by maximal electroshock seizure (MES) and pentylenetetrazole (PTZ) test. Compounds 11, 18, 31, and 32 showed significant and protective effect on seizure, when compared with the standard drug valproate. The same compounds were found to exhibit advanced anticonvulsant activity as well as lower neurotoxicity than the reference drug. From this study, it is quite apparent that there are at least three parameters for the activity of anticonvulsant drugs, that is, a lipophilic domain, a hydrophobic center, and a two-electron donor.
