ABSTRACT
Two series of dimethoxyindanone imbedded novel fluorinated spiropyrrolidine heterocyclic hybrids were synthesized employing two different less explored azomethine ylides and were measured for their efficiency as inhibitors for Alzheimer's disease. Among the spiropyrrolidine heterocyclic hybrids, the indole based fluorinated compound with a methoxy substituent at the meta- position of the aryl ring exhibited the utmost potent AChE and BChE inhibitory activities with an IC50 of 1.97 ± 0.19 µM and 7.08 ± 0.20 µM respectively. The plausible mechanism of inhibition on ChE receptors was unveiled via molecular docking studies.
ABSTRACT
A small library of structurally fascinating spiropyrrolidine tethered imidazole heterocylic hybrids has been synthesized regioselectively in good yields employing [bmim]Br mediated 1,3-diplar cycloaddition strategy. The new class of azomethine ylide generated in situ from l-histidine and 11H-indeno[1,2-b]quinoxalin-11-one reacts with various substituted ß-nitrostyrenes affording the spiropyrrolidine tethered imidazole heterocylic hybrids. Compounds thus synthesized were assessed for their in vitro cholinesterase (ChEs) inhibitory activities, among them compounds possessing 4-methyl and 4-methoxy substituents on the aryl ring showed potent activities with IC50 values of 2.02⯱â¯0.05 and 2.05⯱â¯0.06⯵M against AChE and 12.40⯱â¯0.14 and 11.45⯱â¯0.28⯵M against BChE enzyme, respectively. In addition, the most active compounds were performed for their molecular docking simulation and the results revealed interesting binding templates to the active site channel of cholinesterase enzymes.
Subject(s)
Acetylcholinesterase/metabolism , Butyrylcholinesterase/metabolism , Drug Design , Imidazoles/chemistry , Pyrrolidines/chemistry , Spiro Compounds/chemistry , Acetylcholinesterase/chemistry , Binding Sites , Butyrylcholinesterase/chemistry , Catalytic Domain , Cholinesterase Inhibitors/chemical synthesis , Cholinesterase Inhibitors/metabolism , Cycloaddition Reaction , Humans , Inhibitory Concentration 50 , Molecular Docking Simulation , Structure-Activity RelationshipABSTRACT
Novel highly functionalized 2-amino-4H-pyrans were achieved in excellent yields under simple grinding at ambient temperature and were assessed for their potential for treating Alzheimer's disease (AD). The 2-amino-4H-pyran bearing nitro groups on both the aryl rings showed the highest activity, with an IC50 of 1.98⯱â¯0.09⯵M against acetylcholinesterase (AChE) and 10.62⯱â¯0.21⯵M against butyrylcholinesterase (BChE), the inhibition mechanisms on AChE and BChE receptors were revealed by means of molecular docking simulations.
Subject(s)
Acetylcholinesterase/metabolism , Butyrylcholinesterase/metabolism , Cholinesterase Inhibitors/pharmacology , Pyrans/pharmacology , Cholinesterase Inhibitors/chemical synthesis , Cholinesterase Inhibitors/chemistry , Dose-Response Relationship, Drug , Humans , Molecular Docking Simulation , Molecular Structure , Pyrans/chemical synthesis , Pyrans/chemistry , Structure-Activity RelationshipABSTRACT
A regio and stereo- selective synthesis of hitherto unexplored hybrid heterocyclic system comprising spiropyrrolidine, indolizino[6,7-b]indole units in good to excellent yields, has been developed via three component 1,3-dipolar cycloaddition and concomitant trifluoroacetic acid catalyzed Pictet-Spengler cyclization with paraformaldehyde. The newly synthesized compounds were evaluated for their in vitro acetylcholinesterase (AChE) and butylcholinesterase (BChE) enzyme inhibitory activities. Most of the synthesized compounds showed good inhibitory activity, among them, compounds 4d and 4g displayed highest potency against AChE (IC50 1.88 and 1.98⯵M), and BChE (IC50 18.32 and 10.21⯵M) enzyme, respectively than the standard drug, galanthamine. Molecular modeling simulation was investigated for the most active compounds 4d and 4g on AChE and BChE enzymes to disclose the binding and orientation of these molecules into active site of respective receptors.
