ABSTRACT
Based on the quantitative structure-activity relationship (QSAR), some novel p-aminobenzoic acid derivatives as promising cholinesterase enzyme inhibitors were designed, synthesized, characterized and evaluated to enhance learning and memory. The in vitro enzyme kinetic study of the synthesized compounds revealed the type of inhibition on the respective acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes. The in vivo studies of the synthesized compounds exhibited significant reversal of cognitive deficits in the animal models of amnesia as compared to standard drug donepezil. Further, the ex vivo studies in the specific brain regions like the hippocampus, hypothalamus, and prefrontal cortex regions also exhibited AChE inhibition comparable to standard donepezil. The in silico molecular docking and dynamics simulations studies of the most potent compound 22 revealed the consensual interactions at the active site pocket of the AChE.
Subject(s)
Alzheimer Disease/drug therapy , Cholinesterase Inhibitors/therapeutic use , Nootropic Agents/therapeutic use , para-Aminobenzoates/therapeutic use , Acetylcholinesterase/chemistry , Acetylcholinesterase/metabolism , Animals , Brain/metabolism , Butyrylcholinesterase/chemistry , Butyrylcholinesterase/metabolism , Catalytic Domain , Cholinesterase Inhibitors/chemical synthesis , Cholinesterase Inhibitors/chemistry , Cholinesterase Inhibitors/toxicity , Drug Design , Female , Kinetics , Male , Memory/drug effects , Molecular Docking Simulation , Molecular Dynamics Simulation , Molecular Structure , Nootropic Agents/chemical synthesis , Nootropic Agents/chemistry , Nootropic Agents/toxicity , Quantitative Structure-Activity Relationship , Rats , Semicarbazones/chemical synthesis , Semicarbazones/chemistry , Semicarbazones/therapeutic use , Semicarbazones/toxicity , para-Aminobenzoates/chemical synthesis , para-Aminobenzoates/chemistry , para-Aminobenzoates/toxicityABSTRACT
BACKGROUND: Nipecotic acid is considered to be one of the most potent inhibitors of neuronal and glial γ-aminobutyric acid (GABA) uptake in vitro. However, nipecotic acid does not readily cross the blood-brain barrier (BBB) following peripheral administration, owing to its hydrophilic nature. OBJECTIVE: A series of substituted acetonaphthones tethered nipecotic acid derivatives were designed and synthesized with an aim to improve the lipophilicity and the blood-brain barrier (BBB) permeation. METHODS: Synthesized compounds were tested in mice models of PTZ, pilocarpine, and DMCM induced epilepsy, in vivo. The rota-rod test was performed to determine the acute neurotoxicity of the potential leads (4a, 4b, and 4i). These potential hybrids were also evaluated for their ability to cross the BBB by an in vitro parallel artificial membrane permeability BBB assay (PAMPA-BBB). The leads were subjected to in silico molecular docking and dynamics studies on homology modelled protein of human GABA (γ-amino butyric acid) transporter 1 (GAT1) and prediction of their pharmacokinetic properties. RESULT: Amongst the synthesized derivatives, compounds 3a, 3b, 3i, 4a, 4b, and 4i exhibited increased latency of seizures against subcutaneous pentylenetetrazole (scPTZ) induced seizures in mice. Derivatives 4a, 4b, 4i were more effective compared to nipecotic acid ester counterparts 3a, 3b and 3i placing the importance of the presence of free carboxyl group in the centre. The findings revealed that 4i was comparatively more permeable (Pe= 8.89) across BBB than the standard tiagabine (Pe= 7.86). In silico studies proved the consensual interactions of compound 4i with the active binding pocket. CONCLUSION: Some nipecotic acid-acetonaphthone hybrids with considerable anti-epileptic activity, drug like properties and the ability to permeate the BBB have been successfully synthesized.
Subject(s)
Anticonvulsants/therapeutic use , Epilepsy/drug therapy , Naphthalenes/therapeutic use , Nipecotic Acids/therapeutic use , Animals , Anticonvulsants/chemical synthesis , Anticonvulsants/chemistry , Blood-Brain Barrier/metabolism , Disease Models, Animal , Drosophila , Drug Design , Female , GABA Plasma Membrane Transport Proteins/chemistry , GABA Uptake Inhibitors/chemical synthesis , GABA Uptake Inhibitors/chemistry , GABA Uptake Inhibitors/therapeutic use , Humans , Hydrophobic and Hydrophilic Interactions , Male , Mice , Molecular Docking Simulation , Molecular Dynamics Simulation , Naphthalenes/chemical synthesis , Naphthalenes/chemistry , Nipecotic Acids/chemical synthesis , Nipecotic Acids/chemistry , TiagabineABSTRACT
In 1-deoxy-xylofuranose derivatives possessing a good leaving group at 2-C, participation of allyloxy and propargyloxy substituents at 5-C results in loss of the 2-C substituent and attack of various nucleophiles at 5-C of the oxonium intermediate. Such participation of a benzyloxy or crotyloxy group leads to dioxabicyclo[2.2.1]heptane rings.
