IN SILICO MOLECULAR PROPERTIES AND DOCKING STUDIES OF NEW SCHIFF BASES OF ISATIN DERIVATIVES AS PROSPECTIVE AChE INHIBITORS FOR ALZHEIMER'S DISEASE

Alzheimer's disease (AD) is a longer-term neurodegenerative condition characterized by a gradual decline in cognitive abilities, mostly as a result of neuronal loss in the hippocampus and cerebral cortex, with the frontal as well as temporal lobes showing the first alterations. The cholinergic system is pivotal in learning, memory consolidation, retrieval, and controlling aspects of cognitive function. Acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) are essential enzymes that facilitate the breakdown of acetylcholine, and the inhibition of these enzymes is a recommended treatment option for mild to moderate AD. Donepezil, rivastigmine, galantamine, and tacrine are approved by the FDA as AChE inhibitors that provide symptomatic benefit by enhancing cholinergic neurotransmission, although they do not modify disease progression and are often associated with adverse effects. Isatin, an endogenous indole derivative naturally present in mammalian tissues and abundant in the hippocampus, has emerged as a promising scaffold for designing neuroprotective agents. It has the capacity to cross via the blood-brain barrier, and its documented antioxidant, antiaggregation, enzyme-inhibitory, and neuroprotective activities make it an attractive template for developing multifunctional anti-Alzheimer compounds. This study examines a set of newly Schiff base derivatives of isatin were rationally designed based on known pharmacophoric features associated with cholinesterase inhibition. Physiochemical pharmacokinetic and toxicity properties were evaluated using Molinspiration, Swiss ADME and Osiris property explorer. Molecular docking studies were carried out using a validated docking protocol PyRx to predict the binding affinity and interaction patterns of the designed compounds with the active site of AChE. Donepezil was used as the reference standard. The ligand target interactions were analysed using Biovia Discovery studio visualizer. Docking studies demonstrated strong binding affinities toward AChE, with all proposed derivatives showing better interactions compared with the standard drug, donepezil. The results are promising, but molecular docking only gives us guesses. It needs to be tested in both in vitro and in vivo to confirm its ability to inhibit enzymes, protect neurons, and have good pharmacokinetic-properties.