Anti-Amyloid Aggregation Activity of Isatin Derivatives: An Implication for Alzheimer's Drug Discovery

Alzheimer's disease (AD) is marked by the aggregation of amyloid-beta (Aβ) peptides into plaques, which are key contributors to neurodegeneration and cognitive decline. The search for effective inhibitors of Aβ aggregation is critical for AD drug discovery, and isatin derivatives have emerged as promising candidates due to their diverse biological activities. This study explores the anti-amyloid aggregation potential of various isatin derivatives using a suite of computational tools. Molecular docking studies performed using PyRx software revealed significant binding interactions between the isatin derivatives and Aβ peptides, identifying compounds with high binding affinities. SwissADME was employed to evaluate the pharmacokinetic properties of the derivatives, ensuring their drug-likeness and oral bioavailability. PASS (Prediction of Activity Spectra for Substances) analysis predicted these derivatives to be strong inhibitors of Aβ aggregation. Molinspiration was used to assess molecular properties such as bioactivity scores, further validating their potential as drug-like compounds. The results of these computational analyses highlight several isatin derivatives with potent anti-amyloid activity, supported by favorable docking scores and optimal pharmacokinetic profiles. Structure-activity relationship (SAR) analysis identified key functional groups that enhance the anti-aggregation activity, with some derivatives demonstrating maximum inhibition of Aβ fibril formation. This study suggests that isatin derivatives are strong candidates for Alzheimer's drug discovery, offering a promising avenue for the development of novel anti-amyloid agents based on in silico evaluation. Among the three Isatin derivatives, 3-[2-(4-fluorophenyl) hydrazinyl]indol-2-one obtained the best docking score and hence it can be considered as a promising compound for Alzheimer's treatment.