Journal Article Review Ppublish
PubMed: 42295692 DOI: 10.1007/s11030-026-11618-y
Recent trends in anti-Alzheimer's potential of novel biologically active isatin analogues: synthetic strategies, structural activity relationship studies and molecular docking insights.
Mol Divers 30(6):9167-9201
Authors: Rajarshi Nath, Anhic Chakraborty, Md Jawaid Akhtar, Indrajit Maity, Swastika Ganguly, Bhupender Nehra, Sumel Ashique, Shah Alam Khan, Mohd Tariq, Soumyadeep Bakshi, Biplab Debnath, Sabina Yasmin, Habibullah Khalilullah, Md Yousuf Ansari
Affiliations
- Department of Pharmaceutical Technology, Bharat Technology, Uluberia, Howrah, West Bengal, 711316, India.
- Department of Pharmaceutical Chemistry, National University of Science and Technology, PO-620, PC-130, Azaiba, Bousher, Muscat, Sultanate of Oman.
- Department of Pharmaceutical Science and Technology, Birla Institute of Technology, Mesra, Jharkhand, 835215, India.
- Department of Pharmaceutical Sciences, Guru Jambheshwar University of Science and Technology, Hisar, Haryana, 125001, India.
- Department of Pharmaceutical Technology, School of Health and Medical Sciences, Adamas University, Kolkata, West Bengal, 700126, India.
- Department of Biotechnology, Graphic Era (Deemed to be University), Dehradun, Uttarakhand, 248002, India.
- Department of Pharmaceutical Technology, Bharat Technology, Uluberia, Howrah, West Bengal, 711316, India.
- Department of Pharmaceutical Chemistry, College of Pharmacy, King Khalid University, 62529, Abha, Saudi Arabia.
- Department of Pharmaceutical Chemistry and Pharmacognosy, College of Pharmacy, Qassim University, 51452, Buraydah, Saudi Arabia.
- Ibne Seena Pharmacy College, AMES Group of Institutions, Shahabad, Hardoi, Uttar Pradesh, 241124, India. Dr. A.P.J. Abdul Kalam Technical University, Sec-11, JankipuramVistar, Lucknow, UP, India.
Abstract
Alzheimer's disease is a progressive neurodegenerative illness i.e., characterized by cognitive decline, memory impairment, cholinergic dysfunction, oxidative stress, Aβ aggregation, tau hyperphosphorylation and neuroinflammation. Due to multifactorial nature of AD, conventional single-target therapeutic approaches exhibit limited clinical success. Hence, development of multifunctional small molecules emerged as a promising strategy for management of Alzheimer's diseases i.e., capable to modulate multiple pathological pathways simultaneously. Among various heterocyclic pharmacophores, isatin (1H-indole-2,3-dione) gained considerable attention due to its structural versatility, synthetic accessibility and broad spectrum of biological effects. Recent studies demonstrated that isatin-derived molecules possess significant inhibitory activity against acetylcholinesterase, butyrylcholinesterase, monoamine oxidase-A/B, β-secretase and amyloid aggregation pathways. Furthermore, hybridization of isatin core with pharmacologically active moieties like triazoles, coumarins, tacrine, benzylamine, piperazine, quinoline, hydrazones and melatonin afford more promising multitarget-directed ligands with improved BBB permeability, antioxidant potential and improved neuroprotective properties. Also, docking, MD simulation and ADMET analyses validated favorable binding interactions and drug-likeness characteristics of many isatin analogues. This review comprehensively summarizes recent advances in design, synthesis, biological evaluation, docking investigations and SAR studies of isatin-based anti-Alzheimer agents. In addition, key emphasis is placed on SAR trends which is responsible for promoted potency and selectivity including electron-withdrawing substitutions, linker optimization, hydrophobic interactions and dual-site binding with catalytic as well as peripheral anionic sites of target enzymes. Integration of hybrid isatin scaffolds with complementary pharmacophore combined with advanced in silico modeling and preclinical evaluation may pave the way for next-generation multifunctional therapeutics with improved efficacy and safety in treatment of Alzheimer's disease.
MeSH
Isatin, Alzheimer Disease, Molecular Biology, Therapeutics, Evolution, Molecular