Role of quinoline and indole-based heterocycles in revolutionizing Alzheimer's drug discovery: Promising futuristic structural designs.

Abstract

Imagine a world where memories fade, loved ones become strangers, and the sense of self dissolves. This is the harsh reality for nearly 50 million people worldwide suffering from Alzheimer's disease (AD), a progressive neurodegenerative disorder marked by memory loss, cognitive decline, and behavioral changes. With global prevalence on the rise, the demand for effective therapies is urgent. Yet, despite decades of research, a cure remains out of reach, and current treatments offer only temporary relief, failing to address the root causes of the disease. AD's complex pathology, including amyloid-β plaque accumulation, tau protein tangles, oxidative stress, and neurotransmitter deficits, calls for innovative, multitargeted therapeutic approaches. In this pursuit, heterocyclic compounds have emerged as promising candidates. These molecules, defined by ring structures containing heteroatoms, exhibit broad biological activity. Among them, quinoline and indole derivatives have shown particular promise for their anti-Alzheimer's potential. This review explores the therapeutic relevance of these 2 heterocyclic scaffolds, examining their ability to counter key AD hallmarks and highlighting the link between their chemical structure and biological efficacy. By analyzing structure-activity relationships, we aim to spotlight compounds with the greatest potential to advance AD treatment. SIGNIFICANCE STATEMENT: Quinoline and indole derivatives showed strong dual cholinesterase inhibition and good blood-brain barrier permeability. Piperazine- and piperidine-based hybrids improved bioavailability and central nervous system penetration. Heterocyclic fusion and bioisosteres improved metabolic stability and solubility.