Synthetic strategies of functionalized pyridines and their therapeutic potential as multifunctional anti-Alzheimer's agents

Abstract

Pyridines are renowned as privileged azaheterocycle scaffolds as they are found in diverse natural products, active pharmaceuticals, and functional materials. Pyridine-derived pharmaceuticals like omeprazole, netupitant, abemaciclib, lorlatinib, apalutamide, ivosidenib, delavirdine, cetylpyridinium chloride, zolimidine alpidem, etc., have displayed a broad spectrum of pharmacological activities. Owing to the continued importance of the pyridine core in both biological and chemical fields, for well over a century, chemists have developed a variety of synthetic methodologies for functionalized pyridine analogues like 2-aminocyanopyridines, pyridinium derivatives, imidazopyridines, bis-imidazopyridines, pyrazolopyridines, and furopyridines ranging from traditional condensation strategies to transition-metal-catalyzed cyclization and cross-coupling procedures. Alzheimer's disease (AD) is an incurable chronic and relentlessly progressive neurodegenerative disorder, marked by a significant decline in cognition with loss of memory and executive functions. A disease-modifying drug that stops or delays cognitive decline in AD represents an enormous unmet medical need to date. Historically, functionalized pyridines were found to be multifunctional anti-AD agents with a wide range of biological activities such as inhibition of acetylcholinesterase, and butyrylcholinestrase; neuroprotective and antioxidant activities, anti-Aβ fibril formation, anti-GSK Tau aggregation, and 5-HT4R and PDE4D inhibition. Hence, this chapter covers various synthetic methods of privileged pyridine scaffolds and their anti-AD properties to prove them as forefront molecular prototypes that are capable of interacting with relevant targets in neurodegeneration process of AD.