Recent updates in the development of small molecules as potential clinical candidates for Alzheimer's disease: A review

Abstract

Alzheimer's disease (AD) is one of the prominent causes for disability and lowered quality of life worldwide in elderly population. It has fostered immense burden to AD patients, families and society. Burgeoning progress in the field of pathogenesis over last two decades has persuaded the investigation of novel pharmacological therapeutics that focuses towards the pathophysiological events of AD. Miscellaneous clinical trials, development and testing of interventions aimed at various targets, such as anti-tau and anti-amyloid interventions, neurotransmitter modification, neuroprotection and anti-neuroinflammation interventions, cognitive enhancement and interventions to palliate behavioural symptoms have been carried out. Despite massive efforts to find disease-modifying therapies,there lingers a vital need for continuing the advancement in progress of the AD research. This review features the new developments of small molecule compounds that will be beneficial in evolution of new AD therapies. In particular, this review briefly describes summary of mechanistic causes chiefly associated with AD and focuses on medicinal approach via small molecule inhibitors that can manage cognitive impairment and dysfunction and may combat Alzheimer's development.

Design, synthesis, and evaluation of novel bistrifluoromethyl‐based hydrazones as dual inhibitors of acetylcholinesterase and carbonic anhydrase enzymes for Alzheimer's disease

“…Alzheimer's disease (AD) is frequently characterized by dementia and is widely regarded as a complex, multifactorial conditions (Provensi et al., 2019; Umar et al., 2022). Contemporary research underscores the global scientific community's concerted efforts in elucidating, the pathological aspects of AD, including the investigation of key factors such as beta‐amyloid, tau protein, free radicals, and the inflammatory response.…”

Berberine derivatives as inhibitors of acetylcholinesterase: A systematic review

“…The cholinergic hypothesis is one of the oldest hypothesis of AD described in 1976. The ACh is the main neurotransmitter responsible for the improvement of learning and memory, and the reduced levels of ACh in the brain regions directly lead to cognitive loss (Figure 2; Kumar et al, 2022; Umar et al, 2022). ACh is degraded by two types of ChEs named as acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE; Phadke et al, 2021; Zhou & Huang, 2022a).…”

“…The current treatment option for AD is limited to AChEIs: donepezil (1), rivastigmine (2), galantamine (3), and tacrine (4, withdrawn from the market due to hepatotoxic effect), NMDA receptor antagonist: memantine (5) and recently approved Aβ modulator aducanumab (Figure 3; Marucci et al, 2021; Zhou & Huang, 2022b). Although ChEIs do not reduce the progression of the disease, they have been proven to improve the learning and memory function and are the main drugs in the management of AD (Lopes et al, 2022; Umar et al, 2022; Vogel & Schwabe, 2016). Therefore, developing novel multifunctional ChEIs is a hot topic of interest for most of the researchers across the globe (Zhou & Huang, 2021).…”

Inhibition of Acetylcholinesterase by Novel Lupinine Derivatives

“…The loss of cognitive function due to AD is associated with the rapid hydrolysis of acetylcholine by cholinesterases, including acetylcholinesterase (AChE). Consequently, inhibition of AChE has been proposed to be neuroprotective [2]. Indeed, AChE inhibitors represent the first line of symptomatic drug treatment for mild-tomoderate AD.…”