Developing disease-modifying drugs for the treatment of neurodegenerative dis-eases such as Alzheimer's disease (AD) has turned out to be one of the most challenging problems of modern medicinal chemistry. AD is a chronic, progressive, neuro-degenerative disorder, which is characterized by generalized cortical atrophy, senile plaques and neurofibrillary tangles in the brain (Stelzmann et al., 1995) (Murray et al., 2011; Schultz et al., 2004). It is one of the most common dementia-centered disorder afflicting the elderly population. Structural damage to parts of the brain results in substantial cognitive and functional loss as well as memory impairment (Scheltens et al., 2021). Fig. 1 depicts the pathophysiology of AD. The disease landscape is seen to revolve around two protein cascades involving amyloid β (Aβ) and tau protein.

While the α-secretase pathway is the major amyloid precursor protein (APP) processing pathway in healthy individuals, its abnormal cleavage forms Aβ, which then triggers a series of aggregation events, ultimately leading to plaque formation. Tau is a microtubule-stabilizing protein involved in physiological axonal transport (Serrano-Pozo et al., 2011). Abnormal post-translational modification of tau, especially hyperphosphorylation leads to its dissociation from the microtubules with subsequent aggregation to form neurofibrillary tangles (NFT).

Dysregulation of brain metal ion homeostasis has been implicated in disease progression (Kumar Thakur et al., 2018), aggravating the formation of both Aβ plaques and NFT (Barnham and Bush, 2008). Elevated levels of certain metals in the brain provoke the formation of reactive oxygen species (ROS) that worsens the etiology of disease (Amit et al., 2008; Zheng et al., 2009).

Overaccumulation of Aβ and hyperphosphorylated tau aggregates on the nerves attracts resident microglia, which eventually leads to neuroinflammation and synaptic dysfunction resulting in neuronal loss (Kukharsky et al., 2015) (Nussbaum et al., 2013). The cholinergic neurons are the worst hit during the development of AD, leading to cholinergic deficit, which has been linked to cognitive impairment (dos Santos Picanco et al., 2018; Ferreira-Vieira et al., 2016).

Thus, the pathogenesis of AD is seen to involve a plethora of complex, interconnected and progressive destructive processes that lead to brain atrophy, cognitive impairment and neuropsychiatric manifestations (Scheltens et al., 2021) In light of the multi-factorial, expansive nature of the AD pathogenic landscape, these drugs merely target two downstream brain neurotransmitters. Fortunately, modulating the levels of acetylcholine and glutamate have a significant, albeit transient beneficial impact on the declining cognitive and social skills of AD patients. However, they fail to address the basic underlying neurodegenerative pathology of the disease. Despite the huge unmet medical need for curative therapies, no small molecule drug has been approved for this disease since 2004, accentuating the urgent requirement for safe, efficacious therapies that mitigate disease progression and restore cognitive and functional skills in AD patients.