“…Indeed, a large number of multitarget compounds feature pharmacophoric moieties of the approved AChE inhibitors [ 29 , 30 , 31 , 32 ], even though publications on multitarget anti-AD agents based on other pharmacophores, especially naturally occurring scaffolds such as β-carbolines [ 33 ], naphthoquinones and anthraquinones [ 34 ], or chalcones [ 35 ], just to name a few of those recently reviewed, are continuously appearing. Apart from AChE, other targets and pathogenic mechanisms that, intuitively, seem to have been commonly addressed when designing multitarget anti-AD compounds are glutamante NMDA receptors [ 36 , 37 ], β-amyloid and tau aggregation [ 38 , 39 ], glycogen synthase kinase 3β (GSK-3β) [ 40 ], biometal dyshomeostasis [ 41 ], monoamine oxidases (MAOs) [ 42 ], or oxidative stress [ 43 ]. - It is usually assumed that the linked-pharmacophore strategy is the most popular design strategy, likely because AChE is thought to be the most commonly pursued target in multitarget anti-AD drug design and it is one of those proteins with binding sites buried at the bottom of a deep cavity.
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