Alzheimer's disease (AD) is a multifactorial neurodegenerative process whose effective treatment will require drugs that can act simultaneously on multiple pathogenic targets. Here, we present an overview of our previous multitarget studies of five groups of novel hybrid structures that combine, through spacers, five pharmacophores that have been found promising for AD treatment: γ-
carbolines,
carbazoles, tetrahydrocarbazoles,
phenothiazines, and aminoadamantanes. Biological activity of the compounds was assessed by a battery of assays. These included inhibitory potency against
acetylcholinesterase (AChE) and
butyrylcholinesterase (BChE) as indicators of potential for cognition enhancement and against
carboxylesterase (CaE) to exclude unwanted inhibition of this biotransformation pathway. Displacement of
propidium from the peripheral anionic site of AChE was determined as a predictor of anti-aggregation activity. Binding to the two sites of the
NMDA subtype of the
glutamate receptor was conducted as an additional
indicator of potential cognition enhancement and neuroprotection. Propensity to protect against mitochondrial triggers of cell death was evaluated by tests of mitochondrial potential and
calcium-induced swelling as indicators of mitochondrial permeability transition.
Antioxidant potential was measured to evaluate the tendency to prevent oxidative stress. Potential for disease modification was gauged by the ability to stimulate microtubule assembly. Finally, binding modes of conjugates to AChE and BChE were studied using quantum mechanical-assisted molecular docking. We found selective BChE inhibitors (conjugates of γ-
carbolines and
phenothiazine I, γ-
carbolines and
carbazoles II, and aminoadamantanes and
carbazoles III) as well as inhibitors of both
cholinesterases (conjugates of γ-
carbolines and
methylene blue IV and bis-γ-
carbolines with ditriazole-containing spacers V). These compounds combined potentials for cognition enhancement, neuroprotection, and disease modification. None of the conjugates exhibited high potency against CaE, thereby precluding potential drug-drug interactions from CaE inhibition. Thus, the studied compounds exhibited positive characteristics of multitarget drugs, indicating their potential for the next generation of AD
therapeutics.