Cholinesterases are important biological targets responsible for regulation of cholinergic transmission, and their inhibitors are used for the treatment of Alzheimer’s disease. To design new cholinesterase inhibitors, of different structure-based design strategies was followed, including the modification of compounds from a previously developed library and a fragment-based design approach. This led to the selection of heterodimeric structures as potential inhibitors. Synthesis and biological evaluation of selected candidates confirmed that the designed compounds were acetylcholinesterase inhibitors with IC₅₀ values in the mid-nanomolar to low micromolar range, and some of them were also butyrylcholinesterase inhibitors.

Among the various drug discovery methods, a very promising modern approach consists in designing multi-target-directed ligands (MTDLs). This methodology has been specifically developed for treatment of disorders with complex pathological mechanisms. One such disorder is Alzheimer's disease (AD), currently the most common multifactorial neurodegenerative disease. AD is related to increased levels of the amyloid β peptide (Aβ) and the hyperphosphorylated tau protein, along with loss of neurons and synapses. Moreover, there is some evidence pointing to the role of oxidative stress, metal ion deregulation, inflammation and cell cycle regulatory failure in its pathogenesis. There are many attractive targets for the development of anti-AD drugs, and the multi-factor nature of this disease calls for multi-target-directed compounds which can be beneficial for AD treatment. This review presents the discovery of dualand multi-acting anti-AD drug candidates, focusing on the novel design strategy and the compounds it yields - particularly hybrids obtained by linking structurally active moieties interacting with different targets. The first group of compounds includes cholinesterase inhibitors acting as dual binding site inhibitors and/or inhibitors with additional properties. These compounds are characterized by increased potency against acetylcholinesterase (AChE) and Aβ plaque formation with additional properties such as antioxidant activity, neuroprotective, and metal-complexing property, voltage-dependent calcium channel antagonistic activity, inhibitory activity against glutamate-induced excitotoxicity, histamine H3 receptor antagonism, cannabinoid CB1 receptor antagonism and β-secretase (BACE1) inhibition. A novel class of compounds represents the combination of dual BACE1 inhibitors with metal chelators, and dual modulators of γ-secretase with peroxisome proliferator-ativated receptor γ (PPARγ). We have reviewed the latest reports (2008-2011) presenting new multi-target-directed compounds in Alzheimer's disease treatment.

Alzheimers disease (AD) is a progressive neurodegenerative disorder of the central nervous system (CNS) which is the most common cause of dementia in the elderly. It is characterized by the deficits in the cholinergic system and presence of characteristic hallmarks: neurofibrillary tangles and amyloid plaques. Since the cholinergic system plays an important role in the regulation of learning and memory processes it became a target for the design of antialzheimer drugs. Cholinesterase inhibitors enhance cholinergic transmission indirectly, by inhibiting the enzyme which hydrolyses acetylcholine. It has been also demonstrated that acetylcholinesterase (AChE) is involved in the developement of amyloid plaques. Therefore, substances which are AChE inhibitors (AChEI) are the only drugs approved for the symptomatic treatment of AD. This review presents the main classes of cholinesterase inhibitors developed recently for the treatment of AD. We have started with the analogues of the existing drugs: tacrine, donepezil, rivastigmine and galantamine which are still of interest for many research groups. Among them there is a very interesting group - dual binding site inhibitors characterized by increased inhibitory potency against AChE and amyloid plaques formation. There is also a group of compounds with additional properties such as: antioxidant activity, affinity to 5-HT3 receptors, inhibition of N-methyltransferase that metabolize histamine, which can be beneficial for the treatment of AD. Furthermore there are some interesting compounds which belong to different chemical groups also of natural origin. In this review we sum up current research concerned with development of AChEIs which can be more effective in the future treatment of AD.

In Alzheimer’s disease, neurons slowly degenerate due to the accumulation of misfolded amyloid β and tau proteins. In our research, we performed extended studies directed at amyloid β and tau aggregation inhibition using in cellulo (Escherichia coli model of protein aggregation), in silico, and in vitro kinetic studies. We tested our library of 1-benzylamino-2-hydroxyalkyl multifunctional anti-Alzheimer’s agents and identified very potent dual aggregation inhibitors. Among the tested derivatives, we selected compound 18, which exhibited a unique profile of biological activity. This compound was the most potent and balanced dual aggregation inhibitor (Aβ₄₂ inhibition (inh.) 80.0%, tau inh. 68.3% in 10 μM), with previously reported in vitro inhibitory activity against hBuChE, hBACE1, and Aβ (hBuChE IC₅₀ = 5.74 μM; hBACE1 IC₅₀ = 41.6 μM; Aβ aggregation (aggr.) inh. IC₅₀ = 3.09 μM). In docking studies for both proteins, we tried to explain the different structural requirements for the inhibition of Aβ vs tau. Moreover, docking and kinetic studies showed that compound 18 could inhibit the amyloid aggregation process at several steps and also displayed disaggregating properties. These results may help to design the next generations of dual or selective aggregation inhibitors.