Dual Inhibitors of Acetylcholinesterase and Monoamine Oxidase-B for the Treatment of Alzheimer's Disease

Abstract

Alzheimer's disease (AD) is a multi-factorial neurodegenerative disease with a complex pathomechanism that can be best treated with multi-target medications. Among the possible molecular targets involved in AD, acetylcholinesterase (AChE) and monoamine oxidase B (MAO-B) are well recognized because they control the neurotransmitters responsible for memory processes. This review discusses the current understanding of AD pathology, recent advances in AD treatment, and recent reports in the field of dual AChE/MAO-B inhibitors for treating AD. We provide a classification of dual inhibitors based on their chemical structure and describe active compounds belonging to, i.a., chalcones, coumarins, chromones, imines, and hydrazones. Special emphasis is given to the computer-aided strategies of dual inhibitors design, their structure-activity relationships, and their interactions with the molecular targets at the molecular level.

Keywords: Acetylcholine Esterase (AChE); Monoamine Oxidase-B (MAO-B); SAR; dual inhibitors; molecular modeling.

Figure 1

Schematic illustration of multiple pathogenesis hypotheses implicated in Alzheimer’s disease, including the following: (1) Aβ plaque hypothesis, characterized by the accumulation of Aβ peptides leading to the build-up of plaques; (2) cholinergic hypothesis, proposing deficiency of ACh neurotransmitter in the synaptic cleft; (3) the tau hypothesis, where hyperphosphorylation of tau proteins results in the formation of NFTs; (4) the mitochondrial cascade hypothesis, based on the mitochondrial dysfunction; and (5) oxidative stress hypothesis, proposing a high concentration of ROS and energy imbalance in the system as an early hallmark of AD progression.

Figure 2

Structures of AChE inhibitors and NMDA antagonist used for treating AD.

Figure 3

ALZ-801 (valiltramiprosate).

Figure 4

The crystallographic structures of AChE(PDB: 4EY6) (A) and MAO-B (PDB: 2V5Z) (B). Important sub-sites in the AChE active site are highlighted. The catalytic active site (CAS) is characterized by the presence of Ser203, His447, and Glu334; whereas the peripheral anionic site (PAS) helps in the entry and orientation of the ligand and majorly contains aromatic residues. Binding cavity of MAO-B is shown in surface representation.

Scheme 1

Ellman’s method.

Figure 5

Colored indicator substances.

Scheme 2

AChE activity test using Fast Blue B [87].

Scheme 3

AChE activity test using indoxyl acetate as a substrate [88].

Scheme 4

MAO-B inhibition assays with kynuramine [92].

Scheme 5

MAO-B inhibition assays with Amplex Red.

Figure 6

Rasagiline and selegiline.

Figure 7

Chalcone derivatives [101,102].

Figure 8

Structure of chalcone scaffold and phenol Mannich bases.

Figure 9

Mannich bases [104,105,106].

Scheme 6

Cyclization of the chalcone scaffold [107].

Figure 10

Impact of the chalcone cyclization on AChE- and MAO-B-inhibitory activities [72].

Figure 11

The site of the attachment of substituents in the modification of coumarins.

Figure 12

Coumarins derivatives [109,110,111].

Figure 13

Coumarin-based ethers [112,113,114].

Figure 14

Chromone derivatives [115,116,117,118,119,120].

Figure 15

Structural modifications of chromone-based inhibitors.

Figure 16

Imine and hydrazone derivatives [121,122,123,124,125].

Figure 17

Isothiazolidinone derivatives [126].

Figure 18

Aromatic heterocyclic-based derivatives [84,128,129,130,131].

Figure 19

Diverse scaffold-based dual inhibitors [131,132,133,134].

Figure 20

Structure of a balanced dual inhibitor 52 based on chromone-4-one.

Figure 21

Selective inhibitors of the MAO-B enzyme based on chromen-4-one [146].

Figure 22

Structure of benzimidazole 55 studied in complex with AChE [83].

Figure 23

Example of tested inhibitors for the treatment of AD [143].