hAChE

hAChE-IN-9 (compound 7i) is a selective inhibitor of human acetylcholinesterase (hAChE), showcasing inhibition activities with IC50 values of 0.05 μM for AChE and 2.85 μM for BChE. This compound modulates toxic Aβ oligomers into non-toxic forms and offers antioxidant and neuroprotective effects against Aβ-induced toxicity. hAChE-IN-9 is employed in the study of Alzheimer's disease.

hAChE hBuChE GSK-3β-IN-1 (Compound 6c) is a multi-target compound designed for Alzheimer's treatment capable of crossing the blood-brain barrier. It inhibits hAChE with an IC50 of 28.88 nM, hBuChE with an IC50 of 131.90 nM, and GSK-3β with an IC50 of 51.42 nM. Additionally, it acts as an inhibitor of tau protein and Aβ protein aggregation.

hAChE hBuChE-IN-1 (compound C2) acts as a dual inhibitor of cholinesterases, exhibiting IC50 values of 514 nM for hAChE and 358 nM for hBuChE. It is orally active and capable of enhancing cognitive function and spatial memory.

hAChE-IN-10 (Compound ET11) is an inhibitor of human acetylcholinesterase (AChE) with an IC50 of 6.34 nM. This compound is capable of scavenging free radicals and exhibits antioxidant activity. Additionally, hAChE-IN-10 demonstrates metal-chelating properties, inhibiting Cu2+-induced Aβ1-42 aggregation, reducing amyloid plaque formation, and offering neuroprotective effects. It also ameliorates cognitive impairment in mice induced by Scopolamine.

Compound 16 (hAChE Aβ1-42-IN-1) is a potent inhibitor targeting both hAChE and Aβ1-42 aggregation, demonstrating considerable safety in hepG2 cell lines and excellent brain-blood barrier (BBB) penetration with a broad safety margin. This compound shows promise for Alzheimer's disease (AD) research [1].

hAChE-IN-1 (Compound 24) is a potent inhibitor of human acetylcholinesterase (hAChE), with an inhibition concentration half-maximum (IC50) of 1.09 μM, and inhibits tau-oligomerization with an effective concentration half-maximum (EC50) of 2.71 μM as determined by a cellular tau fluorescence resonance energy transfer (FRET) assay [1].

hAChE-IN-2, a potent inhibitor of human acetylcholinesterase (hAChE), exhibits an inhibitory concentration 50 (IC50) of 0.71 μM and additionally impedes tau-oligomerization with an effective concentration 50 (EC50) of 2.21 μM, demonstrating neuroprotective activity [1].

hAChE-IN-3 (compound 5c) serves as a potent inhibitor for AChE, BuChE, MAO-B, and BACE-1, with respective IC50 values of 0.44, 0.08, 5.15, and 0.38 μM, demonstrating its ability to cross the blood-brain barrier. This compound also exhibits antioxidant properties and metal chelation capabilities. Additionally, it targets peripheral anion sites, potentially modulating β-amyloid and ameliorating neurodegeneration linked to Alzheimer's disease, highlighting its research potential for this condition [1].

Compd 5d (hAChE-IN-4) is a potent hAChE inhibitor that readily crosses the blood-brain barrier, exhibiting an IC50 of 0.25 μM, and is utilized in the study of Alzheimer's disease [1].

hAChE-IN-6 (compound 51) is a brain-penetrant acetylcholinesterase (AChE) inhibitor with an IC50 of 0.16 μM. It also inhibits human butyrylcholinesterase (hBuChE) and glycogen synthase kinase 3 beta (GSK3β), with IC50 values of 0.69 μM and 0.26 μM, respectively. Additionally, hAChE-IN-6 impedes the self-aggregation of tau protein and amyloid-beta 1-42 (Aβ1-42), making it useful for Alzheimer's disease (AD) research [1].

hAChE-IN-5 (compound 49) is a dual inhibitor of human acetylcholinesterase (hAChE) and human butyrylcholinesterase (hBuChE), showing IC50 values of 0.17 μM for both enzymes. It also potently inhibits glycogen synthase kinase 3 beta (GSK3β) with an IC50 of 0.21 μM. Furthermore, it effectively inhibits tau protein and Aβ1-42 peptide self-aggregation, and can bind the peripheral anionic site (PAS) to prevent amyloid-beta (Aβ)-induced neurotoxicity. hAChE-IN-5's ability to cross the blood-brain barrier (BBB) supports its potential in developing multitargeted anti-Alzheimer's agents [1].

Compound AK-2, also known as hAChE hBACE-1-IN-4, is a quinazoline derivative that demonstrates significant inhibitory activity against the enzymes hAChE and hBACE-1 (hAChE, IC 50 = 0.283 μM; hBACE-1, IC 50 = 0.231 μM). This compound also shows potential in inhibiting Aβ aggregation and possesses characteristics such as non-neurotoxicity, blood-brain barrier permeability, and oral activity, making it a valuable agent for research in Alzheimer's disease [1].

hAChE-IN-7 (compound 5s) serves as a mixed inhibitor impacting both the catalytic active site (CAS) and peripheral anionic site (PAS) of hAChE. This compound demonstrates a balanced inhibitory effect with IC 50 values of 69.8 nM for hAChE and 68.0 nM for hBuChE. Additionally, it exhibits an inhibitory activity against β-secretase-1 (BACE-1) with an IC 50 of 3.6 μM. hAChE-IN-7 holds potential for research in Alzheimer's disease (AD) [1].

Donepezil HCl(Aricept) is a selective and effective AChE inhibitor for bAChE and hAChE (IC50: 8.12 11.6 nM).

Donepezil (Aricept) is a piperidine-based, potent, specific, and reversible inhibitor of acetylcholinesterase (AChE). It can be used for the treatment of mild to moderate dementia of the Alzheimer's type.

AChE BChE MAO-B-IN-1 is a reversible, non-time-dependent inhibitor of AChE, BChE, and MAO-B that crosses the blood-brain barrier, exhibiting inhibitory effects on hAChE, hBChE, and hMAO-B with IC50s of 7.31, 0.56, and 26.1 μM, respectively. [AChE BChE MAO-B-IN-1] had a neuroprotective effect and was not significantly cytotoxic.

TA-03 (7-Meota) is a potent inhibitor of AChE in treatment of cognitive manifestation of AD.

Galanthamine N-Oxide, an alkaloid extracted from Zephyranthes concolor bulbs, effectively inhibits acetylcholinesterase (AChE) from electric eel with an EC50 of 26.2 μM. It acts as a significant inhibitor of substrate accommodation within the active sites of Torpedo californica AChE (TcAChE), human AChE (hAChE), and human BChE (hBChE) enzymes.

H3R antagonist 4 (compound 11l) serves as a dual inhibitor of cholinesterases and histamine H3 receptors (H3R), demonstrating IC50 values of 7.04 μM (eeAChE), 9.73 μM (hAChE)(reversible), and 1.09 nM (H3R). It effectively inhibits both self and Cu2+-induced Aβ1-42 aggregation at 95.48% and 88.63%, respectively, and degrades Aβ1-42 protofibrils with 80.16% and 89.30% efficiency under similar conditions. Additionally, H3R antagonist 4 possesses the chelating capability for biometals Cu2+, Zn2+, Al3+, and Fe2+. It significantly reduces tau protein hyperphosphorylation induced by Aβ1-42, inhibits RSL-3 induced apoptosis and ferroptosis in PC12 cells, and shows optimal blood-brain barrier permeability and intestinal absorption characteristics in hCMEC D3 and hPepT1-MDCK cells, respectively. Moreover, the compound improves learning and memory impairments in an Alzheimer's mouse model induced with scopolamine.

ROS151 is an AChE inhibitor with IC50 values of 14 nM (hAChE), 1.68 μM (eqBChE), and 8.17 μM (hFAAH). Additionally, it acts as a chelating agent for Fe3+ and Cu2+. ROS151 is utilized in research related to Alzheimer's disease.

AChE BChE-IN-25 (Compound 6e) is an orally active inhibitor of hAChE and eqBChE, with IC50 values of 7.9 nM and 0.79 nM, respectively. This compound exhibits antioxidant activity, effective in scavenging free radicals with an IC50 of 22.91 μM. AChE BChE-IN-25 demonstrates neuroprotective effects by reducing mitochondrial and cellular oxidative stress in a Drosophila Alzheimer's model and improves spatial and cognitive memory impairments induced by Scopolamine in mouse models.

CUR-IPA is a cholinesterase inhibitor with IC50 values of 5.99 μM for eAChE (electric eel), 59.30 μM for hAChE (human), and 60.66 μM for hBChE (human). It has free radical scavenging and antioxidant activity and is useful for researching cognitive dysfunction.

Memoquin is a multi-target-directed ligand for the therapy of Alzheimer's disease.

AChE BChE BACE-1-IN-2 (Compound 4o) is an orally active AChE, BACE-1, and BChE inhibitor with IC50 values of 0.069, 0.097, and 0.127 μM against hAChE, hBACE-1, and hBChE, respectively. It exhibits remarkable antioxidant potential, considerable binding capability towards PAS-AChE, potential disassembly of Aβ aggregates, and neuroprotective activity against Aβ-induced stress with excellent brain permeation [1].