hAChE

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.

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.

hAChE/hBACE-1-IN-3 (Compound 23a) is a dual inhibitor of hAChE and hBACE-1, with IC50 values of 0.32 μM and 0.39 μM, respectively, and Ki values of 0.26 μM and 0.46 μM. This compound is capable of crossing the blood-brain barrier.

hAChE/hBACE-1-IN-1 (compounds 5d) is an orally active inhibitor of hAChE that can cross the blood-brain barrier. It effectively inhibits hAChE and hBACE-1, with IC50 values of 0.076 and 0.23 μM, respectively. Additionally, hAChE/hBACE-1-IN-1 prevents Aβ1-42 aggregation and enhances learning and memory in mice. This compound is useful in Alzheimer's disease research.

hAChE-IN-8 (Compound S-12) is an orally active and selective inhibitor of hAChE, with an IC50 of 0.486 μM. It also inhibits BACE-1 with an IC50 of 0.542 μM, but shows negligible inhibition of Dyrk1A (IC50>10 μM). This compound reduces Aβ aggregation, exhibits good blood-brain barrier penetration, and is primarily used in Alzheimer's disease research.

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].

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.

sEH/AChE-IN-3 (15) serves as a dual inhibitor targeting both soluble epoxide hydrolase (sEH) and acetylcholinesterase (AChE), demonstrating potent activity and the ability to cross the blood-brain barrier (BBB). It exhibits IC50 values of 0.4 nM for human sEH (hsEH), 1.94 nM for human AChE (hAChE), 615 nM for human butyrylcholinesterase (hBChE), 4.3 nM for mouse sEH (msEH), and 2.61 nM for mouse AChE (mAChE), indicating its efficacy across these enzymes.

sEH/AChE-IN-4 -15 is a potent, blood-brain barrier-penetrating dual inhibitor targeting soluble epoxide hydrolase (sEH) and acetylcholinesterase (AChE). It demonstrates notable inhibition efficacy, with IC50 values of 3.1 nM (hsEH), 1660 nM (hAChE), 179 nM (hBChE, human butyrylcholinesterase), 14.5 nM (msEH), and 102 nM (mAChE), indicating its significant inhibitory action across both targeted enzymes in human and mouse models.

sEH/AChE-IN-1 (Compound 12a) is a dual inhibitor of soluble epoxide hydrolase (sEH) and acetylcholinesterase (AChE) with potential research applications in Alzheimer's disease (AD) due to its cumulative effect against neuroinflammation and memory impairment.

sEH/AChE-IN-2 and acetylcholinesterase ( AChE ). sEH/AChE-IN-2 provides cumulative effects against neuroinflammation and memory impairment. sEH/AChE-IN-2 has the potential for the research of Alzheimer's disease (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.