piroxicam and Protein-Aggregation--Pathological

The complexity of Alzheimer's disease (AD) calls for search of multifunctional compounds as potential candidates for effective therapy. A series of phthalimide and saccharin derivatives linked by different alicyclic fragments (piperazine, hexahydropyrimidine, 3-aminopyrrolidine or 3-aminopiperidine) with phenylalkyl moieties attached have been designed, synthesized, and evaluated as multifunctional anti-AD agents with cholinesterase, β-secretase and β-amyloid inhibitory activities. In vitro studies showed that the majority of saccharin derivatives with piperazine moiety and one phthalimide derivative with 3-aminopiperidine fragment exhibited inhibitory potency toward acetylcholinesterase (AChE) with EeAChE IC

Topics: Amines; Amyloid beta-Peptides; Amyloid Precursor Protein Secretases; Binding Sites; Blood-Brain Barrier; Cholinesterases; Drug Delivery Systems; Drug Design; Enzyme Inhibitors; Humans; Inhibitory Concentration 50; Molecular Structure; Peptide Fragments; Phthalimides; Protein Aggregation, Pathological; Protein Binding; Saccharin

Multitarget compounds are increasingly being pursued for the effective treatment of complex diseases. Herein, we describe the design and synthesis of a novel class of shogaol-huprine hybrids, purported to hit several key targets involved in Alzheimer's disease. The hybrids have been tested in vitro for their inhibitory activity against human acetylcholinesterase and butyrylcholinesterase and antioxidant activity (ABTS.+, DPPH and Folin-Ciocalteu assays), and in intact Escherichia coli cells for their Aβ42 and tau anti-aggregating activity. Also, their brain penetration has been assessed (PAMPA-BBB assay). Even though the hybrids are not as potent AChE inhibitors or antioxidant agents as the parent huprine Y and [4]-shogaol, respectively, they still exhibit very potent anticholinesterase and antioxidant activities and are much more potent Aβ42 and tau anti-aggregating agents than the parent compounds. Overall, the shogaol-huprine hybrids emerge as interesting brain permeable multitarget anti-Alzheimer leads.

Topics: Acetylcholinesterase; Aminoquinolines; Amyloid beta-Peptides; Antioxidants; Catechols; Cholinesterase Inhibitors; Dose-Response Relationship, Drug; Heterocyclic Compounds, 4 or More Rings; Humans; Molecular Structure; Protein Aggregates; Protein Aggregation, Pathological; Structure-Activity Relationship; tau Proteins

A series of tacrine-(β-carboline) hybrids (11a-q) were designed, synthesized and evaluated as multifunctional cholinesterase inhibitors against Alzheimer's disease (AD). In vitro studies showed that most of them exhibited significant potency to inhibit acetylcholinesterase (eeAChE and hAChE), butyrylcholinesterase (BuChE) and self-induced β-amyloid (Aβ) aggregation, Cu(2+)-induced Aβ (1-42) aggregation, and to chelate metal ions. Especially, 11 l presented the greatest ability to inhibit cholinesterase (IC50, 21.6 nM for eeAChE, 63.2 nM for hAChE and 39.8 nM for BuChE), good inhibition of Aβ aggregation (65.8% at 20 μM) and good antioxidant activity (1.57 trolox equivalents). Kinetic and molecular modeling studies indicated that 11 l was a mixed-type inhibitor, binding simultaneously to the catalytic anionic site (CAS) and the peripheral anionic site (PAS) of AChE. In addition, 11 l could chelate metal ions, reduce PC12 cells death induced by oxidative stress and penetrate the blood-brain barrier (BBB). These results suggested that 11 l might be an excellent multifunctional agent for AD treatment.

Topics: Acetylcholinesterase; Alzheimer Disease; Amyloid beta-Peptides; Animals; Antioxidants; Blood-Brain Barrier; Butyrylcholinesterase; Carbolines; Cell Line; Chelating Agents; Cholinesterase Inhibitors; Drug Design; Electrophorus; Horses; Humans; Molecular Docking Simulation; Protein Aggregation, Pathological; Tacrine