Multitarget-directed ligands (MTDLs) are considered a promising therapeutic strategy to address the multifactorial nature of Alzheimer's disease (AD). Novel MTDLs have been designed as inhibitors of human acetylcholinesterases/butyrylcholinesterases, monoamine oxidase A/B, and glycogen synthase kinase 3β and as calcium channel antagonists via the Biginelli multicomponent reaction. Among these MTDLs, (±)-BIGI-3h was identified as a promising new hit compound showing in vitro balanced activities toward the aforementioned recognized AD targets. Additional in vitro studies demonstrated antioxidant effects and brain penetration, along with the ability to inhibit the aggregation of both τ protein and β-amyloid peptide. The in vivo studies have shown that (±)-BIGI-3h (10 mg/kg intraperitoneally) significantly reduces scopolamine-induced cognitive deficits.

• MeSH
• Alzheimerova nemoc * farmakoterapie   MeSH
• blokátory kalciových kanálů farmakologie   terapeutické užití   MeSH
• cholinesterasové inhibitory farmakologie   terapeutické užití   MeSH
• GSK3B MeSH
• lidé MeSH
• ligandy MeSH
• monoaminoxidasa metabolismus   MeSH
• vápníkové kanály MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

New tritarget small molecules combining Ca2+ channels blockade, cholinesterase, and H3 receptor inhibition were obtained by multicomponent synthesis. Compound 3p has been identified as a very promising lead, showing good Ca2+ channels blockade activity (IC50 = 21 ± 1 μM), potent affinity against hH3R (Ki = 565 ± 62 nM), a moderate but selective hBuChE inhibition (IC50 = 7.83 ± 0.10 μM), strong antioxidant power (3.6 TE), and ability to restore cognitive impairment induced by lipopolysaccharide.

• MeSH
• Alzheimerova nemoc farmakoterapie   metabolismus   MeSH
• blokátory kalciových kanálů chemie   farmakologie   MeSH
• cholinesterasové inhibitory chemie   farmakologie   MeSH
• knihovny malých molekul chemie   farmakologie   MeSH
• lidé MeSH
• myši MeSH
• nádorové buňky kultivované MeSH
• neuroblastom farmakoterapie   metabolismus   MeSH
• neuroprotektivní látky chemie   farmakologie   MeSH
• poruchy paměti farmakoterapie   metabolismus   MeSH
• receptory histaminu H3 chemie   MeSH
• vazodilatancia chemie   farmakologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH