Zhong_2022_Bioorg.Chem_130_106224

Reference

Title : Novel AP2238-clorgiline hybrids as multi-target agents for the treatment of Alzheimer's disease: Design, synthesis, and biological evaluation - Zhong_2022_Bioorg.Chem_130_106224
Author(s) : Zhong G , Guo J , Pang C , Su D , Tang C , Jing L , Zhang F , He P , Yan Y , Chen Z , Liu J , Jiang N
Ref : Bioorg Chem , 130 :106224 , 2022
Abstract :

Cholinesterase and monoamine oxidase are potential targets for the therapy of Alzheimer's disease. A series of novel AP2238-clorgiline hybrids as multi-target agents were designed, synthesized and investigated in vitro for their inhibition of cholinesterases and monoamine oxidases. Many compounds displayed balanced and good inhibitory activity against AChE, BuChE and MAO-B with an obvious selective inhibitory effect on MAO-B. Among them, Compound 5l showed the most balanced potency to inhibit ChEs (eeAChE: IC(50) = 4.03 +/- 0.03 microM, eqBuChE: IC(50) = 5.64 +/- 0.53 microM; hAChE: IC(50) = 8.30 +/- 0.04 microM, hBuChE: IC(50) = 1.91 +/- 0.06 microM) and hMAO-B (IC(50) = 3.29 +/- 0.09 microM). Molecular modeling and kinetic studies showed that 5l was a mixed inhibitor for both AChE and BuChE, and a competitive MAO-B inhibitor. Compound 5l exhibited no toxicity to PC12 and BV-2 cells at 12.5 microM and no acute toxicity at a dosage of 2500 mg/kg. Moreover, 5l can improve the memory function of mice with scopolamine-induced memory impairment and have an excellent ability to cross the blood-brain barrier. Overall, these findings suggested that compound 5l could be deemed as a promising, balanced multi-target drug candidate against Alzheimer's disease.

PubMedSearch : Zhong_2022_Bioorg.Chem_130_106224
PubMedID: 36332315

Related information

Inhibitor AP2238

Citations formats

Zhong G, Guo J, Pang C, Su D, Tang C, Jing L, Zhang F, He P, Yan Y, Chen Z, Liu J, Jiang N (2022)
Novel AP2238-clorgiline hybrids as multi-target agents for the treatment of Alzheimer's disease: Design, synthesis, and biological evaluation
Bioorg Chem 130 :106224

Zhong G, Guo J, Pang C, Su D, Tang C, Jing L, Zhang F, He P, Yan Y, Chen Z, Liu J, Jiang N (2022)
Bioorg Chem 130 :106224