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Pregnenolone derivatives for the treatment of Alzheimer's disease: synthesis, and inhibition of amyloid β peptide aggregation, acetylcholinesterase and carbonic anhydrase-II. | LitMetric

AI Article Synopsis

  • The amyloid state of proteins is crucial for understanding both healthy protein functions and the pathological arrangements that cause diseases like Alzheimer's, characterized by amyloid-β peptide accumulation and tau tangles.
  • Promising drug strategies for Alzheimer’s include compounds that can lower amyloid-β production, stop its aggregation, and enhance its clearance by targeting multiple biological pathways rather than focusing on a single target.
  • Recent synthesis and evaluation of pregnenolone derivatives showed effective inhibition of key enzymes and Aβ aggregation, with compounds demonstrating brain barrier penetration and low toxicity, along with supportive docking studies indicating how they interfere with β-sheet formation in the amyloid-β structure.

Article Abstract

The amyloid state, which is a specific conformation of proteins, offers valuable information about both functional protein structures and the pathological assemblies associated with various diseases. One of the major hallmarks of Alzheimer's disease includes primarily the extracellular build-up of a peptide known as amyloid-β, which has a sequence consisting of 39 to 42 amino acid residues, and the formation of intracellular neurofibrillary tangles mostly consisting of hyperphosphorylated tau protein. Drugs that are expected to reduce Aβ production, prevent Aβ aggregation, and promote Aβ clearance are promising approaches for treating AD. Current work is focused on identifying the compounds that have balanced even mild biological activities against multiple targets instead of finding one-target compound with high potency. We synthesized pregnenolone derivatives and evaluated their potential against inhibition of eeAChE/eqBChE, hCA-II and self-mediated Aβ peptide aggregation. Our synthesized derivatives 23, and 25-27 exhibited concomitant inhibition of all the tested macromolecular targets. All the active compounds were found to be BBB penetrants in the PAMPA assay. Furthermore, these selected compounds were found to be non-neurotoxic in the MTT assay on neuroblastoma SH-SY5Y cells. Docking studies support dual binding site (PAS and CAS) inhibition of AChE which showed Aβ aggregation and AChE inhibition. Moreover, docking studies carried out on the 3D crystallographic structure of Aβ peptide (PDB ID = 1IYT) showed significant interactions with amino acid residues Asp 23 and Lys 28, and hydrophobic interactions with the Phe19, Phe20, and Ala 30 effectively impeding the formation of β-sheet structures.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11075139PMC
http://dx.doi.org/10.1039/d4ra01536cDOI Listing

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