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García Marín, Iohanan Daniel; Camarillo López, Raúl Horacio; Martínez, Oscar Aurelio; Padilla-Martínez, Itzia Irene; Correa-Basurto, José; Rosales-Hernández, Martha Cecilia

New compounds from heterocyclic amines scaffold with multitarget inhibitory activity on Aβ aggregation, AChE, and BACE1 in the Alzheimer disease

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  • Medientyp: E-Artikel
  • Titel: New compounds from heterocyclic amines scaffold with multitarget inhibitory activity on Aβ aggregation, AChE, and BACE1 in the Alzheimer disease
  • Beteiligte: García Marín, Iohanan Daniel; Camarillo López, Raúl Horacio; Martínez, Oscar Aurelio; Padilla-Martínez, Itzia Irene; Correa-Basurto, José; Rosales-Hernández, Martha Cecilia
  • Erschienen: Public Library of Science (PLoS), 2022
  • Erschienen in: PLOS ONE
  • Sprache: Englisch
  • DOI: 10.1371/journal.pone.0269129
  • ISSN: 1932-6203
  • Entstehung:
  • Anmerkungen:
  • Beschreibung: <jats:p>The preset neurodegenerations in Alzheimer disease (AD) are due to several mechanisms such as amyloidogenic proteolysis, neuroinflammation, mitochondrial dysfunction, neurofibrillary tangles, cholinergic dysfunction, among others. The aim of this work was to develop multitarget molecules for the treatment of AD. Therefore, a family of 64 molecules was designed based on ligand structure pharmacophores able to inhibit the activity of beta secretase (BACE1) and acetylcholinesterase (AChE) as well as to avoid amyloid beta (Aβ<jats:sub>1–42</jats:sub>) oligomerization. The backbone of designed molecules consisted of a trisubstituted aromatic ring, one of the substituents was a heterocyclic amine (piperidine, morpholine, pyrrolidine or<jats:italic>N</jats:italic>-methyl pyrrolidine) separated from the aromatic system by three carbon atoms. The set of compounds was screened<jats:italic>in silico</jats:italic>employing molecular docking calculations and chemoinformatic analyses. Based on Gibbs free energy of binding, binding mode and<jats:italic>in silico</jats:italic>predicted toxicity results, three of the best candidates were selected, synthesized, and evaluated<jats:italic>in vitro</jats:italic>;<jats:bold>F3S4-m</jats:bold>,<jats:bold>F2S4-m,</jats:bold>and<jats:bold>F2S4-p</jats:bold>. All three compounds prevented Aβ<jats:sub>1–42</jats:sub>aggregation (F3S4-m in 30.5%, F2S4-p in 42.1%, and F2S4-m in 60.9%). Additionally, inhibitory activity against AChE (ki 0.40 μM and 0.19 μM) and BACE1 (IC<jats:sub>50</jats:sub>15.97 μM and 8.38 μM) was also observed for compounds<jats:bold>F2S4-m</jats:bold>and<jats:bold>F3S4-m</jats:bold>, respectively. Despite the BACE IC<jats:sub>50</jats:sub>results demonstrated that all compounds are very less potent respect to peptidomimetic inhibitor (PI-IV IC<jats:sub>50</jats:sub>3.20 nM), we can still say that<jats:bold>F3S4-m</jats:bold>is capable to inhibit AChE and BACE1.</jats:p>
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