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  3. Synthesis, biological evaluation, and in silico studies of pyridoxal-amiridine hybrids as multitargeting anti-Alzheimer's disease agents

Synthesis, biological evaluation, and in silico studies of pyridoxal-amiridine hybrids as multitargeting anti-Alzheimer's disease agents

  • Eur J Med Chem. 2026 Feb 5:303:118397. doi: 10.1016/j.ejmech.2025.118397.
G F Makhaeva 1,  M V Grishchenko 2,  E V Rudakova 1,  N V Kovaleva 1,  N P Boltneva 1,  T S Skornyakova 1,  O G Khudina 2,  E V Shchegolkov 2,  E F Zhilina 2,  T Yu Astakhova 3,  P G Pronkin 3,  E N Timokhina 4,  M A Lapshina 1,  E S Dubrovskaya 1,  E V Radchenko 5,  V A Palyulin 6,  Ya V Burgart 2,  V I Saloutin 2,  V N Charushin 2,  R J Richardson 7
Affiliations

Affiliations

  • 1 Institute of Physiologically Active Compounds at Federal Research Center of Problems of Chemical Physics and Medicinal Chemistry, Russian Academy of Sciences, Chernogolovka, 142432, Russia.
  • 2 Postovsky Institute of Organic Synthesis, Ural Branch of the Russian Academy of Sciences, Ekaterinburg, 620066, Russia.
  • 3 Institute of Physiologically Active Compounds at Federal Research Center of Problems of Chemical Physics and Medicinal Chemistry, Russian Academy of Sciences, Chernogolovka, 142432, Russia; Emanuel Institute of Biochemical Physics, Russian Academy of Sciences, Moscow, 119334, Russia.
  • 4 Emanuel Institute of Biochemical Physics, Russian Academy of Sciences, Moscow, 119334, Russia.
  • 5 Department of Chemistry, Lomonosov Moscow State University, Moscow, 119991, Russia.
  • 6 Institute of Physiologically Active Compounds at Federal Research Center of Problems of Chemical Physics and Medicinal Chemistry, Russian Academy of Sciences, Chernogolovka, 142432, Russia; Department of Chemistry, Lomonosov Moscow State University, Moscow, 119991, Russia.
  • 7 Department of Environmental Health Sciences, University of Michigan, Ann Arbor, MI, 48109, USA; Department of Neurology, University of Michigan, Ann Arbor, MI, 48109, USA; Center for Computational Medicine & Bioinformatics, University of Michigan, Ann Arbor, MI, 48109, USA; Michigan Institute for Computational Discovery & Engineering, University of Michigan, Ann Arbor, MI, 48109, USA; Michigan Institute for Data & AI in Society, University of Michigan, Ann Arbor, MI, 48109, USA. Electronic address: rjrich@umich.edu.
PMID: 41338134 DOI: 10.1016/j.ejmech.2025.118397
Abstract

New conjugates of an anticholinesterase drug, amiridine, linked to vitamin B6 derivatives pyridoximines 3 and pyridoxamines 4 with different lengths of alkylene spacers, were synthesized and assessed as potential multifunctional anti-Alzheimer's disease (anti-AD) agents. All conjugates demonstrated high acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibition (IC50: AChE, 0.386-2.53 μM; BChE, 0.031-1.45 μM), but poor activity against off-target carboxylesterase. Conjugates were mixed-type reversible inhibitors of AChE and BChE and displaced propidium from the AChE peripheral anionic site at the level of donepezil. All conjugates inhibited Aβ42 self-aggregation in the thioflavin test, wherein conjugates 3 were more active; inhibition increased with spacer elongation, being greatest for (CH2)8. Results agreed with molecular docking to AChE, BChE and Aβ42. Conjugates exhibited high ABTS•+-scavenging activity comparable to Trolox and the starting pyridoxal. Moreover, compounds 4 were three times more active than their imine analogues 3, which agreed with quantum chemical analysis. Using the example of imine 3c, the possibility of conjugates of this type to bind biogenic metal ions was shown by UV-Vis spectroscopy. Pyridoxamines 4a,b with spacers n = 4,6 were less toxic in general than imines 3a,b toward HEK293T, HepG2, and SHY5Y cell lines. Additionally, conjugates demonstrated neuroprotection in models of hydrogen peroxide and glutamate-induced oxidative stress in neuroblastoma SH-SY5Y cells, where compounds 4a,b were more active than 3a,b. Altogether, the results indicated that the new conjugates possessed potential for further development as multifunctional anti-AD drug candidates.

Keywords

Alzheimer's disease; Amiridine and pyridoxal derivatives; Antiaggregating and antiradical activities; Anticholinesterase; Neuroprotection.

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