Multicomponent Petasis reaction for the identification of pyrazine based multi-target directed anti-Alzheimer's agents: In-silico design, synthesis, and characterization

  • Eur J Med Chem. 2023 Jun 5;254:115354. doi: 10.1016/j.ejmech.2023.115354.
Hari Madhav  1 ,  Somaya A Abdel-Rahman  2 ,  Md Amiruddin Hashmi  3 ,  Md Ataur Rahman  4 ,  Mohammad Rehan  5 ,  Kavita Pal  1 ,  Shahid M Nayeem  6 ,  Moustafa T Gabr  7 ,  Nasimul Hoda  8
Affiliations
  • 1. Drug Design and Synthesis Laboratory, Department of Chemistry, Jamia Millia Islamia, New Delhi, 110025, India.
  • 2. Molecular Imaging Innovations Institute (MI3), Department of Radiology, Weill Cornell Medicine, New York, NY, 10065, USA; Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt.
  • 3. Interdisciplinary Biotechnology Unit, Faculty of Life Sciences, Aligarh Muslim University, Aligarh, 202002, Uttar Pradesh, India.
  • 4. Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA, 02138, USA.
  • 5. Max-Planck-Institute für Molekulare Physiologie, Abteilung Chemische Biologie, Otto-Hahn-Straße 11, 44227, Dortmund, Germany.
  • 6. Department of Chemistry, Aligarh Muslim University, Aligarh, 202002, Uttar Pradesh, India.
  • 7. Molecular Imaging Innovations Institute (MI3), Department of Radiology, Weill Cornell Medicine, New York, NY, 10065, USA. Electronic address: [email protected].
  • 8. Drug Design and Synthesis Laboratory, Department of Chemistry, Jamia Millia Islamia, New Delhi, 110025, India. Electronic address: [email protected].
PMID: 37043996 DOI: 10.1016/j.ejmech.2023.115354
Abstract

Multi-target directed ligands (MTDLs) have recently attracted significant interest due to their exceptional effectiveness against multi-factorial Alzheimer's disease. The present work described the development of pyrazine-based MTDLs using multicomponent Petasis reaction for the dual inhibition of tau-aggregation and human acetylcholinesterase (hAChE). The molecular structure of synthesized ligands was validated by 1H & 13C NMR and mass spectrometry. The screened compounds were shown to have a strong inhibitory effect at 10 μM concentration against tau-oligomerization and hAChE, but only moderate inhibitory activity against Aβ42. Among all the compounds, the half-maximal inhibitory concentration (IC50) for 21 and 24 against hAChE were 0.71 μM and 1.09 μM, respectively, while they displayed half-maximal effective concentrations (EC50) values of 2.21 μM and 2.71 μM for cellular tau-oligomerization, respectively. Additionally, an MTT experiment using tau-expressing SH-SY5Y neuroblastoma cells revealed that 21 was more neuroprotective than the FDA-approved medication donepezil. Furthermore, an MD simulation study was performed to investigate the dynamics and stability of AChE-21 and AChE-24 complexes in an aqueous environment. The MM-PBSA calculations were performed to evaluate the binding of 21 and 24 with AChE, and the relative binding energy was calculated as -870.578 and -875.697 kJ mol-1, respectively. As a result, the study offered insight into the design of new MTDLs and highlighted 21 as a potential roadblock to the development of anti-AD medications.

Keywords
Acetylcholinesterase; MD simulation; MM-PBSA; Petasis reaction; Pyrazine; Tau-aggregation.
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