In silico design of novel pyridazine derivatives as balanced multifunctional agents against Alzheimer's disease

  • Sci Rep. 2025 May 7;15(1):15910. doi: 10.1038/s41598-025-98182-x.
Mourad Aloui  1 ,  Mohamed El Fadili  2 ,  Somdutt Mujwar  3 ,  Mohammed Er-Rajy  4 ,  Hatem A Abuelizz  5 ,  Sara Er-Rahmani  6 ,  Sara Zarougui  4 ,  Elhalaoui Menana  4
Affiliations
  • 1. LIMAS Laboratory, Faculty of Sciences Dhar El Mahraz, Sidi Mohamed Ben Abdellah University, Fez, Morocco. [email protected].
  • 2. LIMAS Laboratory, Faculty of Sciences Dhar El Mahraz, Sidi Mohamed Ben Abdellah University, Fez, Morocco. [email protected].
  • 3. Chitkara College of Pharmacy, Chitkara University, Rajpura, Punjab, 140401, India.
  • 4. LIMAS Laboratory, Faculty of Sciences Dhar El Mahraz, Sidi Mohamed Ben Abdellah University, Fez, Morocco.
  • 5. Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, PO Box 2457, 11451, Riyadh, Saudi Arabia.
  • 6. Dipartimento Di Chimica, Università di Torino, 10125, Torino, Italy.
PMID: 40335607 DOI: 10.1038/s41598-025-98182-x
Abstract

Alzheimer's disease (AD) necessitates innovative therapeutic approaches that target its multifaceted pathology. This study investigates a series of 2-aminoalkyl-6-(2-hydroxyphenyl)pyridazin-3(2H)-one derivatives as potential multi-target ligands for AD, aiming to simultaneously inhibit acetylcholinesterase (AChE) and amyloid-beta (Aβ) aggregation. To assess the therapeutic potential of these compounds, we employed a comprehensive computational approach, incorporating 2D-QSAR modeling, molecular dynamics simulations, molecular docking, and ADMET property analysis. Based on these analyses, we designed 13 novel pyridazine derivatives exhibiting favorable interactions with key AD-related proteins, enhanced dynamic stability within protein binding sites, and adherence to established drug-likeness principles. Notably, these compounds demonstrated promising oral absorption (96%) and exhibited no significant toxicity in preliminary assessments. These results indicate that the novel pyridazine derivatives warrant further investigation as promising multifunctional agents for the treatment of Alzheimer's disease.

Keywords
ADMET propriety; Alzheimer’s disease; Molecular docking; Molecular dynamic; Pyridazine; QSAR.
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