Quinazolinone-triazole hybrids as multi-target-directed ligands for Alzheimer's disease: discovery of potent and selective MAO-B inhibitors with cholinesterase modulating activity

  • RSC Adv. 2026 Aug 17;16(41):48416-48433. doi: 10.1039/d6ra06124a.
Wagdy M Eldehna  1 ,  Ashraf K El-Damasy  2 ,  Jaeyeop Lim  3 ,  Salma M Hefny  4 ,  Tarfah Al-Warhi  5 ,  Amal S Elgohary  4 ,  Anwar A El-Hamaky  4 ,  Man-Jeong Paik  3 ,  Mohamed R Elnagar  6  7 ,  Diaaeldin M Elimam  8 ,  Yasser M Omar  9  10 ,  Hoon Kim  3 ,  Haytham O Tawfik  4  11
Affiliations
  • 1. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University P. O. Box 33516 Kafrelsheikh Egypt [email protected].
  • 2. Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University Mansoura 35516 Egypt [email protected].
  • 3. College of Pharmacy, Sunchon National University Suncheon 57922 Republic of Korea [email protected].
  • 4. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Tanta University Tanta 31527 Egypt.
  • 5. Department of Chemistry, College of Science, Princess Nourah Bint Abdulrahman University P.O. Box 84428 Riyadh 11671 Saudi Arabia.
  • 6. Department of Pharmacology and Toxicology, Faculty of Pharmacy, Al-Azhar University Cairo 11823 Egypt.
  • 7. Department of Pharmacology, College of Pharmacy, The Islamic University Najaf 54001 Iraq.
  • 8. Department of Pharmacognosy, Faculty of Pharmacy, Kafrelsheikh University Kafrelsheikh 33516 Egypt.
  • 9. Institute of Cancer Therapeutics, University of Bradford BD7 1DP UK.
  • 10. Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Assiut University Assiut 71526 Egypt.
  • 11. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Alsalam University 31511 Tanta Egypt.
PMID: 42610081 DOI: 10.1039/d6ra06124a
Abstract

A new series of quinazolinone-triazole hybrids (QTHs, 5a-n) was designed, synthesized, and evaluated as potential multi-target-directed ligands for Alzheimer's Disease. All synthesized compounds were screened against human Monoamine Oxidase A (MAO-A) and Monoamine Oxidase B (MAO-B). The obtained results revealed pronounced selectivity toward MAO-B, with IC50 values ranging from 0.65 to 7.51 µM, while exhibiting negligible MAO-A inhibition (IC50 > 40 µM). Compounds 5a, 5d, 5g, 5h, and 5m emerged as the most potent and selective MAO-B inhibitors and were subsequently evaluated for inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). Among them, compound 5h displayed the most favorable biological profile, showing potent inhibition of MAO-B (IC50 = 0.65 µM), AChE (IC50 = 0.084 µM), and BuChE (IC50 = 0.667 µM). In silico ADMET analysis indicated acceptable drug-like properties for the lead compounds. Furthermore, molecular docking studies against MAO-B and AChE revealed favorable binding interactions, while a 500 ns molecular dynamics simulation confirmed the stability of the 5h-MAO-B complex. Collectively, the present findings identify compound 5h as a promising lead candidate and highlight quinazolinone-triazole hybrids as attractive scaffolds for the development of selective MAO-B inhibitors with additional cholinesterase inhibitory activity for Alzheimer's Disease treatment.

Products