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  3. Quinazolinone-Hydrazine Cyanoacetamide Hybrids as Potent Multitarget-Directed Druggable Therapeutics against Alzheimer's Disease: Design, Synthesis, and Biochemical, In Silico, and Mechanistic Analyses

Quinazolinone-Hydrazine Cyanoacetamide Hybrids as Potent Multitarget-Directed Druggable Therapeutics against Alzheimer's Disease: Design, Synthesis, and Biochemical, In Silico, and Mechanistic Analyses

  • ACS Chem Neurosci. 2024 Sep 18;15(18):3401-3420. doi: 10.1021/acschemneuro.4c00424.
Kandrakonda Yelamanda Rao 1,  Remya Chandran 2,  K V Dileep 2,  Sri Charitha Gorantla 3,  Shaik Jeelan Basha 1 4,  Sreelakshmi Mothukuru 1,  Irla Siva Kumar 5,  Katta Vamsi 6,  Sandeep Kumar 5 7,  Aramati Bindu Madhava Reddy 3,  Rajagopal Subramanyam 8,  Amooru Gangaiah Damu 1
Affiliations

Affiliations

  • 1 Bioorganic Chemistry Research Laboratory, Department of Chemistry, Yogi Vemana University, Kadapa, Andhra Pradesh 516005, India.
  • 2 Laboratory for Computational and Structural Biology, Jubilee Centre for Medical Research, Jubilee Mission Medical College and Research Institute, Thrissur, Kerala 680005, India.
  • 3 Department of Animal Biology, School of Life Sciences, University of Hyderabad, Hyderabad, Telangana 500046, India.
  • 4 Department of Chemistry, Santhiram Engineering College (Autonomous), Nandyal, Andhra Pradesh 518501, India.
  • 5 Soft Condensed Matter, Raman Research Institute, CV Raman Avenue, Sadashiva Nagar, Bangalore 560080, India.
  • 6 Department of Chemistry, Indian Institute of Science and Education Research (IISER), Tirupati, Andhra Pradesh 517507, India.
  • 7 Nitte Meenakshi Institute of Technology, Yelahanka, Bangalore 560064, India.
  • 8 Department of Plant Sciences, School of Life Sciences, University of Hyderabad, Hyderabad, Telangana 500046, India.
PMID: 39235838 DOI: 10.1021/acschemneuro.4c00424
Abstract

The discovery of effective multitarget-directed ligands (MTDLs) against multifactorial Alzheimer's disease (AD) remnants has been focused in an incessant drug discovery pursuit. In this perception, the current study explores the rational design, synthesis, and evaluation of 26 quinazolinone-hydrazine cyanoacetamide hybrids 7(a-j), 8(a-j), and 9(a-f) as MTDLs against AD. These new compounds were synthesized in four-step processes using simple phthalimide as the starting material without any major workup procedures and were characterized by different spectroscopic techniques. In Ellman's assay, the most potent analogues 7i, 8j, and 9d were identified as selective and mixed-type inhibitors of hAChE. Furthermore, biophysical and computational assessments revealed that the analogues 7i, 8j, and 9d were bound to both the catalytic active site and peripheral anionic site of hAChE with high affinity. The molecular dynamics simulation analysis highlighted the conformational changes of hAChE upon binding of 7i, 8j, and 9d and also the stability of resulting biomolecular systems all over 100 ns simulations. In addition to antioxidant activity, the most active congeners were found to protect substantially SK-N-SH cells from oxidative damage. Decisively, the most active analogues 7i, 8j, and 9d were assessed as potent Aβ1-42 fibril modulators and protective agents against Aβ1-42-induced toxicity in SH-SY5Y cells. Additionally, glioblastoma C6 cell-based assays also demonstrated the use of the most active congeners 7i, 8j, and 9d as protective agents against Aβ1-42-induced toxicity. Overall, this multifunctional capacity of quinazolinone-hydrazine cyanoacetamide hybrids demonstrated the noteworthy potential of these hybrids to develop as effectual MTDLs against AD. However, further pharmacokinetics, toxicology, and behavioral studies are warranted.

Keywords

AChE; Alzheimer’s disease; Aβ; MTDLs; antioxidant; hydrazine cyanoacetamide; quinazolinone.

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