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

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–hydrazin...

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Published in:	ACS chemical neuroscience Vol. 15; no. 18; pp. 3401 - 3420
Main Authors:	Yelamanda Rao, Kandrakonda, Chandran, Remya, Dileep, K. V., Gorantla, Sri Charitha, Jeelan Basha, Shaik, Mothukuru, Sreelakshmi, Siva kumar, Irla, Vamsi, Katta, Kumar, Sandeep, Reddy, Aramati Bindu Madhava, Subramanyam, Rajagopal, Damu, Amooru Gangaiah
Format:	Journal Article
Language:	English
Published:	United States American Chemical Society 18-09-2024
Subjects:	Acetamides - chemical synthesis Acetamides - chemistry Acetamides - pharmacology Alzheimer Disease - drug therapy Alzheimer Disease - metabolism Amyloid beta-Peptides - metabolism Butyrylcholinesterase - drug effects Butyrylcholinesterase - metabolism Computer Simulation Drug Design Humans Hydrazines - chemical synthesis Hydrazines - chemistry Hydrazines - pharmacology Molecular Docking Simulation Molecular Dynamics Simulation Neuroprotective Agents - chemical synthesis Neuroprotective Agents - chemistry Neuroprotective Agents - pharmacology Quinazolinones - chemical synthesis Quinazolinones - chemistry Quinazolinones - pharmacology MTDLs AChE Aβ antioxidant Alzheimer’s disease quinazolinone hydrazine cyanoacetamide
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Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1948-7193 1948-7193
DOI:	10.1021/acschemneuro.4c00424