title: Design, synthesis and evaluation of novel indandione derivatives as multifunctional agents with cholinesterase inhibition, anti-β-amyloid aggregation, antioxidant and neuroprotection properties against Alzheimer's disease.
abstract: A series of novel 2-(4-(4-substituted piperazin-1-yl)benzylidene)-1H-indene-1,3(2H)-diones were designed, synthesized and appraised as multifunctional anti-Alzheimer agents. In vitro studies of compounds 27-38 showed that these compounds exhibit moderate to excellent AChE, BuChE and Aβ aggregation inhibitory activity. Notably, compounds 34 and 38 appeared as most active multifunctional agents in the entire series and exhibited excellent inhibition against AChE (IC50=0.048μM: 34; 0.036μM: 38), Aβ aggregation (max% inhibition 82.2%, IC50=9.2μM: 34; max% inhibition 80.9%, IC50=10.11μM: 38) and displayed significant antioxidant potential in ORAC-FL assay. Both compounds also successfully diminished H2O2 induced oxidative stress in SH-SY5Y cells. Fascinatingly, compounds 34 and 38 showed admirable neuroprotective effects against H2O2 and Aβ induced toxicity in SH-SY5Y cells. Additionally, both derivatives showed no considerable toxicity in neuronal cell viability assay and represented drug likeness properties in the primarily pharmacokinetics study. All these results together, propelled out that compounds 34 and 38 might serve as promising multi-functional lead candidates for treatment of AD in the future.
authors.affiliation: Bio-Organic Research Laboratory, Dr. B. R. Ambedkar Centre for Biomedical Research, University of Delhi, Delhi 110007, India.
authors.forename: Chandra Bhushan
authors.initials: CB
authors.lastname: Mishra
authors.affiliation: Bio-Organic Research Laboratory, Dr. B. R. Ambedkar Centre for Biomedical Research, University of Delhi, Delhi 110007, India.
authors.forename: Apra
authors.initials: A
authors.lastname: Manral
authors.affiliation: Bio-Organic Research Laboratory, Dr. B. R. Ambedkar Centre for Biomedical Research, University of Delhi, Delhi 110007, India.
authors.forename: Shikha
authors.initials: S
authors.lastname: Kumari
authors.affiliation: Bio-Organic Research Laboratory, Dr. B. R. Ambedkar Centre for Biomedical Research, University of Delhi, Delhi 110007, India.
authors.forename: Vikas
authors.initials: V
authors.lastname: Saini
authors.affiliation: Bio-Organic Research Laboratory, Dr. B. R. Ambedkar Centre for Biomedical Research, University of Delhi, Delhi 110007, India. Electronic address: mtiwari07@gmail.com.
authors.forename: Manisha
authors.initials: M
authors.lastname: Tiwari
mesh_terms: D000544:Alzheimer Disease / Q000517:prevention & control*; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors*; D000975:Antioxidants / Q000494:pharmacology*; D002460:Cell Line; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D006801:Humans; D006861:Hydrogen Peroxide / Q000633:toxicity; D007189:Indans / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D007700:Kinetics; D046529:Microscopy, Electron, Transmission; D018696:Neuroprotective Agents / Q000494:pharmacology*
chemical_list: C413384:1,2-indanedione; D016229:Amyloid beta-Peptides; D000975:Antioxidants; D002800:Cholinesterase Inhibitors; D007189:Indans; D018696:Neuroprotective Agents; D006861:Hydrogen Peroxide
keywords: Alzheimer’s disease; Indandione; Neurotoxicity; Piperazine