title: Synthesis, biological evaluation and molecular docking study of novel piperidine and piperazine derivatives as multi-targeted agents to treat Alzheimer's disease.
abstract: Development of Multi-Target Directed Ligands (MTDLs) has emerged as a promising approach for targeting complex etiology of Alzheimer's disease (AD). Following this approach, a new series of N'-(4-benzylpiperidin-/piperazin-/benzhydrylpiperazin-1-yl)alkylamine derivatives were designed, synthesized and biologically evaluated as inhibitors of cholinesterases (ChEs), amyloid-beta (Aβ) self aggregation and also for their radical scavenging activity. The in vitro studies showed that the majority of synthesized derivatives strongly inhibited acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) with IC50 values in the low-nanomolar range, and were clearly more potent than the reference compound donepezil in this regard. Among them, inhibitors 5h and 5k, strongly inhibited AChE, with IC50 value of 6.83nM and 2.13nM, respectively, and particularly, compound 5k was found to be highly selective for AChE (∼38-fold). Moreover, both kinetic analysis of AChE inhibition and the docking study suggested that 5k binds simultaneously to catalytic active site and peripheral anionic site of AChE. Besides, these compounds also exhibited greater ability to inhibit self-induced Aβ1-42 aggregation at 25μM with percentage inhibition from ∼54% to 89% and specially compound 5k provided highest inhibition (88.81%). Also, the derivatives containing methoxy and hydroxy groups showed potent oxygen radical absorbance capacity (ORAC) ranging from 2.2- to 4.4-fold of the Trolox value. Furthermore, results of ADMET studies suggested that all compounds exhibited appropriate drug like properties. Taken together, these results suggest that 5k might be a promising lead compound for further AD drug development.
authors.affiliation: Bio-Organic Chemistry Laboratory, Dr. B. R. Ambedkar Centre for Biomedical Research, University of Delhi, Delhi 110007, India.
authors.forename: Poonam
authors.initials: P
authors.lastname: Meena
authors.affiliation: Neuropharmaceutical Chemistry Laboratory, Dr. B. R. Ambedkar Centre for Biomedical Research, University of Delhi, Delhi 110007, India.
authors.forename: Vishal
authors.initials: V
authors.lastname: Nemaysh
authors.affiliation: Shaheed Rajguru College of Applied Sciences for Women, University of Delhi, Delhi 110096, India.
authors.forename: Manisha
authors.initials: M
authors.lastname: Khatri
authors.affiliation: Bio-Organic Chemistry 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: Neuropharmaceutical Chemistry Laboratory, Dr. B. R. Ambedkar Centre for Biomedical Research, University of Delhi, Delhi 110007, India.
authors.forename: Pratibha Mehta
authors.initials: PM
authors.lastname: Luthra
authors.affiliation: Bio-Organic Chemistry 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: D000110:Acetylcholinesterase / Q000187:drug effects; D000544:Alzheimer Disease / Q000188:drug therapy*; D000975:Antioxidants / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use*; D004353:Drug Evaluation, Preclinical; D006801:Humans; D007700:Kinetics; D062105:Molecular Docking Simulation; D018384:Oxidative Stress / Q000187:drug effects; D010879:Piperazines / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use*; D010880:Piperidines / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D000975:Antioxidants; D002800:Cholinesterase Inhibitors; D010879:Piperazines; D010880:Piperidines; D000110:Acetylcholinesterase
keywords: Alzheimer’s disease; Antioxidants; Aβ aggregation; Cholinesterases; Molecular docking; Multi-target directed ligands