title: Design, synthesis, in-silico and biological evaluation of novel donepezil derivatives as multi-target-directed ligands for the treatment of Alzheimer's disease.
abstract: A novel series of donepezil based multi-functional agents "(E)-5,6-dimethoxy-2-(4-(4-substituted piperazin-1-yl)benzylidene)-2,3-dihydro-1H-inden-1-ones" have been designed and synthesized as potential anti-Alzheimer's agents. In-vitro studies revealed that these compounds demonstrated moderate to good AChE and Aβ aggregation inhibitory activity. These derivatives are also endowed with admirable antioxidant activity. Among the entire series compounds IP-9, IP-13 and IP-15 appeared as most active multi-functional agents and displayed marked AChE inhibitory, Aβ disaggregation and antioxidant activity. Studies indicate that IP-13 and IP-15 showed better AChE inhibitory activity than the standard drug donepezil and IP-9, IP-13 as well as IP-15 exhibited better Aβ aggregation inhibitory activity than curcumin. These compounds (IP-9, IP-13 and IP-15) successfully diminished H2O2induced oxidative stress in SH-SY5Y cells and displayed excellent neuroprotective activity against H2O2as well as Aβ induced toxicity in SH-SY5Y cells in a concentration dependent manner. Moreover, these derivatives did not exert any significant toxicity in neuronal SH-SY5Y cells in cytotoxicity assay. To elucidate the plausible binding mode of the compounds IP-9, IP-13 and IP-15, molecular docking studies and molecular dynamics (MD) simulation studies were also performed and the results indicate their significant interactions with the active sites of AChE as well as Aβ1-42peptide. Thus, the present study evidently showed that IP-9, IP-13 and IP-15 are potent multi-functional agents against Alzheimer's disease and might serve as promising lead candidates for anti-Alzheimer drug development.
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: 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: Apra
authors.initials: A
authors.lastname: Manral
authors.affiliation: School of Computational & Integrative Sciences, Jawaharlal Nehru University, New Delhi 110067, India.
authors.forename: Amresh
authors.initials: A
authors.lastname: Prakash
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: School of Computational & Integrative Sciences, Jawaharlal Nehru University, New Delhi 110067, India.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Lynn
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: D000109:Acetylcholine / Q000737:chemistry; D000544:Alzheimer Disease / Q000188:drug therapy*; D002460:Cell Line; D000077265:Donepezil; D016503:Drug Delivery Systems; D015195:Drug Design; D006801:Humans; D007189:Indans / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D008024:Ligands; D046529:Microscopy, Electron, Transmission; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D018696:Neuroprotective Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D010880:Piperidines / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D066263:Protein Aggregation, Pathological / Q000188:drug therapy; D011485:Protein Binding / Q000187:drug effects
chemical_list: D007189:Indans; D008024:Ligands; D018696:Neuroprotective Agents; D010880:Piperidines; D000077265:Donepezil; D000109:Acetylcholine
keywords: Alzheimer's disease; Donepezil derivatives; In-vitro; Synthesis; TEM assay