title: Benzylpiperidine-Linked Diarylthiazoles as Potential Anti-Alzheimer's Agents: Synthesis and Biological Evaluation.
abstract: A novel series of hybrid molecules were designed and synthesized by fusing the pharmacophoric features of cholinesterase inhibitor donepezil and diarylthiazole as potential multitarget-directed ligands for the treatment of Alzheimer's disease (AD). The compounds showed significant in vitro anticholinesterase (anti-ChE) activity, the most potent compound (44) among them showing the highest activity (IC50 value of 0.30 ± 0.01 μM) for AChE and (1.84 ± 0.03 μM) for BuChE. Compound 44 showed mixed inhibition of AChE in the enzyme kinetic studies. Some compounds exhibited moderate to high inhibition of AChE-induced Aβ1-42 aggregation and noticeable in vitro antioxidant and antiapoptotic properties. Compound 44 showed significant in vivo anti-ChE and antioxidant activities. Furthermore, compound 44 demonstrated in vivo neuroprotection by decreasing Aβ1-42-induced toxicity by attenuating abnormal levels of Aβ1-42, p-Tau, cleaved caspase-3, and cleaved PARP proteins. Compound 44 exhibited good oral absorption and was well tolerated up to 2000 mg/kg, po, dose without showing toxic effects.
authors.affiliation: Faculty of Pharmacy, Kalabhavan Campus, The Maharaja Sayajirao University of Baroda , Vadodara, 390 001, India.
authors.forename: Mahesh
authors.initials: M
authors.lastname: Shidore
authors.affiliation: Faculty of Pharmacy, Kalabhavan Campus, The Maharaja Sayajirao University of Baroda , Vadodara, 390 001, India.
authors.forename: Jatin
authors.initials: J
authors.lastname: Machhi
authors.affiliation: Faculty of Pharmacy, Kalabhavan Campus, The Maharaja Sayajirao University of Baroda , Vadodara, 390 001, India.
authors.forename: Kaushik
authors.initials: K
authors.lastname: Shingala
authors.affiliation: Faculty of Pharmacy, Kalabhavan Campus, The Maharaja Sayajirao University of Baroda , Vadodara, 390 001, India.
authors.forename: Prashant
authors.initials: P
authors.lastname: Murumkar
authors.affiliation: Faculty of Pharmacy, Kalabhavan Campus, The Maharaja Sayajirao University of Baroda , Vadodara, 390 001, India.
authors.forename: Mayank Kumar
authors.initials: MK
authors.lastname: Sharma
authors.affiliation: Faculty of Pharmacy, Kalabhavan Campus, The Maharaja Sayajirao University of Baroda , Vadodara, 390 001, India.
authors.forename: Neetesh
authors.initials: N
authors.lastname: Agrawal
authors.affiliation: Zoology Department, Faculty of Science, The Maharaja Sayajirao University of Baroda Vadodara, 390 001, India.
authors.forename: Ashutosh
authors.initials: A
authors.lastname: Tripathi
authors.affiliation: Zoology Department, Faculty of Science, The Maharaja Sayajirao University of Baroda Vadodara, 390 001, India.
authors.forename: Zalak
authors.initials: Z
authors.lastname: Parikh
authors.affiliation: Zoology Department, Faculty of Science, The Maharaja Sayajirao University of Baroda Vadodara, 390 001, India.
authors.forename: Prakash
authors.initials: P
authors.lastname: Pillai
authors.affiliation: Faculty of Pharmacy, Kalabhavan Campus, The Maharaja Sayajirao University of Baroda , Vadodara, 390 001, India.
authors.forename: Mange Ram
authors.initials: MR
authors.lastname: Yadav
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism; D000544:Alzheimer Disease / Q000188:drug therapy*; D000818:Animals; D000975:Antioxidants / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002091:Butyrylcholinesterase / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006801:Humans; D008297:Male; D051379:Mice; D015394:Molecular Structure; D010880:Piperidines / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: D000975:Antioxidants; D002800:Cholinesterase Inhibitors; D010880:Piperidines; D017382:Reactive Oxygen Species; D013844:Thiazoles; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase