Search

[Display omitted] • Design and synthesis of N -benzylpyrrolidine analogs. • Compounds 8f and 12f exhibited balanced inhibition of AChE, BChE, and BACE-1. • Propidium iodide displacement and inhibition of Aβ aggregation by 8f and 12f. • Ex vivo study of rat hippocampal homogenates suggested antioxidant potential. • Amelioration of scopolamine- and Aβ-induced cognitive impairment in AD rat models. Novel N -Benzylpyrrolidine hybrids were designed, synthesized, and tested against multiple in-vitro and in-vivo parameters. Among all the synthesized molecules, 8f and 12f showed extensive inhibition against beta-secretase-1 (hBACE-1), human acetylcholinesterase (hAChE) & human butyrylcholinesterase (hBuChE). These molecules are also endowed with significant AChE-peripheral anionic site (PAS) binding capability, blood-brain barrier permeability, potential disassembly of Aβ aggregates along with neuroprotection ability on SHSY-5Y cell lines. Results of the Y-Maze and Morris water maze test concluded that compounds 8f and 12f ameliorated cognitive dysfunction induced by scopolamine and Aβ. The ex-vivo activity was executed on rat's brain homogenate indicating a reduction in AChE level and oxidative stress. The pharmacokinetic investigation ascertained considerable oral absorption profile of the lead 12f. The results of the in silico docking studies and molecular dynamics simulations demonstrated stable interactions of compounds 8f and 12f with the target residues of hAChE, hBuChE and hBACE-1. [ABSTRACT FROM AUTHOR]

• Design and synthesis of ferulic acid-based 1,3,4-oxadiazole hybrids. • Compounds 6j and 6k exhibited balanced inhibition of AChE, BChE and BACE-1. • Propidium iodide displacement and inhibition of Aβ aggregation by 6j and 6k. • Ex vivo study of rat hippocampal homogenates suggested antioxidant potential. • Amelioration of scopolamine- and Aβ-induced cognitive impairment in AD rat models. Thirty ferulic acid-based 1,3,4-oxadiazole molecular hybrids were designed, synthesized, and screened them for multifunctional inhibitory potential against acetylcholinesterase (AChE), butyrylcholinesterase (BChE) and beta-secretase-1 (BACE-1). Compound 6j was the most potent inhibitor of AChE (IC 50 = 0.068 µM). It also showed equipotent inhibition of BChE and BACE-1 with IC 50 values of 0.218 µM and 0.255 µM, respectively. Compound 6k possessed the most significant inhibition of BChE and BACE-1 with IC 50 values, 0.163 µM and 0.211 µM, respectively. Compounds 6j and 6k elicited significant displacement of propidium iodide from PAS-AChE, excellent BBB permeability in PAMPA assay, and anti-Aβ aggregatory activity in self- and AChE-induced experiments with neuroprotective activity towards neuroblastoma SH-SY5Y cells. The in vivo behavioral studies suggested amelioration of cognitive dysfunction by 6j and 6k in the Y maze test. The ex vivo study signified brain AChE inhibition and antioxidant activity from these compounds. Moreover, 6j showed improvement in learning and memory behavior in the Aβ-induced ICV rat model by Morris water maze test with excellent oral absorption characteristics ascertained by pharmacokinetic studies. [ABSTRACT FROM AUTHOR]

The diverse nature of Alzheimer's disease (AD) has prompted researchers to develop multi-functional agents. Herein, we have designed and synthesized molecular hybrids of 2-pyridylpiperazine and 5-phenyl-1,3,4-oxadiazoles. Biological activities of synthesized compounds suggested significant and balanced inhibitory potential against target enzymes. In particular, compound 49 containing 2,4-difluoro substitution at terminal phenyl ring considered as most potential lead with inhibition of acetylcholinesterase (hAChE, IC 50 = 0.054 μM), butyrylcholinesterase (hBChE, IC 50 = 0.787 μM) and beta-secretase-1 (hBACE-1, IC 50 = 0.098 μM). The enzyme kinetics study of 49 against hAChE suggested a mixed type of inhibition (Ki = 0.030 μM). Also, 48 and 49 showed significant displacement of propidium iodide from the peripheral anionic site (PAS) of hAChE, excellent blood-brain barrier (BBB) permeability in parallel artificial membrane permeation assay (PAMPA), and neuroprotective ability against SH-SY5Y neuroblastoma cell lines. Further, 49 also exhibited anti-Aβ aggregation activity in self- and AChE-induced thioflavin T assay, which was ascertained by morphological characterization by atomic force microscopy (AFM). Moreover, in vivo behavioral studies signified learning and memory improvement by compound 49 in scopolamine- and Aβ-induced cognitive dysfunctions performed on Y-maze and Morris water maze. The ex vivo studies suggested decreased AChE activity and antioxidant potential of compound 49 , with good oral absorption characteristics ascertained by pharmacokinetic studies. Image 1 • Design and synthesis of 2-pyridylpiperazine and 5-phenyl-1,3,4-oxadiazoles hybrids. • Compounds 48 and 49 exhibited balanced inhibition of AChE and BACE-1. • Propidium iodide displacement and inhibition of Aβ aggregation by 48 and 49. • Ex vivo study of rat hippocampal homogenates suggested antioxidant potential. • Amelioration of scopolamine- and Aβ-induced cognitive impairment in AD rat models. [ABSTRACT FROM AUTHOR]

• 4-AP tethered 1,3,4-oxadiazole derivatives were designed and synthesized. • Compound 9 elicited significant non-competitive type of hAChE inhibition. • Compound 9 showed significant brain permeability in PAMPA-BBB assay. • Compound 9 ameliorated scopolamine- induced cognitive impairment in mice models. • Biochemical analysis using brain homogenates suggested antioxidant activity by 9. The novel hybrids bearing 4-aminopyridine (4-AP) tethered with substituted 1,3,4-oxadiazole nucleus were designed, synthesized, and evaluated for their potential AChE inhibitory property along with significant antioxidant potential. The inhibitory potential (IC 50) of synthesized analogs was evaluated against human cholinesterases (hAChE and hBChE) using Ellman's method. Among all the compounds, 9 with 4-hydroxyl substituent showed maximum hAChE inhibition with the non-competitive type of enzyme inhibition (IC 50 = 1.098 µM; Ki = 0.960 µM). Further, parallel artificial membrane permeation assay (PAMPA-BBB) showed significant BBB permeability in most of the synthesized compounds. Meanwhile, compound 9 also inhibited AChE-induced Aβ aggregation (38.2–65.9%) by thioflavin T assay. The in vivo behavioral studies showed dose-dependent improvement in learning and memory by compound 9. The ex vivo studies also affirmed the significant AChE inhibition and antioxidant potential of compound 9 in brain homogenates. [ABSTRACT FROM AUTHOR]