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[Display omitted] • Multi-targetable chalcones bearing n -aryl piperazine moiety were designed synthesized, and evaluated for the treatment of AD. • Compound 41 identified as potential ligand and may be considered as promising "lead". • It ameliorated cognitive dysfunctions and signified memory improvement in the in-vivo behavioural studies. • Ex vivo biochemical analysis showed reduced AChE and increased ACh levels along with antioxidant potential. The multi-target directed ligand (MTDL) discovery has been gaining immense attention in the development of therapeutics for Alzheimer's disease (AD). The strategy has been evolved as an auspicious approach suitable to combat the heterogeneity and the multifactorial nature of AD. Therefore, multi-targetable chalcone derivatives bearing N -aryl piperazine moiety were designed, synthesized, and evaluated for the treatment of AD. All the synthesized compounds were screened for the in vitro activity against acetylcholinesterase (AChE), butylcholinesterase (BuChE), β-secretase-1 (BACE-1), and inhibition of amyloid β (Aβ) aggregation. Amongst all the tested derivatives, compound 41 bearing unsubstituted benzylpiperazine fragment and para -bromo substitution at the chalcone scaffold exhibited balanced inhibitory profile against the selected targets. Compound 41 elicited favourable permeation across the blood–brain barrier in the PAMPA assay. The molecular docking and dynamics simulation studies revealed the binding mode analysis and protein–ligand stability of the compound with AChE and BACE-1. Furthermore, it ameliorated cognitive dysfunctions and signified memory improvement in the in-vivo behavioural studies (scopolamine-induced amnesia model). The ex vivo biochemical analysis of mice brain homogenates established the reduced AChE and increased ACh levels. The antioxidant activity of compound 41 was accessed with the determination of catalase (CAT) and malondialdehyde (MDA) levels. The findings suggested that compound 41 , containing a privileged chalcone scaffold, can act as a lead molecule for developing AD therapeutics. [ABSTRACT FROM AUTHOR]

[Display omitted] • The study provides structural insight into rGCase and its mechanism of interactions with chaperone. • Residues TYR 263, GLN 266, TYR 331, and GLU 358 play a major role in rGCase-chaperone interactions. • Chaperone shows stronger inhibitory activity and binding affinity for rGCase at pH 7.0 than pH 4.5. • AMB acted as a potent rGCase stabilizer, which improved rGCase thermostability. Disease-modifying treatment strategy for Parkinson's disease (PD) by stabilization of Glucocerebrosidase (GCase) enzyme by chaperones is of particular interest. Wild-type rat is a widely used animal model for PD; however, the in-silico model to elucidate the nature of rat GCase (rGCase)-chaperone interactions, mechanisms, and structural stability is still unavailable. Hence, we have developed pH-dependent rGCase homology models, in-silico (docking and molecular dynamics), and in-vitro techniques (enzyme kinetics and thermal stability) to address this gap. The homology modeling results revealed ≥ 90% rGCase residues were in the favored regions, representing adequate models quality. In-silico studies showed an interaction between chaperone (Ambroxol, AMB) and the active site residues TYR 331, TYR 263, GLN 266, and GLU 358 with the higher affinity at neutral pH than acidic pH. In-vitro studies showed higher inhibitory activity (IC 50) and binding affinity (K i) of AMB at neutral pH (IC 50 : 8.2 ± 2.6 µM and K i : 4.3 ± 1.2 µM) than acidic pH (IC 50 and K i : not identified). AMB improved rGCase thermostability was confirmed by thermal denaturation assay. We have developed the homology model for rGCase, which provides a perspective for designing and screening the chaperones at the initial phases of drug discovery to ameliorate PD. [ABSTRACT FROM AUTHOR]

Neuroinflammation is considered as one of the predisposing factor in the etiology of several neurodegenerative disorders. Therefore, the objective of the present study was to evaluate the protective effect of silibinin (SIL) in the lipopolysaccharide (LPS)-induced neuroinflammatory model. The effect of SIL on memory function was also evaluated on normal rats without LPS administration. In the first experiment, male rats were divided into five groups. Except control group animals, all rats received bilateral intracerebroventricular injection of LPS (5 μg/5 μl) into lateral ventricles on the first day of the experimental schedule. Control rats received bilateral intracerebroventricular injection of artificial cerebrospinal fluid into lateral ventricles. SIL in doses of 50, 100 and 200 mg/kg, p.o. was administered 1 h before LPS injection and continued for 7 days. On Day-7, SIL attenuated the LPS-induced long-term and working memory loss in elevated plus and Y-maze test respectively. Further, SIL dose-dependently attenuated LPS-induced decrease in acetylcholine level and increase in the acetylcholinestrase activity in hippocampus and pre-frontal cortex. SIL ameliorated LPS-induced decrease in the mitochondrial complex activity (I, IV and V) and integrity, increase in lipid peroxidation and decrease in the activity of superoxide dismutase in both the brain regions. SIL attenuated amyloidogenesis in the hippocampus, while it decreased the LPS-induced increase in the level of NFκB in the pre-frontal cortex. In another study, SIL dose-dependently, enhanced memory functions in the normal rats, indicating its nootropic activity. Hence, SIL could be a potential candidate in the management of neuroinflammation-related memory disorders. [ABSTRACT FROM AUTHOR]

Abstract: Asparagus Racemosus (AR) is an Ayurvedic rasayana possessing multiple neuropharmacological activities. The adpatogenic and antidepressant activity of AR is well documented. The present study was undertaken to assess nootropic and anti-amnesic activities of MAR in rats. The Morris water maze (MWM) and elevated plus maze (EPM) models were employed to evaluate learning and memory activity. Subsequently, the anti-amnestic activity was evaluated in scopolamine and sodium nitrite (NaNO2)-induced amnestic models in rats. Rats pre-treated with MAR (50, 100 and 200mg/kg, p.o) for 7days showed significant decrease in escape latency in the MWM test indicating nootropic activity. MAR also significantly reversed scopolamine and sodium nitrite-induced increase in transfer latency on EPM indicating anti-amnesic activity. Further, MAR dose-dependently inhibited acetylcholinesterase enzyme in specific brain regions (prefrontal cortex, hippocampus and hypothalamus). Thus, MAR showed nootropic and anti-amnesic activities in the models tested and these effects may probably be mediated through augmentation of cholinergic system due to its anti-cholinesterase activity. [ABSTRACT FROM AUTHOR]

• Development of acetyl cholinesterase inhibitors by fragment growing strategy driven de novo drug design approach. • Novel 3,5-diarylpyrazole analogs and hit optimization studies of spiropyrazoline derivatives were reported. • Compounds 44 and 67 exhibited inhibition of AChE, BuChE and Aβ 1-42 aggregation. • Compound 67 represents a beneficial hit compound for development of new chemical entities for cholinesterase inhibition. Cholinergic hypothesis of Alzheimer's disease has been advocated as an essential tool in the last couple of decades for the drug development. Here in, we report de novo fragment growing strategy for the design of novel 3,5-diarylpyrazoles and hit optimization of spiropyrazoline derivatives as acetyl cholinesterase inhibitors. Both type of scaffolds numbering forty compounds were synthesized and evaluated for their potencies against AChE, BuChE and PAMPA. Introduction of lipophilic cyclohexane ring in 3,5-diarylpyrazole analogs led to spiropyrazoline derivatives, which facilitated and improved the potencies. Compound 44 (AChE = 1.937 ± 0.066 µM; BuChE = 1.166 ± 0.088 µM; hAChE = 1.758 ± 0.095 µM; P e = 9.491 ± 0.34 × 10−6 cm s1) showed positive results, which on further optimization led to the development of compound 67 (AChE = 0.464 ± 0.166 µM; BuChE = 0.754 ± 0.121 µM; hAChE = 0.472 ± 0.042 µM; P e = 13.92 ± 0.022 × 10−6 cm s1). Compounds 44 and 67 produced significant displacement of propidium iodide from the peripheral anionic site (PAS) of AChE. They were found to be safer to MC65 cells and decreased metal induced Aβ 1-42 aggregation. Further, in-vivo behavioral studies, on scopolamine induced amnesia model, the compounds resulted in better percentage spontaneous alternation scores and were safe, had no influence on locomotion in tested animal groups at dose of 3 mg/kg. Early pharmacokinetic assessment of optimized hit molecules was supportive for further drug development. [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]