In silico studies, nitric oxide, and cholinesterases inhibition activities of pyrazole and pyrazoline analogs of diarylpentanoids.

A new series of pyrazole, phenylpyrazole, and pyrazoline analogs of diarylpentanoids (excluding compounds 3a, 4a, 5a, and 5b) was pan-assay interference compounds-filtered and synthesized via the reaction of diarylpentanoids with hydrazine monohydrate and phenylhydrazine. Each analog was evaluated for its anti-inflammatory ability via the suppression of nitric oxide (NO) on IFN-γ/LPS-activated RAW264.7 macrophage cells. The compounds were also investigated for their inhibitory capability toward acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), using a modification of Ellman's spectrophotometric method. The most potent NO inhibitor was found to be phenylpyrazole analog 4c, followed by 4e, when compared with curcumin. In contrast, pyrazole 3a and pyrazoline 5a were found to be the most selective and effective BChE inhibitors over AChE. The data collected from the single-crystal X-ray diffraction analysis of compound 5a were then applied in a docking simulation to determine the potential binding interactions that were responsible for the anti-BChE activity. The results obtained signify the potential of these pyrazole and pyrazoline scaffolds to be developed as therapeutic agents against inflammatory conditions and Alzheimer's disease.

Thieno[2,3-b]pyridine amines: Synthesis and evaluation of tacrine analogs against biological activities related to Alzheimer's disease.

In search of safer tacrine analogs, various thieno[2,3-b]pyridine amine derivatives were synthesized and evaluated for their inhibitory activity against cholinesterases (ChEs). Among the synthesized compounds, compounds 5e and 5d showed the highest activity towards acetylcholinesterase and butyrylcholinesterase, with IC50 values of 1.55 and 0.23 µM, respectively. The most active ChE inhibitors (5e and 5d) were also candidates for further complementary assays, such as kinetic and molecular docking studies as well as studies on inhibitory activity towards amyloid-beta (ßA) aggregation and ß-secretase 1, neuroprotectivity, and cytotoxicity against HepG2 cells. Our results indicated efficient anti-Alzheimer's activity of the synthesized compounds.

Chemical composition and anticholinesterase inhibitory activity of Pavetta graciliflora Wall. ex Ridl. essential oil.

Chemical composition and anticholinesterase activity of the essential oil of Pavetta graciliflora Wall. ex Ridl. (Rubiaceae) was examined for the first time. The essential oil was obtained by hydrodistillation and was fully characterized by gas chromatography (GC) and gas chromatography-mass spectrometry (GC-MS). A total of 20 components were identified in the essential oil, which made up 92.85% of the total oil. The essential oil is composed mainly of ß-caryophyllene (42.52%), caryophyllene oxide (25.33%), ß-pinene (8.67%), and α-pinene (6.52%). The essential oil showed weak inhibitory activity against acetylcholinesterase (AChE) (I%: 62.5%) and butyrylcholinesterase (BChE) (I%: 65.4%) assays. Our findings were shown to be very useful for the characterization, pharmaceutical, and therapeutic applications of the essential oil from P. graciliflora.

Structural and functional characterization of an organometallic ruthenium complex as a potential myorelaxant drug.

In addition to antibacterial and antitumor effects, synthetic ruthenium complexes have been reported to inhibit several medicinally important enzymes, including acetylcholinesterase (AChE). They may also interact with muscle-type nicotinic acetylcholine receptors (nAChRs) and thus affect the neuromuscular transmission and muscle function. In the present study, the effects of the organometallic ruthenium complex of 5-nitro-1,10-phenanthroline (nitrophen) were evaluated on these systems. The organoruthenium-nitrophen complex [(η6-p-cymene)Ru(nitrophen)Cl]Cl; C22H21Cl2N3O2Ru (C1-Cl) was synthesized, structurally characterized and evaluated in vitro for its inhibitory activity against electric eel acetylcholinesterase (eeAChE), human recombinant acetylcholinesterase (hrAChE), horse serum butyrylcholinesterase (hsBChE) and horse liver glutathione-S-transferase. The physiological effects of C1-Cl were then studied on isolated mouse phrenic nerve-hemidiaphragm muscle preparations, by means of single twitch measurements and electrophysiological recordings. The compound C1-Cl acted as a competitive inhibitor of eeAChE, hrAChE and hsBChE with concentrations producing 50 % inhibition (IC50) of enzyme activity ranging from 16 to 26 µM. Moreover, C1-Cl inhibited the nerve-evoked isometric muscle contraction (IC50 = 19.44 µM), without affecting the directly-evoked muscle single twitch up to 40 µM. The blocking effect of C1-Cl was rapid and almost completely reversed by neostigmine, a reversible cholinesterase inhibitor. The endplate potentials were also inhibited by C1-Cl in a concentration-dependent manner (IC50 = 7.6 µM) without any significant change in the resting membrane potential of muscle fibers up to 40 µM. Finally, C1-Cl (5-40 µM) decreased (i) the amplitude of miniature endplate potentials until a complete block by concentrations higher than 25 µM and (ii) their frequency at 10 µM or higher concentrations. The compound C1-Cl reversibly blocked the neuromuscular transmission in vitro by a non-depolarizing mechanism and mainly through an action on postsynaptic nAChRs. The compound C1-Cl may be therefore interesting for further preclinical testing as a new competitive neuromuscular blocking, and thus myorelaxant, drug.

Resveratrol oligomers from Paeonia suffruticosa protect mice against cognitive dysfunction by regulating cholinergic, antioxidant and anti-inflammatory pathways.

ETHNOPHARMACOLOGICAL RELEVANCE: Paeonia suffruticosa Andr. has been widely used in traditional Chinese medicine as an anti-tumour, anti-oxidant, anti-inflammatory and neuroprotective agent. Resveratrol oligomers are the main components of the seed coat extracts of Paeonia suffruticosa (PSCE) and have DPPH free radical scavenging and ß-secretase inhibitory activity. However, studies of its effect on ameliorating cognitive deficits are limited, and analyses of the underlying mechanisms are insufficient. AIM OF STUDY: This study aimed to investigate the cholinesterase inhibitory activities of resveratrol oligomers from P. suffruticosa in vitro and their effects on diminishing the oxygen-glucose deprivation/reoxygenation (OGD/R) -induced cytotoxicity in PC12 cells and scopolamine-induced cognitive deficits in mice. Moreover, the underlying mechanisms were further explored. MATERIALS AND METHODS: In vitro, the inhibitory effects of PSCE and its 10 stilbenes on acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) were evaluated using the Ellman's assay, and its protective effects on normal and OGD/R-injured PC12 cells were evaluated using the MTT assay. For the in vivo assay, C57BL/6 mice were orally administered with PSCE at doses of 150 and 600 mg/kg for 28 days, and injected with scopolamine (1.5 mg/kg) to induce cognitive deficits. The memory behaviours were evaluated using the novel object recognition, Morris water maze and inhibitory avoidance test. Levels of various biochemical markers were also examined, including AChE, choline acetyltransferase (ChAT), acetylcholine (ACh), superoxide dismutase (SOD), catalase (CAT), glutathione (GSH) in the mouse brain and interleukin-1ß (IL-1ß), interleukin-6 (IL-6), tumour necrosis factor-α (TNF-α), interleukin-4 (IL-4) in serum. RESULTS: PSCE and its 10 stilbenes display good inhibition of AChE and BuChE activities and significantly increase the viability of normal and OGD/R-injured PC12 cells. PSCE improves the cognitive performance of scopolamine-treated mice in behavioural tests. Meanwhile, PSCE increases AChE, ChAT, SOD, and CAT activities and ACh, GSH, IL-4 levels, and decreases IL-1ß, IL-6, TNF-α levels in the model animals. CONCLUSIONS: Resveratrol oligomers from P. suffruticosa show neuroprotective effect in vitro and in vivo by regulating cholinergic, antioxidant and anti-inflammatory pathways, may have promising application in the treatment of Alzheimer's disease.

Design, synthesis and cholinesterase inhibitory activity of α-mangostin derivatives.

α-mangostin, a polyphenol xanthone derivative, was mainly isolated from pericarps of the mangosteen fruit (Garcinia mangostana L.). In present investigation, a series of derivatives were designed, synthesised and evaluated in vitro for their inhibitory activity of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). Among the synthesised xanthones, compounds 1, 9, 13 and 16 showed AChE selective inhibitory activity, 15 was a BuChE selective inhibitor while 2, 3, 5, 6, 7, 12 and 14 were dual inhibitors. The most potent inhibitor of AChE was 16 while 5 was the most potent inhibitor of BuChE with IC50 values of 5.26 µM and 7.55 µM respectively.

Multidirectional biological investigation and phytochemical profile of Rubus sanctus and Rubus ibericus.

In the present study, the biological properties, including, the enzyme inhibitory and antioxidant activities, as well as, the phytochemical profile of the ethyl acetate, methanol, and water extracts of Rubus sanctus Schreb. and Rubus ibericus Juz. leaves were determined using in vitro bioassays. Wide range of phytochemicals, including, hydroxybenzoic acids, hydroxycinnamic acids, acylquinic acids, ellagitannins, flavonoids, and triterpenoid saponins were determined using UHPLC-ESI/HRMS technique. The ethyl acetate and methanol extracts of the studied Rubus species effectively inhibited acetyl and butyryl cholinesterase. On the other hand, R. sanctus water extract showed low inhibition against α-amylase and prominent inhibitory action against α-glucosidase. Data collected from this study reported the radical scavenging and reducing potential of the studied Rubus species. Investigation of the protective effects of the different extracts of R. sanctus and R. ibericus in experimental model of ulcerative colitis was performed. The extracts were also tested on spontaneous migration of human colon cancer cells (HCT116) in wound healing experimental paradigm. Only R. sanctus methanol extract inhibited spontaneous HCT116 migration in the wound healing test. Our results suggested that R. sanctus and R. ibericus may be potential candidates as sources of biologically-active compounds for the development of nutraceuticals, pharmaceuticals, and/or cosmetics.

Design and Synthesis of Selective Acetylcholinesterase Inhibitors: Arylisoxazole-Phenylpiperazine Derivatives.

In this work, a novel series of arylisoxazole-phenylpiperazines were designed, synthesized, and evaluated toward acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Our results revealed that [5-(2-chlorophenyl)-1,2-oxazol-3-yl](4-phenylpiperazin-1-yl)methanone (5c) was the most potent AChE inhibitor with IC50 of 21.85 µm. It should be noted that most of synthesized compounds showed no BChE inhibitory activity and [5-(2-fluorophenyl)-1,2-oxazol-3-yl](4-phenylpiperazin-1-yl)methanone (5a) was the most active anti-BChE derivative (IC50 =51.66 µm). Also, kinetic studies for the AChE and BChE inhibitory activity of compounds 5c and 5a confirmed that they have simultaneously bound to the catalytic site (CS) and peripheral anionic site (PAS) of both AChE and BChE. Furthermore, docking study of compound 5c showed desired interactions of that compound with amino acid residues located in the active and peripheral anionic sites. Compound 5c was also evaluated for its BACE1 inhibitory activity and demonstrated IC50 =76.78 µm. Finally, neuroprotectivity of compound 5c on Aß-treated neurotoxicity in PC12 cells depicted low activity.

Design, synthesis, and biological evaluation of selective and potent Carbazole-based butyrylcholinesterase inhibitors.

Alzheimer's disease (AD) is the most common form of dementia. Inhibition of BChE might be a useful therapeutic target for AD. A new series of Carbazole-Benzyl Pyridine derivatives were designed synthesized and evaluated as butyrylcholinesterase (BChE) inhibitors. In vitro assay revealed that all of the derivatives had selective and potent anti- BChE activities. 3-((9H-Carbazol-9-yl)methyl)-1-(4-chlorobenzyl)pyridin-1-ium chloride (compound 8f) had the most potent anti-BChE activity (IC50 value = 0.073 µM), the highest BChE selectivity and mixed-type inhibition. Docking study revealed that 8f interacted with the peripheral site, the choline binding site, catalytic site and the acyl pocket of BChE. Physicochemical properties were accurate to Lipinski's rule. In addition, compound 8f demonstrated neuroprotective activity at 10 µM. This compound could also inhibit AChE-induced and self-induced Aß peptide aggregation at concentration of 100 µM and 10 µM respectively. The in-vivo study showed that compound 8f in 10 mg/kg increased the time spent in target quadrant in the probe day and decreased mean training period scape latency in rats. All results suggest that new sets of potent selective inhibitors of BChE have a therapeutic potential for the treatment of AD.

meta-Cyanobenzyl substituted benzimidazolium salts: Synthesis, characterization, crystal structure and carbonic anhydrase, α-glycosidase, butyrylcholinesterase, and acetylcholinesterase inhibitory properties.

meta-Cyanobenzyl-substituted N-heterocyclic carbene (NHC) precursors were synthesized by the reaction of a series of N-(alkyl)benzimidazolium with 3-bromomethyl-benzonitrile. These benzimidazolium salts were characterized by using 1 H NMR, 13 C NMR, FTIR spectroscopy, and elemental analysis techniques. The molecular and crystal structures of 2f and 2g complexes were obtained by using the single-crystal X-ray diffraction method. The derivatives of these novel NHC precursors were effective inhibitors of α-glycosidase (AG), the cytosolic carbonic anhydrase I and II isoforms (hCA I and II), butyrylcholinesterase (BChE), and acetylcholinesterase (AChE) with Ki values in the range of 1.01-2.12 nM for AG, 189.56-402.44 nM for hCA I, 112.50-277.37 nM for hCA II, 95.45-352.58 nM for AChE, and 132.91-571.18 nM for BChE. In the last years, inhibition of the CA enzyme has been considered as a promising factor for pharmacologic intervention in a diversity of disturbances such as obesity, glaucoma, cancer, and epilepsy.

Can nonalcoholic beer, silicon and hops reduce the brain damage and behavioral changes induced by aluminum nitrate in young male Wistar rats?

Aluminum consumption has been associated with various neurodegenerative diseases. Previous studies suggest that regular beer intake reverses the pro-oxidant and inflammatory statuses induced by aluminum nitrate intoxication. This paper aims to evaluate the in vitro antioxidant capacity and acetylcholinesterase inhibitory activity of non-alcoholic beer (NABeer), silicon or hops, as well as their effect on animal behavior (e.g. curiosity, immobilization, rearing, grooming, swimming) and brain antioxidant enzyme (activity and gene expression) and anti-inflammatory status in aluminum nitrate intoxicated rats. Male Wistar rats were divided into five groups: 1) Control, 2) Aluminum nitrate (450 µg/kg/day), 3) Aluminum nitrate plus NABeer, 4) Aluminum nitrate plus hops, and 5) Aluminum nitrate plus silicon. Hops showed the highest in vitro antioxidant capacity and silicon the highest anticholinesterase activity. In the Aluminum group the brain aluminum/silicon ratio increased with impairment of brain antioxidant and inflammatory statuses. NABeer, silicon and hops block the negative effect on the in vivo antioxidant and inflammatory statuses induced by Aluminum nitrate and improve swimming and rearing behavioral tests. The various positive results suggest that NABeer is useful as a functional multi-target drink in the prevention of some neurodegenerative events caused by aluminum intoxication. More studies are required to conclude present results.

New tacrine-acridine hybrids as promising multifunctional drugs for potential treatment of Alzheimer's disease.

The synthesis, biological tests, and computer modeling of a series of novel promising tacrine hybrids for the therapy of Alzheimer's disease are reported. Firstly, new tacrine-acridine hybrids with different carbon linker lengths were synthesized. Secondly, all the compounds were tested in vitro for their ability to inhibit acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) enzyme activity. After that, the most promising compound 3d was tested using the amyloid-ß aggregation assay. To evaluate possible toxic effects, cytotoxicity tests were conducted. The most active compound 3d (IC50 = 7.6 pM for AChE and 1.7 pM for BuChE) appeared to be a much more active inhibitor than tacrine (IC50 = 89.9 nM for AChE and 14.9 nM for BuChE). At the highest concentration (100 µM), 3d exhibited 57.77% activity, retaining it as the concentration decreased: 50 µM - 54.74%, 20 µM - 48.28%, 10 µM - 31.66%. The compound showed no significant cytotoxic effect at the tested concentrations. At the end, docking studies using methods of computer modeling were performed to visualize the binding mode of the inhibitor 3d. It showed dual-binding mode for AChE, by binding to the catalytic anionic site and the peripheral anionic site simultaneously. Thus, compound 3d is a promising multitarget hybrid that can be used for the treatment of Alzheimer's disease.

In Silico Identification and Experimental Validation of Novel Anti-Alzheimer's Multitargeted Ligands from a Marine Source Featuring a "2-Aminoimidazole plus Aromatic Group" Scaffold.

Multitargeting or polypharmacological approaches, looking for single chemical entities retaining the ability to bind two or more molecular targets, are a potentially powerful strategy to fight complex, multifactorial pathologies. Unfortunately, the search for multiligand agents is challenging because only a small subset of molecules contained in molecular databases are bioactive and even fewer are active on a preselected set of multiple targets. However, collections of natural compounds feature a significantly higher fraction of bioactive molecules than synthetic ones. In this view, we searched our library of 1175 natural compounds from marine sources for molecules including a 2-aminoimidazole+aromatic group motif, found in known compounds active on single relevant targets for Alzheimer's disease (AD). This identified two molecules, a pseudozoanthoxanthin (1) and a bromo-pyrrole alkaloid (2), which were predicted by a computational approach to possess interesting multitarget profiles on AD target proteins. Biochemical assays experimentally confirmed their biological activities. The two compounds inhibit acetylcholinesterase, butyrylcholinesterase, and ß-secretase enzymes in high- to sub-micromolar range. They are also able to prevent and revert ß-amyloid (Aß) aggregation of both Aß1-40 and Aß1-42 peptides, with 1 being more active than 2. Preliminary in vivo studies suggest that compound 1 is able to restore cholinergic cortico-hippocampal functional connectivity.

Discovery of Novel Pyrazolopyrimidinone Derivatives as Phosphodiesterase 9A Inhibitors Capable of Inhibiting Butyrylcholinesterase for Treatment of Alzheimer's Disease.

Discovery of multitarget-directed ligands (MTDLs), targeting different factors simultaneously to control the complicated pathogenesis of Alzheimer's disease (AD), has become an important research area in recent years. Both phosphodiesterase 9A (PDE9A) and butyrylcholinesterase (BuChE) inhibitors could participate in different processes of AD to attenuate neuronal injuries and improve cognitive impairments. However, research on MTDLs combining the inhibition of PDE9A and BuChE simultaneously has not been reported yet. In this study, a series of novel pyrazolopyrimidinone-rivastigmine hybrids were designed, synthesized, and evaluated in vitro. Most compounds exhibited remarkable inhibitory activities against both PDE9A and BuChE. Compounds 6c and 6f showed the best IC50 values against PDE9A (6c, 14 nM; 6f, 17 nM) together with the considerable inhibition against BuChE (IC50, 6c, 3.3 µM; 6f, 0.97 µM). Their inhibitory potencies against BuChE were even higher than the anti-AD drug rivastigmine. It is worthy mentioning that both showed moderate selectivity for BuChE over acetylcholinesterase (AChE). Molecular docking studies revealed their binding patterns and explained the influence of configuration and substitutions on the inhibition of PDE9A and BuChE. Furthermore, compounds 6c and 6f exhibited negligible toxicity, which made them suitable for the further study of AD in vivo.

Acetamide Derivatives of Chromen-2-ones as Potent Cholinesterase Inhibitors.

Alzheimer's disease (AD), a neurodegenerative disorder, is a serious medical issue worldwide with drastic social consequences. Inhibition of cholinesterase is one of the rational and effective approaches to retard the symptoms of AD and, hence, consistent efforts are being made to develop efficient anti-cholinesterase agents. In pursuit of this, a series of 19 acetamide derivatives of chromen-2-ones were synthesized and evaluated for their acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory potential. All the synthesized compounds exhibited significant anti-AChE and anti-BChE activity, with IC50 values in the range of 0.24-10.19 µM and 0.64-30.08 µM, respectively, using donepezil hydrochloride as the standard. Out of 19 compounds screened, 3 compounds, viz. 22, 40, and 43, caused 50% inhibition of AChE at 0.24, 0.25, and 0.25 µM, respectively. A kinetic study revealed them to be mixed-type inhibitors, binding with both the CAS and PAS sites of AChE. The above-selected compounds were found to be effective inhibitors of AChE-induced and self-mediated Aß1-42 aggregation. ADMET predictions demonstrated that these compounds may possess suitable blood-brain barrier (BBB) permeability. Hemolytic assay results revealed that these compounds did not lyse human RBCs up to a thousand times of their IC50 value. MTT assays performed for the shortlisted compounds showed them to be negligibly toxic after 24 h of treatment with the SH-SY5Y neuroblastoma cells. These results provide insights for further optimization of the scaffolds for designing the next generation of compounds as lead cholinesterase inhibitors.

Aflatoxins produced by Aspergillus parasiticus present in the diet of quails increase the activities of cholinesterase and adenosine deaminase.

The aim of this study was to evaluate the effects of aflatoxins on cholinesterases (acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), and adenosine deaminase (ADA) activities in quails. For this, twenty male quails were randomly distributed into two groups (n = 10 each): the group A was composed by quails that received feed without aflatoxin (the control group); while the group B was composed by quails that received feed contaminated with 200 ppm/kg of feed of aflatoxin. On day 20, the animals were euthanized to measure the activities of AChE (total blood and brain), BChE (serum) and ADA (serum, liver, and brain), as well as for histopathological analyses (liver and intestine). AChE, BChE, and ADA levels increased in animals intoxicated by aflatoxin compared to the control group. The presence of aflatoxin lead to severe hydropic degeneration of hepatocytes and small focus of hepatocyte necrosis. In conclusion, aflatoxins poisoning increased AChE, BChE, and ADA activities, suggesting the involvement of these enzymes during this type of intoxication, in addition to the fact that they are well known molecules that participate in physiological and pathological events as inflammatory mediators. In summary, increased AChE, BChE and ADA activities contribute directly to the inflammatory process and tissue damage, and they might be involved in disease development.

Green synthesis of novel spiro-indenoquinoxaline derivatives and their cholinesterases inhibition activity.

A convenient synthesis of substituted spiroindenoquinoxalines at mild and green conditions was developed. Multicomponent reaction of substituted phenylene diamines, ninhydrin, malononitrile and N,N'-substituted-2-nitroethene-1,1-diamines produced the target compounds. Twelve new spiroindenoquinoxalines were obtained, and their ability in inhibition of acetyl and butyrylcholinesterases were investigated both in vitro and in silico. All compounds showed moderate level activity against both acetyl and butyrylcholinesterases.

Design, synthesis and evaluation of novel ferulic acid-O-alkylamine derivatives as potential multifunctional agents for the treatment of Alzheimer's disease.

A series of novel ferulic acid-O-alkylamines derivatives were designed, synthesized, and evaluated as multitarget-directed ligands against Alzheimer's disease. In vitro studies displayed that all the synthesized target compounds showed impressive inhibitory activity against butyrylcholinesterase (BuChE), significant inhibition/disaggregation of self-induced ß-amyloid (Aß) aggregation and acted as potential antioxidants. Particularly, compound 7f, one of the most potent BuChE inhibitor (IC50 value of 0.021 µM for equine serum BuChE, 8.63 µM for ratBuChE and 0.07 µM for human serum BuChE), was found to be a good acetylcholinesterase (AChE) inhibitor (IC50 = 2.13 µM for electric eel AChE, 1.8 µM for ratAChE and 3.82 µM for human erythrocytes AChE), and the result of molecular docking provided an explanation for its selective BuChE inhibitory activity. Compound 7f also had noteworthy inhibitory effects on self-induced Aß1-42 aggregation (50.8 ± 0.82%) and was found to disaggregate self-induced Aß1-42 aggregation (38.7 ± 0.65%), which was further elucidated by the transmission electron microscopy. Meanwhile, compound 7f showed the modest antioxidant activity (0.55 eq of Trolox), good protective effect against H2O2-induced PC12 cell injury, with low toxicity. Moreover, compound 7f could cross the blood-brain barrier (BBB) in vitro. Significantly, compound 7f did not exhibit any acute toxicity in mice at doses up to 1000 mg/kg, and the step-down passive avoidance test showed this compound significantly reversed scopolamine-induced memory deficit in mice. Taken together, the results indicated that compound 7f is a very promising multifunctional agent in the treatment of Alzheimer's disease, particularly the advanced stages of AD.

Phenolic Extracts from Clerodendrum volubile Leaves Inhibit Cholinergic and Monoaminergic Enzymes Relevant to the Management of Some Neurodegenerative Diseases.

This study investigated the inhibitory effects of phenolic-rich extracts from Clerodendrum volubile leaves on cholinergic [acetylcholinesterase (AChE) and butyrylcholinesterase (BChE)] and monoaminergic [monoamine oxidase (MAO)] enzymes' activities and pro-oxidants [Fe2+ and quinolinic acid-(QA)] induced lipid peroxidation in rats brain homogenates in vitro. Free phenolic extracts (FPE) and bound phenolic extracts (BPE) were obtained via solvent extraction, and the total phenol and flavonoid contents were evaluated. The phenolic constituents of the extracts were also determined using high performance liquid chromatography coupled with diode array detector (HPLC-DAD). Our findings revealed that FPE had higher AChE (2.06 µg/mL), BChE (2.79 µg/mL), and MAO (2.81 µg/mL) inhibitory effects than BPE [AChE, 2.80 µg/mL; BChE, 3.40 µg/mL; MAO, 3.39 µg/mL]. Furthermore, FPE also had significantly (P < 0.05) higher inhibitory effects on Fe2+ and QA-induced lipid peroxidation compared to BPE. FPE (162.61 mg GAE/g) had higher total phenol content than BPE. However, BPE (18.65 mg QE/g) had significantly higher total flavonoid content than FPE (13.32 mg QE/g). Phenolic acids (such as gallic acid, catechin, chlorogenic, caffeic, ellagic, p-Coumaric acids) and flavonoids (catechins, rutin and quercetin) were present in both extracts. This study revealed that the enzymes' inhibitory activities and antioxidant potentials of phenolic-rich extracts from C. volubile could be part of the mechanism of actions behind its use for memory/cognitive function as obtained in folklore. However, FPE exhibited significantly higher enzymes, inhibitory and antioxidant potentials than BPE.

Evaluation of multifunctional synthetic tetralone derivatives for treatment of Alzheimer's disease.

Neurodegeneration, a complex disease state, comprises several pathways that contribute to cell death. Conventional approach of targeting only one of these pathways has not been proven to be entirely successful and has demanded a hypothetical change as to how researchers design and develop new drugs. In this study, effects of a series of α, ß-unsaturated carbonyl-based tetralone derivatives against Alzheimer's disease (AD) were investigated. Moreover, their activity toward amyloid ß-induced cytotoxicity was also studied. Six compounds including 3f, 3o, 3u, 3ae, 3af, and 3ag were discovered to be most protective against Aß-induced neuronal cell death in PC12 cells. The findings of in vitro experiment revealed that most of these compounds exhibited potent inhibitory activity against MAO-B, AChE, and self-induced Aß1-42 aggregation. The compound 3f exhibited best AChE (IC50  = 0.045 ± 0.02 µm) inhibitory potential in addition to potent inhibition of MAO-B (IC50  = 0.88 ± 0.12 µm). Furthermore, compound 3f disassembled the Aß fibrils produced by self-induced Aß aggregation by 78.2 ± 4.8%. Collectively, these findings suggest that some compounds from this series have potential to be promising multifunctional agents for AD treatment.