Novel Multifunctional Ascorbic Triazole Derivatives for Amyloidogenic Pathway Inhibition,Anti-Inflammation,and Neuroprotection

Alzheimer’s disease (AD) is a common neurodegenerative disorder. The number of patients with AD is projected to reach 152 million by 2050. Donepezil, rivastigmine, galantamine, and memantine are the only four drugs currently approved by the United States Food and Drug Administration for AD treatment. However, these drugs can only alleviate AD symptoms. Thus, this research focuses on the discovery of novel lead compounds that possess multitarget regulation of AD etiopathology relating to amyloid cascade. The ascorbic acid structure has been designated as a core functional domain due to several characteristics, including antioxidant activities, amyloid aggregation inhibition, and the ability to be transported to the brain and neurons. Multifunctional ascorbic derivatives were synthesized by copper (I)-catalyzed azide–alkyne cycloaddition reaction (click chemistry). The in vitro and cell-based assays showed that compounds 2c and 5c exhibited prominent multifunctional activities as beta-secretase 1 inhibitors, amyloid aggregation inhibitors, and antioxidant, neuroprotectant, and anti-inflammatory agents. Significant changes in activities promoting neuroprotection and anti-inflammation were observed at a considerably low concentration at a nanomolar level. Moreover, an in silico study showed that compounds 2c and 5c were capable of being permeated across the blood–brain barrier by sodium-dependent vitamin C transporter-2.     

Non-Alkaloid Cholinesterase Inhibitory Compounds from Natural Sources

Alzheimer’s disease (AD) is a severe neurodegenerative disorder of different brain regions accompanied by distresses and affecting more than 25 million people in the world. This progressive brain deterioration affects the central nervous system and has negative impacts on a patient’s daily activities such as memory impairment. The most important challenge concerning AD is the development of new drugs for long-term treatment or prevention, with lesser side effects and greater efficiency as cholinesterases inhibitors and the ability to remove amyloid-beta(Aβ) deposits and other related AD neuropathologies. Natural sources provide promising alternatives to synthetic cholinesterase inhibitors and many have been reported for alkaloids while neglecting other classes with potential cholinesterase inhibition. This review summarizes information about the therapeutic potential of small natural molecules from medicinal herbs, belonging to terpenoids, coumarins, and phenolic compounds, and others, which have gained special attention due to their specific modes of action and their advantages of low toxicity and high efficiency in the treatment of AD. Some show superior drug-like features in comparison to synthetic cholinesterase inhibitors. We expect that the listed phytoconstituents in this review will serve as promising tools and chemical scaffolds for the discovery of new potent therapeutic leads for the amelioration and treatment of Alzheimer’s disease.     

Synthesis, characterization, acetylcholinesterase inhibition, molecular modeling and antioxidant activities of some novel Schiff bases derived from 1-(2-ketoiminoethyl)piperazines

Some novel Schiff bases derived from 1-(2-ketoiminoethyl)piperazines were synthesized and characterized by mass spectroscopy, FTIR, UV-Visible, 1H and 13C-NMR. The compounds were tested for inhibitory activities on human acetylcholinesterase (hAChE), antioxidant activities, acute oral toxicity and further studied by molecular modeling techniques. The study identified the compound (DHP) to have the highest activity among the series in hAChE inhibition and DPPH assay while the compound LP revealed the highest activity in the FRAP assay. The hAChE inhibitory activity of DHP is comparable with that of propidium, a known AChE inhibitor. This high activity of DHP was checked by molecular modeling which showed that DHP could not be considered as a bivalent ligand due to its incapability to occupy the esteratic site (ES) region of the 3D crystal structure of hAChE. The antioxidant study unveiled varying results in 1,1-diphenyl-1-picrylhydrazyl (DPPH) and ferric reducing antioxidant power (FRAP) assays. This indicates mechanistic variations of the compounds in the two assays. The potential therapeutic applications and safety of these compounds were suggested for use as human acetylcholinesterase inhibitors and antioxidants.     

Synthesis and biological evaluation of lycorine derivatives as dual inhibitors of human acetylcholinesterase and butyrylcholinesterase

ABSTRACT: BACKGROUND: Alzheimer's disease (AD) is a neurologically degenerative disorder that affects more than 20 million people worldwide. The selective butyrylcholinesterase (BChE) inhibitors and bivalent cholinesterase (ChE) inhibitors represent new treatments for AD. FINDINGS: A series of lycorine derivatives (1--10) were synthesized and evaluated for anti-cholinesterase activity. Result showed that the novel compound 2-O-tert-butyldimethylsilyl-1-O-(methylthio)methyllycorine (7) was a dual inhibitor of human acetylcholinesterase (hAChE) and butyrylcholinesterase (hBChE) with IC50 values of 11.40 [PLUS-MINUS SIGN] 0.66 muM and 4.17 [PLUS-MINUS SIGN] 0.29 muM, respectively. The structure-activity relationships indicated that (i) the 1-O-(methylthio)methyl substituent in lycorine was better than the 1-O-acetyl group for the inhibition of cholinesterase; (ii) the acylated or etherified derivatives of lycorine and lycorin-2-one were more potent against hBChE than hAChE; and (iii) the oxidation of lycorine at C-2 decreases the activity. CONCLUSION: Acylated or etherified derivatives of lycorine are potential dual inhibitors of hBChE and hAChE. Hence, further study on the modification of lycorine for ChE inhibition is necessary.     

Potential of Ramalin and Its Derivatives for the Treatment of Alzheimer’s Disease

The pathogenesis of Alzheimer’s disease (AD) is still unclear, and presently there is no cure for the disease that can be used for its treatment or to stop its progression. Here, we investigated the therapeutic potential of ramalin (isolated from the Antarctic lichen, Ramalina terebrata), which exhibits various physiological activities, in AD. Specifically, derivatives were synthesized based on the structure of ramalin, which has a strong antioxidant effect, BACE-1 inhibition activity, and anti-inflammatory effects. Therefore, ramalin and its derivatives exhibit activity against multiple targets associated with AD and can serve as potential therapeutic agents for the disease.     

Hologram QSAR Models of 4-[(Diethylamino)methyl]-phenol Inhibitors of Acetyl/Butyrylcholinesterase Enzymes as Potential Anti-Alzheimer Agents

Hologram QSAR models were developed for a series of 36 inhibitors (29 training set and seven test set compounds) of acetyl/butyrylcholinesterase (AChE/BChE) enzymes, an attractive molecular target for Alzheimer's disease (AD) treatment. The HQSAR models (N = 29) exhibited significant cross-validated (AChE, q² = 0.787; BChE, q² = 0. 904) and non-cross-validated (AChE, r² = 0.965; BChE, r² = 0.952) correlation coefficients. The models were used to predict the inhibitory potencies of the test set compounds, and agreement between the experimental and predicted values was verified, exhibiting a powerful predictive capability. Contribution maps show that structural fragments containing aromatic moieties and long side chains increase potency. Both the HQSAR models and the contribution maps should be useful for the further design of novel, structurally related cholinesterase inhibitors.     

Dual inhibitors of Interleukin-6 and acetylcholinesterase for treatment of Alzheimer's disease: Design,docking, synthesis and biological evaluation

Multitarget compounds intercept two or more functionally complementary pathways simultaneously, and are therefore considered to have potential in effectively treating complex multifactorial diseases like Alzheimer's disease (AD). In the present study, novel molecules are designed by coupling a chromone and a N,N-disubstituted carbamoyl amine as pharmacophore for interleukin-6 (IL-6) and acetylcholinesterase (AChE) inhibition, respectively. Four series (Y1–Y4) of 40 compounds are designed by using alkyl linkers of different lengths (1–4 carbon atoms) for the coupling of the two selected pharmacophore. Docking of all designed compounds in AChE leads to the identification of twelve best fit compounds (Docking score >8.3). The data suggests that a 1- or 2-carbon atom linker is the most conducive to orient the pharmacophore for optimum binding with AChE active site. The predicted ADME properties of the 12 selected compounds suggest that these can cross the blood brain barrier (BBB) with good oral bioavailability. These compounds are synthesised and evaluated for anti-AChE activity. Five compounds, showing >45% inhibition of AChE, are further evaluated for IL-6 inhibitory activity. Compound Y1f is found to be the most potent inhibitor of both AChE and IL-6 (IC₅₀ 0.7 and 0.8 ​μM, respectively). It suggests that a chromone moiety connected to a piperidine ring through a 1-carbon atom linker may provide a useful template to medical chemists for the development of new chemical entities effective against AD.     

Antioxidant and anti-inflammatory related activities of selected synthetic chalcones: structure-activity relationship studies using computational tools

Synthetic derivatives of 1-(2-hydroxy-3-(2-hydroxy-cyclohexyl)-4,6-dimethoxy-phenyl)-methanone were evaluated in-vitro for their activities related to antioxidant and anti-inflammatory. The antioxidant potential was determined by calculating reducing potential, OH and DPPH (2,2-diphenyl-1-picryl hydrazine) radical scavenging activities. The in-vitro anti-inflammatory related activities of synthetic chalcones (SCs) were demonstrated by performing inhibition assays of trypsin, beta-glucuronidase and diene conjugates. The results of the various parameters studied shows that the selected derivatives were found to be effective reducing agents and were reactive towards stabilizing the OH and DPPH radicals. The compounds have showed moderate to poor or no inhibition profile towards trypsin and beta-glucuronidase, but were found to be effective inhibitor of dien conjugates (hydroperoxides). An attempt has been made to define structure activity relationship using BioMed CAChe 6.1.10: a computer-aided molecular modeling tool which applies equations from classical and quantum mechanics. The experimental and in silico results of the present investigation shows that the basic nucleus 1-(2-hydroxy-3-(2-hydroxy-cyclohexyl)-4,6-dimethoxy-phenyl)-methanone can be considered as a potential candidate for the design and development of lead antioxidant and anti-inflammatory agents.     

Preparative separation of the flavonoid fractions from Periploca forrestii Schltr. ethanol extracts using macroporous resin combined with HPLC analysis and evaluation of their biological activities

A preparative separation method using macroporous absorptive resin coupled with high‐performance liquid chromatography was developed for the separation of six fractions of the 80% ethanol extract of Periploca forrestii Schltr. The six ethanol fractions (5–95; A, B, C, D, E, and F) obtained were carefully analyzed to locate the corresponding peaks in the high‐performance liquid chromatography chromatogram of the total extract, which was established in a previous study. Furthermore, the biological activities, including antioxidant activities, acetyl cholinesterase inhibitory capacities, antihyaluronidase activities, and anti‐inflammatory effects, were evaluated in MH7A cells. The results demonstrated that fraction E could significantly prevent oxidation and inhibit hyaluronidase and acetyl cholinesterase. Finally, the main flavonoids in fractions A and E from P. forrestii Schltr. were purified, and the compounds were identified as chlorogenic acid, quercetin‐3‐O‐α‐L‐arabinopyranoside, and quercetin‐7‐O‐β‐D‐glucopyranoside. The chemical structures were confirmed by mass spectrometry and nuclear magnetic resonance spectroscopy. Furthermore, the inhibitory effects of these compounds against complete Freund's adjuvant‐induced secondary immune arthritis in rats were evaluated.     

Synthesis,antioxidant, and anticholinesterase activities of novel N-arylsulfonyl hydrazones bearing sulfonate ester scaffold

In this research, two new series of N-arylsulfonyl hydrazone compounds ( 14 – 25 ) possessing a sulfonate moiety were synthesized and characterized by elemental analysis and various spectroscopic techniques including fourier transform infrared (FT-IR), ¹H-, and ¹³C nuclear magnetic resonance (NMR). These compounds synthesized as target molecules ( 14 – 25 ) were tested for their in vitro acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibition activities and antioxidant potential. The antioxidant capacities of the tested molecules were determined by four different assays. The IC₅₀ values of the screened molecules were determined in the range of 60.14 ± 0.25–84.81 ± 1.09 μM against AChE and in the range of 70.11 ± 0.67–93.60 ± 0.47 μM against BChE. In the AChE assay, 4-hydroxybenzaldehyde-based compound 25 (60.14 ± 0.25 μM) showed the highest activity in comparison to rivastigmine (501 ± 3.08 μM). This compound (71.42 ± 0.19 μM) is also one of the compounds with the highest activity against BChE. In the BChE assay, 2-hydroxybenzaldehyde-based compound 19 (70.11 ± 0.67 μM) indicated the highest activity in comparison to rivastigmine (19.95 ± 0.20 μM). In antioxidant activity studies, the tested molecules showed lower activities than the standard compounds (butylated hydroxytoluene and α-tocopherol). Consequently, some novel compounds can be used as potential inhibitor candidates in future studies.     

Antibacterial, Antiurease, and Antioxidant Activities of Some Arylidene Barbiturates

Some series of arylidene barbiturates and thiobarbiturates were evaluated for their antibacterial, antioxidant, and urease inhibition activities. The arylidene barbiturates and thiobarbiturates were tested for antimicrobial activity using the agar well diffusion technique against 13 bacteria. The synthesized compounds (1a–g) were screened for antiurease and antioxidant activities. The results showed that the synthesized compounds (1a–g) had effective antiurease, antioxidant, and antibacterial activities.     

Design,Synthesis, and Evaluation of Novel 2H-Benzo[b][1,4]thiazin-3(4H)-one Derivatives as New Acetylcholinesterase Inhibitors

Alzheimer’s disease (AD) is a slowly progressive neurodegenerative disease that causes dementia in people aged 65 and over. In the present study, a series of thiadiazole hybrid compounds with benzothiazine derivatives as acetylcholinesterase inhibitors were developed and evaluated for their biological activity. The AChE and BChE inhibition potentials of all compounds were evaluated by using the in vitro Ellman method. The biological evaluation showed that compounds 3i and 3j displayed significant inhibitory activity against AChE. Compounds 3i and 3j showed IC₅₀ values of 0.027 µM and 0.025 µM against AChE, respectively. The reference drug donepezil (IC₅₀ = 0.021 µM) also showed significant inhibition against AChE. Further docking simulation also revealed that these compounds (3i and 3j) interacted with the active site of the enzyme similarly to donepezil. The antioxidant study revealed that compounds 3i and 3j exhibited greater antioxidant effects. An in vitro blood–brain barrier permeability study showed that compounds 3i and 3j are promising compounds against AD. The cytotoxicity study of compounds 3i and 3j showed non-cytotoxic with an IC₅₀ value of 98.29 ± 3.98 µM and 159.68 ± 5.53 µM against NIH/3T3 cells, respectively.     

Phytochemical profiling,antioxidant, enzyme inhibition and cytotoxic potential of Bougainvillea glabra flowers

Abstract

In this study, phytochemical composition, antioxidant, enzyme inhibition and cytotoxic activities of methanol and dichloromethane (DCM) extracts of Bougainvillea glabra (B. glabra) flowers were investigated. Methanol extract was found to have higher total bioactive contents and UHPLC-MS analysis of methanol extract revealed the presence of well-known phenolic and flavonoid compounds. Antioxidant activities were performed by radical scavenging (DPPH and ABTS), reducing power (FRAP and CUPRAC), phosphomolybdenum (TAC) and metal chelating assays. From our result, we observed that methanol extract had many antioxidant compounds. The DCM extract exhibited higher cholinesterases and α-glucosidase enzyme inhibition, while methanol extract showed significant urease inhibition. Both extracts exhibited strong to moderate cytotoxicity against MCF-7, MDA-MB-231, CaSki, DU-145 and SW-480 cancer cells with IC₅₀ values ranging from 88.49 to 304.7 µg/mL. The findings showed the B. glabra to possess considerable antioxidant, enzyme inhibition and cytotoxic potentials and therefore has potential to discover novel bioactive molecules.     

Synthesis, molecular structure and reactivity of 5-methylidene-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolines

Synthesis of novel 5-methylidene-1,2,3,5-tetrahydro[2,1-b]-quinazoline derivatives 2-4 with potential biological activities mediated by alpha-adrenergic and/or imidazoline receptors was performed by reacting 2-chloro-4,5-dihydroimidazole (1) with the corresponding 2-aminoacetophenones. Compound 2, which incorporates an enamine moiety, underwent a 1,3-dipolar cycloaddition reaction with the appropriate nitrones 5-9 to give 1,2,3,5-tetrahydro-imidazo[2,1-b]quinazolin-5,5'-spiro-2',3'-diphenylisoxazol-idines 10-14. Reactions of the title compounds 2 and 4 with dimethyl acetylene-dicarboxylate (DMAD) afforded dimethyl 2-(2,3-dihydroimidazo[2,1-b]quinazolin-5(1H)-ylidenemethyl)but-2-enedioates 15, 16. Imidazo[2,1-b]quinazoline 2 was further treated with acetyl chloride, benzoyl chloride and mesyl chloride to give the 1-substituted derivatives 17, 18 and 19, respectively. The structures of all new compounds obtained were confirmed by elemental analysis and spectral data (IR, (1)H- and (13)C-NMR) as well asX-ray crystallographic analysis of 3 and 18.     

Synthesis,Characterization, and Antioxidant Evaluations of New 2‐Oxochromene and Benzofuran Derivatives Catalyzed by KF/CP

An eco‐friendly one‐pot procedure has been developed for the preparation of novel 2‐oxochromene and benzofuran derivatives through the sequential addition/intramolecular cyclization reactions of 1‐(6‐hydroxy‐2‐isopropenyl‐1‐benzofuran‐5‐yl)‐1‐ethanone, activated acetylenic compounds, and triphenylphosphine in the presence of catalytic amount of potassium fluoride impregnated clinoptilolite nanocatalyst in water at room temperature. The antioxidant activities of the newly synthesized derivatives ( 4a , 4b , and 5a ) were also screened by diphenyl‐2‐picrylhydrazyl radical scavenging and ferric ion reducing potential assays compared with the synthetic antioxidants (2‐tert‐butylhydroquinone and butylated hydroxytoluene). Compounds 4a and 4b were shown good antioxidant activities.     

Cystoseira algae (Fucaceae): update on their chemical entities and biological activities

Cystoseira (Sargassaceae) is a genus of marine brown algae composed of about 40 species, which is distributed along the Eastern Atlantic and Mediterranean coasts. The biological potential of the Cystoseira genus has been investigated and several activities have been reported. Chemically, this genus contains a wide variety of secondary metabolites, such as terpenoids, steroids, phlorotannins and phenolic compounds. Additionally, other chemical components as, for instance, carbohydrates, triacylglycerols/fatty acids, pigments as well as vitamins have been identified in the studied species. Some of the isolated compounds were associated with the reported pharmacological properties, as for example antioxidant, anti-inflammatory, cytotoxicity, anticancer, cholinesterase inhibition, anti-diabetic, activities but also antibacterial, antifungal and anti-parasitic activities. In this review, we provide a comprehensive overview of the compounds isolated and identified after 1995 from the different species of Cystoseira, compiling more than 200 compounds isolated, together with their therapeutic potential.     

Synthesis of Novel 4‐Substituted Coumarins,Docking Studies,and DHODH Inhibitory Activity

Coumarins are the important class of naturally occurring heterocyclic compounds. Activities like antioxidant, antibacterial, anti‐inflammatory, and anticancer have been reported for coumarin derivatives. Present work details the synthesis of substituted coumarin‐4‐pyrrolones as well as coumarin‐4‐acetyl amino acids and their DHODH inhibitory activity, which is a dual target for malaria and cancer. Coumarin‐4‐acetic acids ( 2a – c ) were coupled with different methyl esters of α‐amino acids ( 3 ) giving rise to corresponding coumarin‐4‐acetyl amino acid methyl esters ( 4a – o ), which on hydrolysis under basic condition underwent cyclization forming substituted dihydropyrrole‐2‐ones ( 5a – i ), dihydroindolizine‐3‐ones ( 5j – l ), and dihydropyrrolizin‐3‐one ( 5m – o ). Acidic hydrolysis of the compounds ( 4a – o ) yielded corresponding coumarin‐4‐acetyl amino acids ( 6a – f ). The docking study was performed with the protein 4IGH (obtained from PDB) using Surflex–Dock module. The newly synthesized compounds were tested for DHODH inhibitory activity using Brequinar as the standard. Compound 6b showed remarkable inhibition compared with the standard, and the other compounds with terminal COOH showed moderate inhibition.     

A new chromone, 11-hydroxy-sec-O-glucosylhamaudol from Ostericum koreanum

From the ethyl acetate fraction of the roots of Ostericum koreanum, a new chromone, 11-hydroxy-sec-O-glucosylhamaudol (1) along with the known compounds: four chromones, three coumarins, six phenolic compounds, and three quinic acids were isolated. These compounds were assessed for antioxidant activities in the DPPH radical and superoxide anion radical scavenging assay systems. Among isolates, 4-(2-hydroxy-vinyl)-benzene-1,2-diol (12) showed the most potent DPPH radical scavenging activity (IC(50)=4.80+/-0.62 mug/ml) and superoxide anion radical scavenging activity (IC(50)=11.05+/-0.83 microg/ml) in the xanthine/xanthine oxidase system. The antioxidant activities of 12 were comparable to those of quercetin and luteolin.     

Biocomputational Screening of Natural Compounds against Acetylcholinesterase

Alzheimer’s disease (AD) is the most common form of dementia and is characterized by irreversible and progressive neurodegeneration. Cholinergic dysfunction has been reported in AD, and several cholinesterase inhibitors, including natural compounds and synthetic analogs, have been developed to treat the disease. However, there is currently no treatment for AD, as most drug-like compounds have failed in clinical trials. Acetylcholinesterase (AChE) is the target of most drugs used commercially to treat AD. This work focused on screening natural compounds obtained from the ZINC database (224, 205 compounds) against AChE to identify those possibly capable of enabling the management of AD. Indirubin and dehydroevodiamine were the best potential AChE inhibitors with free binding energies of −10.03 and −9.00 kcal/mol, respectively. The key residue (His⁴⁴⁷) of the active site of AChE was found to participate in complex interactions with these two molecules. Six H-bonds were involved in the ‘indirubin–AChE’ interaction and three H-bonds in the ‘dehydroevodiamine–AChE’ interaction. These compounds were predicted to cross the blood–brain barrier (BBB) and to exhibit high levels of intestinal absorption. Furthermore, ‘indirubin–AChE’ and ‘dehydroevodiamine–AChE’ complexes were found to be stable, as determined by root mean square deviation (RMSD) during a 50 ns molecular dynamics simulation study. Based on the free binding energies and stabilities obtained by simulation studies, we recommend that experimental studies be undertaken on indirubin and dehydroevodiamine with a view towards their potential use as treatments for AD.