Synthesis of stemofoline analogues as acetylcholinesterase inhibitors

Thirty-two new stemofoline analogues were prepared from didehydrostemofoline for studies as AChE inhibitors. C-3 Side-chain modified amino, carbamate, triazole and oxazole stemofoline derivatives were prepared. In general the amine derivatives were found to be stronger inhibitors of AChE than their alcohol analogues that we previously reported. Compounds 5 and 26, with small C-3 side-chain substituents, were two of the most active inhibitors. Preliminary molecular docking studies suggested that these compounds may inhibit AChE by binding horizontally along the passage of the active-site gorge and block access to acetylcholine.     

Synthesis and biological evaluation of thiophene derivatives as acetylcholinesterase inhibitors

A series of new thiophene derivatives has been synthesized using the Gewald protocol. The acetylcholinesterase inhibition activity was assayed according to Ellman's method using donepezil as reference. Some of the compounds were found to be more potent inhibitors than the reference. 2-(2-(4-(4-Methoxyphenyl)piperazin-1-yl)acetamido)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (IIId) showed 60% inhibition, compared to only 40% inhibition by donepezil.     

Facile synthesis of chrysin-derivatives with promising activities as aromatase inhibitors

Flavones such as chrysin show structural similarities to androgens, the substrates of human aromatase, which converts androgens to estrogens. Aromatase is a key target in the treatment of hormone-dependent tumors, including breast cancer. Flavone-based aromatase inhibitors are of growing interest, and chrysin in particular provides a (natural) lead structure. This paper reports multicomponent synthesis as a means for facile modification of the chrysin core structure in order to add functional elements. A Mannich-type reaction was used to synthesize a range of mono- and disubstituted chrysin derivatives, some of which are more effective aromatase inhibitors than the benchmark compound, aminoglutethimide. Similarly, the reaction of chrysin with various isonitriles and acetylene dicarboxylates results in a new class of flavone derivatives, tricyclic pyrano-flavones which also inhibit human aromatase. Multicomponent reactions involving flavones therefore enable the synthesis of a variety of derivatives, some of which may be useful as anticancer agents.     

Tyrosol 1,2,3-triazole analogues as new acetylcholinesterase (AChE) inhibitors

The present work proposed the preparation of triazolic analogues of tyrosol, a biophenol found in olive oil and whose wide range of bioactivities has been the target of many studies. We obtained fifteen novel tyrosol derivatives and the compounds of the series were later evaluated as acetylcholinesterase (AChE) inhibitors. The study of AChE inhibition is important for the development of new drugs and pesticides, and especially the research for managing Alzheimer's disease. The most active compound, namely 7-({1-[2-(4-hydroxyphenyl)ethyl]-1H-1,2,3-triazol-4-yl}methoxy)-4-methyl-2H-chromen-2-one (30), showed IC₅₀ value of 14.66 ± 2.29 μmol L⁻¹. Docking experiments corroborated by kinetic assay are suggestive of a competitive inhibition mechanism. Derivatives interacted with amino acids from the AChE active site associated to the development of Alzheimer's disease. The results indicate that the compounds synthesized have a high potential as prototypes for the development of new acetylcholinesterase inhibitors.     

Design and activity of cationic fullerene derivatives as inhibitors of acetylcholinesterase

Four different regioisomers of cationic bis-N,N-dimethylfulleropyrrolidinium salts have been prepared and evaluated as inhibitors of the enzymatic activity of acetylcholinesterase. These fullerene-based derivatives were found to be noncompetitive inhibitors of acetylthiocholine hydrolysis. Molecular modelling was used to describe the possible interactions between the fullerene cage and the amino acids surrounding the cavity of the enzyme. The cationic C(60) derivatives used in this study represent a new class of molecules potentially able to modulate the enzymatic activity of acetylcholinesterase.     

Synthesis of diastereomeric 13-amido-substituted huprines as potential high affinity acetylcholinesterase inhibitors

Two diastereomeric huprines additionally functionalized at position 13 with a methanesulfonamido group have been synthesized in seven steps from the known 9,9-ethylenedioxybicyclo[3.3.1]nonane-3,7-dione (5). In a key-step, nickel boride non-stereoselective reduction of an oxime gave a mixture of amines which was separated as methanesulfonamido derivatives. The substitution pattern of these huprines could lead to an extended binding near the active site of acetylcholinesterase (AChE), and consequently to improved AChE inhibitors.     

Novel pyridine and pyrimidine derivatives as promising anticancer agents: A review

Pyridines and pyrimidines are the class of heterocyclic nitrogenous compounds having plethora of applications in anticancer drug development. These synthetic sources serve as the potent class of compounds in treatment of breast cancer, myeloid leukemia, pancreatic cancer, liver cancer and idiopathic respiratory fibrosis etc. The present review enumerates the results of studies published during past three years (2019–2021) on pyridine and pyrimidine analogues with their respective anticancer properties characterized in vitro or through in silico studies and illustrates their potential in development of anticancer agents. Recent advances on pyridine and pyrimidine analogues mentioned in this review add to the appealing opportunities for cancer therapy.     

New acetylcholinesterase inhibitors isolated from Delphinium uncinatum

The inhibition of acetylcholinesterase (AChE), the key enzyme in the breakdown of acetylcholine, is presently the most common pharmacological approach available for Alzheimer’s disease (AD). Despite research on the molecular bases of AD, potent therapeutic agent against its expansion is still needed. In searching for natural cholinesterase inhibitors, the present study was focused on the isolation of three new norditerpenoid alkaloids, uncinatine B-D together with known virescenine from Delphinium uncinatum. Chemical structures for all the isolated norditerpenoids (1–4) were established using latest spectroscopic techniques. The isolated undescribed compounds along with known virescenine were testified for their acetylcholinesterase inhibitory activity supported by docking analyses. Molecular docking simulation showed that the isolated compounds (1–4) were observed to adhered in the active site of AChE with docking scores ? 13.5322 (1), ?11.8173 (2), ?12.4240 (3) and ? 8.9352 (4) respectively. Overall results demonstrated that these natural norditerpenoids compounds were found as selective inhibitors of AChE. This is the first report regarding the use of bioactive ingredients of Delphinium uncinatum in testing against Alzheimer's disease.     

Using sulfinamides as high oxidation state sulfur reagent for preparation of sulfenamides

Traditional preparation of sulfenamides require the use of low oxidation state of sulfur reagent such as RSCl, (RS)₂ or RSH, which are toxic, odorous and difficult to deal with due to the harsh reaction conditions. Here high oxidation state of sulfur reagent—aliphatic sulfinamide, were used for preparation of sulfenamide in one step efficiently. Different aromatic amines with all sorts of functional groups, especially amino groups and hydroxyl groups, were transformed to the corresponding sulfenamides in moderate yields, which was difficult to obtain with previous methods.     

Theoretical studies and NMR assay of coumarins and neoflavanones derivatives as potential inhibitors of acetylcholinesterase

Currently Alzheimer's disease (AD) is a devastating neurological disorder that mainly affects the elderly. The treatment of AD has as main objective to increase the levels of ACh in the synaptic cleft by inhibiting the cholinesterase enzymes, which are responsible for the degradation of ACh. Twenty one synthesized coumarins and neoflavanones (4-arylcoumarins) and theoretical studies were used to select the most promising ligands for in vitro experimental studies by Nuclear Magnetic Resonance. The eight compounds selected for the experimental study only 12b (effectiveness 68.54 ± 3.22%) was promising AChE inhibitor. This compound (12b) presents substituents at positions 4, 5, 6, 7 and 8 in a coumarin nucleus, being the most significant characteristic in comparison to the other studied compounds. These results can be used for the design and synthesis of other possible derivatives with inhibitory potential of AChE.     

Synthesis of bicyclic azacompounds (3‐dimethylcarbamoyloxyphenyl) substituted as acetylcholinesterase inhibitors

This paper describes the synthesis of some bicyclic 2‐(3‐dimethylcarbamoyloxyphenyl) substituted azaderivatives, obtained from 1,4‐ and 1,5‐diketones, which were cyclized with ammonium acetate, methylamine and by reductive amination. Corresponding 3‐substituted derivatives were instead prepared by reaction of 1,5‐ketoesters with formamide. The carbamates were tested as in vitro acetylcholinesterase inhibitors.     

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.     

Novel thiazole‐piperazine derivatives as potential cholinesterase inhibitors

Dementia is a cognitive disorder mostly associated with Alzheimer's disease (AD) in addition to being seen in many other diseases of the central nervous system (CNS). The limited number of drugs is not sufficient to provide adequate improvement to increase the quality of life of patients suffering from this symptom; therefore, all treatment options should be evaluated in detail. In this study, new molecules, [2‐(4‐(2/3/4‐substituted phenyl)piperazin‐1‐yl)‐4‐phenylthiazol‐5‐yl][3/4‐substituted phenyl]methanone derivatives ( 1‐44 ), were obtained and analyzed in terms of their anticholinesterase activities. Kinetic mode and molecular interactions were also evaluated. An enzyme inhibition study was undertaken on acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) using the Ellman method. Maestro program was used in molecular modeling studies. Forty‐four compounds were evaluated on AChE and BChE enzymes at 10^?3 and 10^?4 concentrations. The inhibition concentrations were calculated as 0.268μM to 2.104μM for six compounds ( 4 , 5 , 16 , 27 , 37 , and 38 ) on AChE. Compound 5 including the 4‐methoxy substituent (IC₅₀: 0.268μM) and compound 38 containing the 4‐methoxy and 3‐methyl substituents (IC₅₀: 0.286μM) showed the highest AChE inhibitory activity. They were further examined in terms of hydrogen bonding with Arg296 and Ar‐Ar interaction with Trp286. The activity of compound 5 was also assessed in mixed‐type kinetic mode.     

Synthesis and pharmacological effects of novel benzenesulfonamides carrying benzamide moiety as carbonic anhydrase and acetylcholinesterase inhibitors

N -(1-(4-Methoxyphenyl)-3-oxo-3-((4-( N -(substituted)sulfamoyl)phenyl)amino)prop-1-en-1-yl)benzamides 3a – g were designed since sulfonamide and benzamide pharmacophores draw great attention in novel drug design due to their wide range of bioactivities including acetylcholinesterase (AChE) and human carbonic anhydrase I and II (hCA I and hCA II) inhibitory potencies. Structure elucidation of the compounds was carried out by 1H NMR, 13C NMR, and HRMS spectra. In vitro enzyme assays showed that the compounds had significant inhibitory potential against hCA I, hCA II, and AChE enzymes at nanomolar levels. Ki values were in the range of 4.07 ± 0.38 – 29.70 ± 3.18 nM for hCA I and 10.68 ± 0.98 – 37.16 ± 7.55 nM for hCA II while Ki values for AChE were in the range of 8.91 ± 1.65 – 34.02 ± 5.90 nM. The most potent inhibitors 3g (Ki = 4.07 ± 0.38 nM, hCA I), 3c (Ki = 10.68 ± 0.98 nM, hCA II ) , and 3f (Ki = 8.91 ± 1.65 nM, AChE) can be considered as lead compounds of this study with their promising bioactivity results. Secondary sulfonamides showed promising enzyme inhibitory effects on AChE while primary sulfonamide derivative was generally effective on hCA I and hCA II isoenzymes.