Physostigmine Analogues Research Articles

Mutasynthesis of Physostigmines in Myxococcus xanthus.

The alkaloid physostigmine is an approved anticholinergic drug and an important lead structure for the development of novel therapeutics. Using a complementary approach that merged chemical synthesis with pathway refactoring, we produced a series of physostigmine analogues with altered specificity and toxicity profiles in the heterologous host Myxococcus xanthus. The compounds that were generated by applying a simple feeding strategy include the promising drug candidate phenserine, which was previously accessible only by total synthesis.

Computational insight into the anticholinesterase activities and electronic properties of physostigmine analogs.

Aim: Alzheimer's disease (AD) is known to be themajor cause of dementia among the elderly. The structural properties and binding interactions of the AD drug physostigmine (-)-phy, and its analogues (-)-hex and (-)-phe and (+)-phe, were examined, as well as their impact on the conformational changes of two different AD target enzymes AChE and BChE.Materials & methods: The conformational changes were studied using molecular dynamics and structural properties using Quantum mechanics.Results & conclusions: The binding free energy (ΔGbind) and the change in the free energy surface (FES) computed from the funnel metadynamics (FMD) simulation, both support the idea that inhibitors (-)-phe and (-)-hex have better binding activities toward enzyme AChE, and that (-)-phe is stronger in binding than the present AD drug (-)-phy.

Novel synthesis of physovenine and physostigmine analogs

This Letter describes a versatile synthetic approach to prepare physovenine and physostigmine analogs. A series of analogs were synthesized and evaluated for cholinesterase inhibition activities, including human acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) from human serum.

Synthesis and anticholinesterase activity of (−)-physostigmine analogues with modifications at C3a and C5

A new series of physostigmine analogues 3a—3j with modifications at the C3a and C5 positions was designed and synthesized. Bioassay of the synthetic analogues 3a—3j, along with the previous synthesized C3a-ethyl-C5-triazole physostigmine analogues 1a—1g and 2a—2j was performed, which indicates that the replacement of the carbamoyl moiety of C3a-ethyl-C5-triazole analogues 1 and 2 with a triazole moiety decreased acetylcholinesterase(AchE) inhibitory activity, whereas the introduction of heterocycles into the triazole ring increased both AChE and butyrylcholinesterase(BchE) inhibitory activities. Structure-activity relationship(SAR) studies of C3a-methyl-C5-triazole analogues 3 reveal the C3a-methyl substituent is important for AChE and BChE inhibition and the introduction of a second ionizable N center improved the binding of the synthetic analogues to both AChE and BChE.

An Efficient Synthesis of a (−)‐Physostigmine's Library for Identifying Potential Anti‐Alzheimer's Agents

AbstractAn efficient route for the synthesis of (−)‐physostigmine analogs 1a–1g and 2a–2k is described. Analogs 1a–1g were synthesized via copper(I)‐catalyzed cycloaddition between the optically pure azide 10 and a variety of alkynes. Similarly, analogs 2a–2k were prepared through ‘three‐component Huisgen cycloaddition’ using various amines, propargyl bromine, and 10 in H2O. Facile preparation of 10 via MacMillan's organocatalysis has made it possible to generate a great diversity of natural product‐like compounds that can be screened for anti‐Alzheimer's effects.

Synthesis of physostigmine analogues and evaluation of their anticholinesterase activities

A series of physostigmine analogues were prepared and evaluated for cholinesterase inhibition activities, including acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Most of them showed potent inhibition activities against AChE, in which compound 17 especially exhibited significantly higher selectivity over BChE than phenserine, a compound currently on clinical trial. Discussion about the relationships between structure and activity of these derivatives was also presented.

Ligand‐based 3D‐QSAR Studies of Physostigmine Analogues as Acetylcholinesterase Inhibitors

Natural alkaloid Physostigmine is one of the most potent pseudo-irreversible inhibitor of Acetylcholinesterase. It was found to accelerate long-term memory process, but due to its short half life and variable bioavailability, has inconsistent clinical efficacy. 3D-QSAR studies based on the comparative molecular field analysis and comparative molecular similarity indices analysis were applied to a set of 40 Physostigmine derivatives which are divided into two classes: A and B. The study was conducted to obtain a highly reliable and extensive dynamic QSAR model based on alignment procedure with co-crystallized Ganstigmine as template. The strategy yielded significant 3D-QSAR models with the cross-validated q(2) values 0.762 and 0.754 for comparative molecular field analysis and comparative molecular similarity indices analysis, respectively. Resulted models were validated by external set of eight compounds yielding high correlation coefficient r(2) values of 0.730 and 0.720 for comparative molecular field analysis and comparative molecular similarity indices analysis, respectively. Furthermore, the analysis of comparative molecular field analysis and comparative molecular similarity indices analysis contour maps within the active site of AChE were conducted in order to understand the interactions between the receptor and the Physostigmine derivatives. This study will facilitate the rational design of more potent Physostigmine compounds which might have better activity and reduce toxicity for the treatment of Alzheimer disease.

Accommodation of physostigmine and its analogues by acetylcholinesterase is dominated by hydrophobic interactions

The role of the functional architecture of the HuAChE (human acetylcholinesterase) in reactivity toward the carbamates pyridostigmine, rivastigmine and several analogues of physostigmine, that are currently used or considered for use as drugs for Alzheimer's disease, was analysed using over 20 mutants of residues that constitute the interaction subsites in the active centre. Both steps of the HuAChE carbamylation reaction, formation of the Michaelis complex as well as the nucleophilic process, are sensitive to accommodation of the ligand by the enzyme. For certain carbamate/HuAChE combinations, the mode of inhibition shifted from a covalent to a noncovalent type, according to the balance between dissociation and covalent reaction rates. Whereas the charged moieties of pyridostigmine and rivastigmine contribute significantly to the stability of the corresponding HuAChE complexes, no such effect was observed for physostigmine and its analogues, phenserine and cymserine. Moreover, physostigmine-like ligands carrying oxygen instead of nitrogen at position -1 of the tricyclic moiety (physovenine and tetrahydrofurobenzofuran analogues) displayed comparable structure-function characteristics toward the various HuAChE enzymes. The essential role of the HuAChE hydrophobic pocket, comprising mostly residues Trp(86) and Tyr(337), in accommodating (-)-physostigmine and in conferring approximately 300-fold stereoselectivity toward physostigmines, was elucidated through examination of the reactivity of selected HuAChE mutations toward enantiomeric pairs of different physostigmine analogues. The present study demonstrates that certain charged and uncharged ligands, like analogues of physostigmine and physovenine, seem to be accommodated by the enzyme mostly through hydrophobic interactions.

Novel Anticholinesterases Based on the Molecular Skeletons of Furobenzofuran and Methanobenzodioxepine

Reductive cyclization of 5-hydroxy-3-methyl-3-methoxycarbonylmethylenebenzofuran-2(3H)-one (4) gave 5-hydroxy-3a-methyl-2,3,3a,8a-tatrahydrofuro[2,3-b]benzofuran (5) and the rearrangement product 7-hydroxy-4,5-dihydro-2,5-methano-1,3-benzodioxepine (6). Reaction of compounds 5 and 6 with different isocyanates provided two series novel carbamates (7-12) whose structures were confirmed by X-ray crystallography. These were assessed for anticholinesterase action against freshly prepared human enzyme and proved to be potent inhibitors of either acetyl- (AChE) or butyrylcholinesterase (BChE) with specific compounds exhibiting remarkable selectivity. Because the two series of carbamates (7-12) differ in their phenolic moieties, their respective potency and selectivity for AChE versus BChE was governed by their N-substituted groups. This same characteristic was also present in a series of physovenine analogues (1, 13, 15, 17) and physostigmine analogues (2, 14, 16, 18). These structure-activity relations proved valuable in elucidating the mechanisms underpinning the interaction between carbamate-based cholinesterase inhibitors and their enzyme target. In addition, because physostigmine analogues have demonstrated activity in lowering the Alzheimer's disease protein, amyloid precursor protein (APP), examples of the two new series of carbamates were characterized in culture assays of quantifying cell viability and synthesis of APP.

P31 DNA methylation profiles in breast cancer — relation to hormone receptors and role in response to adjuvant endocrine treatment

This Letter describes a versatile synthetic approach to prepare physovenine and physostigmine analogs. A series of analogs were synthesized and evaluated for cholinesterase inhibition activities, including human acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) from human serum.

Inhibition of acetylcholinesterase by physostigmine analogs: conformational mobility of cysteine loop due to the steric effect of the alkyl chain.

The effect of a series of physostigmine analogs on acetylcholinesterase activity was investigated. The second-order rate constant k(on) of the enzyme-inhibitor complex correlates with the conformational positioning of aromatic residues, especially Trp84, in the transition state complex. The van der Waals interactions are an important structural element of this conformational change. A transient mobility of the cysteine loop (Cys67-Cys94) was confined only to the presence of a significant steric effect. Even with this limitation, however, the steric effect seems to be an appropriate model for future tests on the "back door" hypothesis involving facilitated opening for faster product clearance.

The Pharmacology of Physostigmine

The Pharmacology of Physostigmine

A comparative QSAR analysis of acetylcholinesterase inhibitors currently studied for the treatment of Alzheimer's disease

Considering the relevance of acetylcholinesterase inhibitors as potential agents for the treatment of the Alzheimer's disease, we have undertaken a comparative QSAR analysis aimed at individuating the physico-chemical properties governing the inhibitory activity of such compounds. The QSAR equations for 13 series of derivatives have been calculated and discussed. The series studied are all those we found in the literature suitable for a QSAR analysis and represent the three main classes of acetylcholinesterase inhibitors currently investigated, namely, physostigmine analogues, 1,2,3,4-tetrahydroacridines and benzylamines. The equations we obtained show that, within each class, the main physico-chemical properties affecting the inhibitory activity are almost the same for all the series and can be individuated by the use of proper parameters. The conclusions of this study can be summarized as follows: (a) hydrophobicity plays a critical role in both the physostigmineand the benzylamine-derived classes; (b) electronic effects are important for the interactions carried out by the variable portion of benzylamine derivatives; and (c) steric factors are also significant, but, as in other cases, the collinearity between steric and hydrophobic parameters does not allow one to draw any final conclusion.

Synthesis and structure-activity relationships of new acetylcholinesterase inhibitors: Morpholinoalkylcarbamoyloxyeseroline derivatives

Several new potent acetylcholinesterase inhibitors have been synthesised as potential drugs for the treatment of Alzheimer's disease. Heptylphysostigmine (MF201) is a drug analogue of physostigmine under clinical evaluation. In order to obtain new physostigmine analogues, the methylcarbomoyloxy group was substituted with ω-morpholinoalkylcarbamoyloxy moieties of different chain lengths (C2–C12). Potent in vitro inhibition is seen when the chain length is composed of eight to twelve methylene groups. The inhibitory activity of the C10 and C11 is 7-fold greater with respect to heptylphysostigmine.

Novel, long-acting and selective physostigmine analogues as potential therapeutics for Alzheimer's disease

Novel, long-acting and selective physostigmine analogues as potential therapeutics for Alzheimer's disease

High-performance liquid chromatographic enantioseparation of intermediates relating to the total synthesis of (−)-physostigmine

()-Physostigmine (1) is a clinically useful anticholinesterase agent which has been used in the treatment of myasthenia gravis and glaucoma. More recently, selected ()-physostigmine analogues have also shown promise as Alzheimer’s disease therapeutic agents. Our interests in new (-)-physostigmine analogues have led us to develop a stereoselective synthesis of ()-physostigmine [I] (Fig. 1). To facilitate our synthetic effort and to ensure a high optical purity of the synthetic material, we required analytical high-performance liquid chromatographic (HPLC) enantioseparation of the intermediates as shown in the scheme. We report herein the application of derivatized cellulose-based chiral stationary phase (CSP) to the separation of these intermediates.

New analogs of physostigmine: Alternative drugs for Alzheimer's disease?

The synthesis of a series of physostigmine analogs, in which the methylcarbamyl group has been substituted with monoalkylcarbamyl, dimethyl- and diethylcarbamyl groups, is reported. These compounds were prepared with the aim of investigating their possible therapeutic effects in the treatment of Alzheimer's type dementia. The new analogs of physostigmine are inhibitors of acetylcholinesterase from Electroforus electricus, with a value of the reactivation constant, k3 smaller than the one of physostigmine. The percentage of anticholinesterase activity in vitro and in vivo, the acute toxicity and some behavioural effects were also evaluated for selected derivatives. The reactivation constant, in vitro, supports the view that the derivatives described would be more suitable for therapeutic use than physostigmine.

Study of the Hydrolysis of Several Physostigmine Analogs

Study of the Hydrolysis of Several Physostigmine Analogs