Electrophoretically mediated microanalysis technique as a tool for the rapid screening of novel acetylcholinesterase inhibitors

An electrophoretically mediated microanalysis technique was developed for the rapid screening of acetylcholinesterase inhibitors. Activity of four original compounds, N-benzylpiperidine, carbamoyloxyphenyl derivatives and reference inhibitor ñ tacrine was determined and compared with the data obtained from Ellmanís assay. Percentage of enzyme inhibition detected at inhibitor concentration of 3.33Σ10-4 M was between 0 and 78% and was the highest for tacrine. The comparison of data obtained from the EMMA assay and Ellmanís test proved inhibitory activity of novel compounds

Multifunctional Ligand Approach : search for Effective Therapy Against Alzheimers Disease

Alzheimer’s disease is a progressive, incurable, and complex neurodegenerative disease. Currently, an effective treatment that can slow down or stop the damage and death of neurons, which is a characteristic of Alzheimer’s disease, is lacking. Taking into account the complex nature of the disease, a multitarget design approach has been developed for the production of new potential anti-AD agents. The goal of this approach is to create a single molecule that can interact selectively with several desired molecular targets relevant to the disease. This strategy was successfully developed two decades ago and has been improved in recent years. This chapter describes the progress made in the discovery and design of selected multitargeted drugs based on molecular targets, which can be used for treating Alzheimer’s disease. The most promising among these drugs are the molecules having properties that are valuable not only in the symptomatic therapy but also in the causal treatment of the disease. The main hypotheses of Alzheimer’s disease, such as β-amyloid (Aβ), tau, and cholinergic, suggest that compounds capable of inhibiting the aggregation of neurotoxic Aβ amyloid peptide and tau protein, and improving the cholinergic neurotransmission, may possess such properties. Examples of such multifunctional molecules, which have been recently reported in the literature, are presented in this chapter

Recent development of multifunctional agents as potential drug candidates for the treatment of Alzheimer's disease

Alzheimer’s disease (AD) is a complex and progressive neurodegenerative disorder. The available therapy is limited to the symptomatic treatment and its efficacy remains unsatisfactory. In view of the prevalence and expected increase in the incidence of AD, the development of an effective therapy is crucial for public health. Due to the multifactorial aetiology of this disease, the multi-target-directed ligand (MTDL) approach is a promising method in search for new drugs for AD. This review updates information on the development of multifunctional potential anti-AD agents published within the last three years. The majority of the recently reported structures are acetylcholinesterase inhibitors, often endowed with some additional properties. These properties enrich the pharmacological profile of the compounds giving hope for not only symptomatic but also causal treatment of the disease. Among these advantageous properties, the most often reported are an amyloid- antiaggregation activity, inhibition of -secretase and monoamine oxidase, an antioxidant and metal chelating activity, NOreleasing ability and interaction with cannabinoid, NMDA or histamine H3 receptors. The majority of novel molecules possess heterodimeric structures, able to interact with multiple targets by combining different pharmacophores, original or derived from natural products or existing therapeutics (tacrine, donepezil, galantamine, memantine). Among the described compounds, several seem to be promising drug candidates, while others may serve as a valuable inspiration in the search for new effective therapies for AD

Synthesis of novel N-benzyl substituted piperidine amides of 1H-indole-5-carboxylic acid as potential inhibitors of cholinesterases

A series of novel N-benzyl substituted amides of 1H-indole-5-carboxylic acid were synthesized and evaluated for their ability to inhibit acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). The target compounds (6bñ6e) displayed moderate potency to inhibit BuChE. One of the compounds tested, i.e., 1- benzylpiperidine amide of 1H-indole-5-carboxylic acid (6a) was a weak, non-selective inhibitor for both enzymes. The highest inhibitory activity towards BuChE (30.06% [10 μM]) was determined for compound (6c) which is 1-(3-chloro)benzylpiperidine amide of 1H-indole-5-carboxylic acid

Application of computational methods for the design of BACE-1 inhibitors : validation of in silico modelling

β-Secretase (BACE-1) constitutes an important target for search of anti-Alzheimer’s drugs. The first inhibitors of this enzyme were peptidic compounds with high molecular weight and low bioavailability. Therefore, the search for new efficient non-peptidic inhibitors has been undertaken by many scientific groups. We started our work from the development of in silico methodology for the design of novel BACE-1 ligands. It was validated on the basis of crystal structures of complexes with inhibitors, redocking, cross-docking and training/test sets of reference ligands. The presented procedure of assessment of the novel compounds as β-secretase inhibitors could be widely used in the design process

Search for potential cholinesterase inhibitors from the zinc database by virtual screening method

A virtual screening of the ZINC database was applied for the identification of novel cholinesterase inhibitors. The first step allowed to select compounds with favorable physicochemical properties. Then, the compounds were screened with the pharmacophore models built using crystal structures of donepezil, tacrine, decamethonium and bis-7-tacrine with acetylcholinesterase and well characterized interactions of bis-nor meptazinol with butyrylcholinesterase. The selected compounds from the group of donepezil were docked to acetylcholinesterase giving 7 structures for further studies. These compounds were tested against cholinesterases and two of them, 1-[4-(1H-indol-3-ylmethyl)piperazin-1-yl]-2-phenoxyethanone 2 and 2-[(1-benzylpiperidine-4 yl)amino]-1-phenylethanol 4 displayed, respectively, 50.1% and 79.5% of inhibition against butyrylcholinesterase at the concentration of 100 μM

Evaluation of antinociceptive and antioxidant properties of 3-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]-dihydrofuran-2-one in mice

The aim of this study was to evaluate the influence of 3-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]-dihydrofuran-2-one (LPP1) on nociceptive thresholds in mouse models of persistent pain. Influence of LPP1 on motor coordination and its antioxidant capacity in mouse brain tissue homogenates were also assessed. Pain sensitivity thresholds in animals treated with LPP1 were established using 5 % formalin solution in normoglycemic mice and in streptozotocin (STZ)-treated diabetic mice in the von Frey, hot plate, innocuous, and noxious cold water tests (water at 10 °C and 4 °C, respectively). Motor deficits were assessed in the rotarod test, whereas antioxidant capacities were evaluated using ferric reducing ability of plasma (FRAP) assay, catalase (CAT), and superoxide dismutase (SOD) activities. LPP1was antinociceptive in both phases of the formalin test, in particular, in the late phase (at doses 0.9–30 mg/kg for 66–99 % vs. control normoglycemic mice) and in a statistically significant manner increased nociceptive thresholds in response to mechanical, heat, and noxious cold stimulation in neuropathic mice (at 30 mg/kg for 274, 192, and 316 %, respectively vs. diabetic control). LPP1 did not impair motor coordination of mice in the rotarod revolving at 6 or 18 rpm. In brain tissue homogenates, it demonstrated antioxidant capacity in FRAP assay and increased SOD activity for 63 % (acute administration) and 28 % (chronic administration) vs. control. No influence on CAT activity was observed. LPP1 has significant antinociceptive properties in the formalin model and elevates pain thresholds in neuropathic mice. It has antioxidant capacity and is devoid of negative influence on animals' motor coordination