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The main protease (Mpro) of SARS-CoV-2 is an essential enzyme that plays a critical part in the virus's life cycle, making it a significant target for developing antiviral drugs. The inhibition of SARS-CoV-2 Mpro has emerged as a promising approach for developing therapeutic agents to treat COVID-19. This review explores the structure of the Mpro protein and analyzes the progress made in understanding protein–ligand interactions of Mpro inhibitors. It focuses on binding kinetics, origin, and the chemical structure of these inhibitors. The review provides an in-depth analysis of recent clinical trials involving covalent and non-covalent inhibitors and emerging dual inhibitors targeting SARS-CoV-2 Mpro. By integrating findings from the literature and ongoing clinical trials, this review captures the current state of research into Mpro inhibitors, offering a comprehensive understanding of challenges and directions in their future development as anti-coronavirus agents. This information provides new insights and inspiration for medicinal chemists, paving the way for developing more effective Mpro inhibitors as novel COVID-19 therapies. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a progressive neurodegenerative brain disease. Thus, drugs including donepezil, rivastigmine, and galantamine are not entirely effective in the treatment of this multifactorial disease. The present study evaluates eight derivatives (3a–3h) as candidates with stronger anti-AD potential but with less side effects. Reactive oxygen species (ROS) assays were used to assess oxidative stress which involve in the neurodegeneration. The neuroprotective properties of 3e against oxidative stress were done in three experiments using MTT test. The anti-AD potential was determined based on their anticholinesterase inhibition ability, determined using Ellman's method, Aβ aggregation potential according to thioflavin (Th) fluorescence assay, and their antioxidative and anti-inflammatory activities. Compound 3e exhibited moderate cholinesterase inhibition activity (AChE, IC50 = 0.131 µM; BuChE, IC50 = 0.116 µM; SI = 1.13), significant inhibition of Aβ(1–42) aggregation (55.7%, at 5 µM) and acceptable neuroprotective activity. Extensive analysis of in vitro and in vivo assays indicates that new cyclopentaquinoline derivatives offer promise as candidates for new anti-AD drugs. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by memory loss and behavioral and psychological symptoms of dementia (BPSD). Given that cholinergic neurons are predominantly affected in AD, current treatments primarily aim to enhance cholinergic neurotransmission. However, imbalances in other neurotransmitters, such as γ‐aminobutyric acid (GABA), also contribute to AD symptomatology. In the presented research, using a combination of crystallography and computational methods we developed compound 6 as a dual modulator of GABAergic and cholinergic neurotransmission systems. Compound 6 demonstrated inhibition of BuChE (IC50=0.21 μM) and GABA transporter 1 (IC50=10.96 μM) and 3 (IC50=7.76 μM), along with a favorable drug‐likeness profile. Subsequent in vivo studies revealed the effectiveness of 6 in enhancing memory retention and alleviating anxiety and depression symptoms in animal models, while also proving safe and bioavailable for oral administration. The innovative multi‐target‐directed ligand 6 offers a new approach to treating cognitive deficits and BPSD in AD. [ABSTRACT FROM AUTHOR]

Alzheimer’s disease (AD) is the most common progressive form of brain neurodegeneration and the most prevailing cause of dementia. Unfortunately, the aetiology of AD is not completely studied but different factors are associated with the development of AD such as among others low level of acetylcholine, aggregation of β-amyloid (Aβ), hyperphosphorylated tau protein, oxidative stress, and inflammation. The study encompass organic syntheses of 2,3-dihydro-1H-cyclopenta[b]quinoline with 5,6-dichloronicotinic acid and suitable linkers derivatives as multifunctional agents for AD treatment. Afterwards self-induced amyloid beta aggregation, inhibition studies of acetylcholinesterase and butyrylcholinesterase and molecular docking studies were performed. The results showed that 3b compound exhibited the best acetylcholinesterase inhibitory activity, with IC50 value of 0.052 µM which is lower compared to references. Besides, all synthesised compounds showed good butyrylcholinesterase inhibitory activity with IC50 values from 0.071 to 0.797 µM. Compound 3b exhibited strong Aβ1-42 aggregation inhibitory effect with 25.7% at 5 µM to 92.8% at 100 µM as well as good anti-inflammatory effect. Thus, new compounds could create new perspectives for further development as a multi-target-directed agent for AD treatment. [ABSTRACT FROM AUTHOR]

A series of new biphenyl bis -sulfonamide derivatives 2a – 3p were synthesized in good to excellent yield (76–98%). The inhibitory potential of the synthesized compounds on acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) was investigated. Most of the screened compounds showed modest in vitro inhibition for both AChE and BChE. Compared to the reference compound eserine (IC 50 0.04 ± 0.0001 μM for AChE) and (IC 50 0.85 ± 0.0001 μM for BChE), the IC 50 values of these compounds were ranged from 2.27 ± 0.01 to 123.11 ± 0.04 μM for AChE and 7.74 ± 0.07 to <400 μM for BuChE. Among the tested compounds, 3p was found to be the most potent against AChE ( IC 50 2.27 ± 0.01 μM), whereas 3g exhibited the highest inhibition for BChE (IC 50 7.74 ± 0.07 μM). Structure–activity relationship (SAR) of these compounds was developed and elaborated with the help of molecular docking studies. [ABSTRACT FROM AUTHOR]

The study presents the discovery of novel butyrylcholinesterase (BuChE) inhibitors among derivatives of azaphenothiazines by application of in silico and in vitro screening methods. From an in-house library of compounds, 143 heterocyclic molecules derived from the azaphenothiazine scaffold were chosen for virtual screening. Based on results of the docking procedure, 15 compounds were identified as exhibiting the best fit for the two screening complexes (ligand - AChE and ligand - BuChE). Five compounds displayed moderate AChE and good BuChE inhibitory activity at screening concentrations of 10 µM. The IC50 values for active BuChE inhibitors were in the 11.8-122.2 nM range. Three of the most active inhibitors are tetra- or pentacyclic derivatives of azaphenothiazines with the same N-methyl-2-piperidinethyl substituent. [ABSTRACT FROM AUTHOR]

Aim. To analyze tears in sterile surgical gloves used by surgeons in the operating theatre of the Trauma and Orthopedic Surgery Department, Copernicus Memorial Hospital, Łódź, Poland Materials and Method. This study analyzes tears in sterile surgical gloves used by surgeons by ICD-9 and ICD-10 codes. 1,404 gloves were collected from 581 surgical procedures. All gloves were tested immediately following surgery using the test method described in Standard EN455-1 (each glove was inflated with 1,000 ± 50 ml of water and observed for leaks for 2-3 min.). Results. Analysis of tears took into consideration the role of medical personnel (operator, first assistant, second assistant) during surgical procedure, the type of procedure according to ICD-9 and ICD-10 codes, and the elective or emergency nature of the procedure. The results of the study show that these factors have a significant influence on the risk of glove tears. Significant differences were observed in tear frequency and tear location depending on the function performed by the surgeon during the procedure. Conclusion. The study proved that the role performed by the surgeon during the procedure (operator, first assistant, second assistant) has a significant influence on the risk of glove tearing. The role in the procedure determines exposure to glove tears. Implementing a double gloving procedure in surgical procedures or using single gloves characterized by higher tear resistance should be considered. [ABSTRACT FROM AUTHOR]

In response to the complex and still not fully understood pathomechanism of Alzheimer's disease, many researchers have turned towards the promising paradigm of designing ligands with a multi-target nature1. One of the possible benefits of this approach in Alzheimer's disease is an opportunity to merge activity against cholinesterases, which are used in the current symptomatic therapies, with disease-modifying targets associated with ß-amyloid and tau protein pathways2. Optimization of ligand with respect to several biological targets while maintaining good physicochemical parameters is not an easy task. Computer modeling can be a huge help in this task. Computer modeling in the design of biologically active substances can be used to effectively search through the huge, available chemical space, or provide support for drawing conclusions of results obtained during the study3. In the work presented here, we would like to describe how the molecular modeling methods were used to design and obtain new series of 1-benzylamino-2-hydroxyalkyl derivatives that are effective against both acetyl- and butyrylcholinesterase as valid, symptomatic targets with an anti-aggregating properties against Tau protein, ß- amyloid and inhibition properties against ß-secretase (BACE-1) as disease-modified targets4. [ABSTRACT FROM AUTHOR]

Modulation of α1β2γ2GABA-A receptor subpopulation expressed in the basal ganglia region is a conceptually novel mode of pharmacological strategy that offers prospects to tackle a variety of neurological dysfunction. Although clinical findings provided compelling evidence for the validity of this strategy, the current chemical space of molecules able to modulate the α1/γ2 interface of the GABA-A receptor is limited to imidazo[1,2- a ]pyridine derivatives that undergo rapid biotransformation. In response to a deficiency in the chemical repertoire of GABA-A receptors, we identified a series of 2-(4-fluorophenyl)-1 H -benzo[ d ]imidazoles as positive allosteric modulators (PAMs) with improved metabolic stability and reduced potential for hepatotoxicity, where lead molecules 9 and 23 displayed interesting features in a preliminary investigation. We further disclose that the identified scaffold shows a preference for interaction with the α1/γ2 interface of the GABA-A receptor, delivering several PAMs of the GABA-A receptor. The present work provides useful chemical templates to further explore the therapeutic potential of GABA-A receptor ligands and enriches the chemical space of molecules suitable for the interaction with the α1/γ2 interface.

This article describes the discovery of novel potent muscarinic receptor antagonists identified during a search for more active histamine H 3 receptor (H 3 R) ligands. The idea was to replace the flexible seven methylene linker with a semirigid 1,4-cyclohexylene or p -phenylene substituted group of the previously described histamine H 3 R antagonists ADS1017 and ADS1020 . These simple structural modifications of the histamine H 3 R antagonist led to the emergence of additional pharmacological effects, some of which unexpectedly showed strong antagonist potency at muscarinic receptors. This paper reports the routes of synthesis and pharmacological characterization of guanidine derivatives, a novel chemotype of muscarinic receptor antagonists binding to the human muscarinic M 2 and M 4 receptors (hM 2 R and hM 4 R, respectively) in nanomolar concentration ranges. The affinities of the newly synthesized ADS10227 (1-{4-{4-{[4-(phenoxymethyl)cyclohexyl]methyl}piperazin-1-yl}but-1-yl}-1-(benzyl)guanidine) at hM 2 R and hM 4 R were 2.8 nM and 5.1 nM, respectively.

A series of 2-pyrimidinyl-piperazinyl-alkyl derivatives of 1H-imidazo[2,1-f]purine-2,4(3H,8H)-dione has been synthesized in an attempt to discover a new class of psychotropic agents. Compounds were evaluated for their in vitro affinity for serotonin 5-HT 1A , 5-HT 7 , and phosphodiesterases PDE4 and PDE10. The most potent compound 2-pyrimidinyl-1-piperazinyl-butyl-imidazo[2,1-f]purine-2,4-dione (4b) behaved as strong and selective antagonist of 5-HT 1A . Molecular modeling studies revealed differences in binding mode between compound 4b and buspirone, which might reflect variation of the ligands' affinity and potency in the 5-HT 1A receptor. Compound 4b in silico models demonstrated drug-likeness properties and, contrary to buspirone, showed a metabolic stability in mouse liver microsomes system. Experimentally obtained value of apparent permeability coefficient P app for 4b in parallel artificial permeability assay indicates the possibility of binding weakly to plasma proteins and high intestinal absorption fraction. Evaluation of the antidepressant- and anxiolytic-like activities of 4b revealed both activities at the same dose of 1.25 mg/kg and seemed to be specific. The antidepressant and/or anxiolytic properties of 4b may be related to its first-pass effect., (© 2018 John Wiley & Sons A/S.)