Multifunctional, Fluorene-Based Modulator of Cholinergic and GABAergic Neurotransmission as a Novel Drug Candidate for Palliative Treatment of Alzheimer's Disease.

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.

Dizocilpine derivatives as neuroprotective NMDA receptor antagonists without psychomimetic side effects.

We aimed to prepare novel dibenzo [a,d][7]annulen derivatives that act on N-methyl-d-aspartate (NMDA) receptors with potential neuroprotective effects. Our approach involved modifying the tropane moiety of MK-801, a potent open-channel blocker known for its psychomimetic side effects, by introducing a seven-membered ring with substituted base moieties specifically to alleviate these undesirable effects. Our in silico analyses showed that these derivatives should have high gastrointestinal absorption and cross the blood-brain barrier (BBB).

Pro-cognitive effects of dual tacrine derivatives acting as cholinesterase inhibitors and NMDA receptor antagonists.

Therapeutic options for Alzheimer's disease are limited. Dual compounds targeting two pathways concurrently may enable enhanced effect. The study focuses on tacrine derivatives inhibiting acetylcholinesterase (AChE) and simultaneously N-methyl-D-aspartate (NMDA) receptors.

Carltonine-derived compounds for targeted butyrylcholinesterase inhibition.

The investigation into human butyrylcholinesterase (BChE) inhibitors as therapeutic agents for Alzheimer's disease (AD) holds significant promise, addressing both symptomatic relief and disease progression. In the pursuit of novel drug candidates with a selective BChE inhibition pattern, we focused on naturally occurring template structures, specifically Amaryllidaceae alkaloids of the carltonine-type. Herein, we explored a series of compounds implementing an innovative chemical scaffold built on the 3- and 4-benzyloxy-benzylamino chemotype.

A-agents, misleadingly known as "Novichoks": a narrative review.

"Novichok" refers to a new group of nerve agents called the A-series agents. Their existence came to light in 2018 after incidents in the UK and again in 2020 in Russia. They are unique organophosphorus-based compounds developed during the Cold War in a program called Foliant in the USSR.

Inhibitors of phosphoinositide 3-kinase (PI3K) and phosphoinositide 3-kinase-related protein kinase family (PIKK).

Phosphoinositide 3-kinases (PI3K) and phosphoinositide 3-kinase-related protein kinases (PIKK) are two structurally related families of kinases that play vital roles in cell growth and DNA damage repair. Dysfunction of PIKK members and aberrant stimulation of the PI3K/AKT/mTOR signalling pathway are linked to a plethora of diseases including cancer. In recent decades, numerous inhibitors related to the PI3K/AKT/mTOR signalling have made great strides in cancer treatment, like copanlisib and sirolimus.

2,6-Disubstituted 7-(naphthalen-2-ylmethyl)-7H-purines as a new class of potent antitubercular agents inhibiting DprE1.

Phenotypic screening of an in-house library of small molecule purine derivatives against Mycobacterium tuberculosis (Mtb) led to the identification of 2-morpholino-7-(naphthalen-2-ylmethyl)-1,7-dihydro-6H-purin-6-one 10 as a potent antimycobacterial agent with MIC of 4 μM. Thorough structure-activity relationship studies revealed the importance of 7-(naphthalen-2-ylmethyl) substitution for antimycobacterial activity, yet opened the possibility of structural modifications at positions 2 and 6 of the purine core. As the result, optimized analogues with 6-amino or ethylamino substitution 56 and 64, respectively, were developed.

Dopaminergic and glutamatergic models of psychosis show differential sensitivity to aripiprazole and a novel experimental compound modulating D/5-HT receptor activity.

Dopamine type 2 receptors (DRs) constitute the main molecular target in the pharmacotherapy of schizophrenia. However, the second and third generation of antipsychotics comprises multi-target ligands, also binding serotonin type 3 receptors (5-HTRs) and other receptor classes as well. Here, we examined two experimental compounds (marked compound K1697 and K1700) from the group of 1,4-di-substituted aromatic piperazines, previously described in the study of Juza et al.

Structure-Guided Design of -Methylpropargylamino-Quinazoline Derivatives as Multipotent Agents for the Treatment of Alzheimer's Disease.

Alzheimer's disease (AD) is a complex disease with an unknown etiology. Available treatments, limited to cholinesterase inhibitors and -methyl-d-aspartate receptor (NMDAR) antagonists, provide symptomatic relief only. As single-target therapies have not proven effective, rational specific-targeted combination into a single molecule represents a more promising approach for treating AD, and is expected to yield greater benefits in alleviating symptoms and slowing disease progression.

Differentiated SH-SY5Y neuroblastoma cells as a model for evaluation of nerve agent-associated neurotoxicity.

Organophosphorus compounds (OPs) involving life-threatening nerve agents (NA) have been known for several decades. Despite a clear mechanism of their lethality caused by the irreversible inhibition of acetylcholinesterase (AChE) and manifested via overstimulation of peripheral nicotinic and muscarinic acetylcholine (ACh) receptors, the mechanism for central neurotoxicity responsible for acute or delayed symptoms of the poisoning has not been thoroughly uncovered. One of the reasons is the lack of a suitable model.

Highly selective butyrylcholinesterase inhibitors related to Amaryllidaceae alkaloids - Design, synthesis, and biological evaluation.

Butyrylcholinesterase (BChE) is one of the most frequently implicated enzymes in the advanced stage of Alzheimer's disease (AD). As part of our endeavors to develop new drug candidates for AD, we have focused on natural template structures, namely the Amaryllidaceae alkaloids carltonine A and B endowed with high BChE selectivity. Herein, we report the design, synthesis, and in vitro evaluation of 57 novel highly selective human BChE (hBChE) inhibitors.

Pyrimidine derivatives with antitubercular activity.

Small molecules with antitubercular activity containing the pyrimidine motif in their structure have gained more attention after three drugs, namely GSK 2556286 (GSK-286), TBA-7371 and SPR720, have entered clinical trials. This review provides an overview of recent advances in the hit-to-lead drug discovery studies of antitubercular pyrimidine-containing compounds with the aim to highlight their structural diversity. In the first part, the review discusses the pyrimidine compounds according to their targets, pinpointing the structure-activity relationships of each pyrimidine family.

Neurotoxicity evoked by organophosphates and available countermeasures.

Organophosphorus compounds (OP) are a constant problem, both in the military and in the civilian field, not only in the form of acute poisoning but also for their long-lasting consequences. No antidote has been found that satisfactorily protects against the toxic effects of organophosphates. Likewise, there is no universal cure to avert damage after poisoning.

Privileged multi-target directed propargyl-tacrines combining cholinesterase and monoamine oxidase inhibition activities.

Twenty-four novel compounds bearing tetrahydroacridine and -propargyl moieties have been designed, synthesised, and evaluated for their anti-cholinesterase and anti-monoamine oxidase activities. Propargyltacrine (IC = 21 nM) was the most potent acetylcholinesterase (AChE) inhibitor, compound (IC = 78 nM) showed the best inhibitory human butyrylcholinesterase (BChE) profile, and ligand afforded equipotent and significant values on both ChEs (human AChE [AChE]: IC = 0.095 ± 0.

Recent advances in dopamine D receptor ligands in the treatment of neuropsychiatric disorders.

Dopamine is a biologically active amine synthesized in the central and peripheral nervous system. This biogenic monoamine acts by activating five types of dopamine receptors (D Rs), which belong to the G protein-coupled receptor family. Antagonists and partial agonists of D Rs are used to treat schizophrenia, Parkinson's disease, depression, and anxiety.

Non-covalent acetylcholinesterase inhibitors: In vitro screening and molecular modeling for novel selective insecticides.

Insecticides represent the most crucial element in the integrated management approach to malaria and other vector-borne diseases. The evolution of insect resistance to long-used substances and the toxicity of organophosphates (OPs) and carbamates are the main factors contributing to the development of new, environmentally safe pesticides. In our work, fourteen compounds of 7-methoxytacrine-tacrine heterodimers were tested for their insecticidal effect.

Chemical and Biological Threats, Hazard Potential and Countermeasures.

The scope of this Special Issue is to pay attention to various aspects of toxicology specifically focused on the chemical and biological threats, which may accidentally, or on purpose, endanger human health [...

Physicochemistry shapes bioactivity landscape of pan-ABC transporter modulators: Anchor point for innovative Alzheimer's disease therapeutics.

Alzheimer's disease (AD) is a devastating neurological disorder characterized by the pathological accumulation of macromolecular Aβ and tau leading to neuronal death. Drugs approved to treat AD may ameliorate disease symptoms, however, no curative treatment exists. Aβ peptides were discovered to be substrates of adenosine triphosphate-(ATP)-binding cassette (ABC) transporters.