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An increasing microbial resistance to known antibiotics raises a demand for new antimicrobials. In this study the antimicrobial properties of a series of new N-Alkylpyridinium quaternary ammonium compounds (QACs) with varying alkyl chain lengths were evaluated for several nosocomial pathogens. The chemical identities of the new QACs were determined by NMR, LC-MS, and HRMS. All the planktonic bacteria tested were susceptible to the new QACs as evaluated by MIC and MBC assays. The antimicrobial effect was most pronounced against Staphylococcus aureus clinical isolates. Live/dead staining CLSM was used to test the effectiveness of the QACs in biofilms. The effectiveness was up to 10-fold lower than in the plankton. When QACs were used as irrigants in Er:YAG – SSP photoacoustic steaming, their effectiveness significantly increased. The combined use of irrigants and photoacoustic streaming increased biofilm removal from the surface and increased the killing rate of the cells remaining on the surface. This may allow for a shorter chemical exposure time and lower dosage of QACs used in applications. The results demonstrate that the new QACs have potential to be applied as antibacterial compounds effective against planktonic and biofilm bacteria as well as irrigants in removal of difficult-to-reach biofilms.

Benzoxonium chloride belongs to the group of quaternary ammonium salts, which have been widely used for decades as disinfectants because of their high efficacy, low toxicity, and thermal stability. In this study, we have prepared the C10-C18 set of benzoxonium-like salts to evaluate the effect of their chemical and biological decontamination capabilities. In particular, biocidal activity against a panel of bacterial strains including Staphylococcus aureus in biofilm form was screened. In addition, the most promising compounds were successfully tested against Francisella tularensis as a representative of potential biological warfare agents. From a point of view of chemical warfare protection, the efficiency of BOC-like compounds to degrade the organophosphate simulant fenitrothion was examined. Notwithstanding that no single compound with universal effectiveness was identified, a mixture of only two compounds from this group would be able to satisfactorily cover the proposed decontamination spectrum. In addition, the compounds were evaluated for their cytotoxicity as a basic safety parameter for potential use in practice. In summary, the dual effect on chemical and biological agents of benzoxonium-like salts offer attractive potential as active components of decontamination mixtures in the case of a terrorist threat or chemical or biological accidents.

Alzheimer’s disease (AD) is a complex disorder with unknown etiology. Currently, only symptomatic therapy of AD is available, comprising cholinesterase inhibitors and N-methyl-d-aspartate (NMDA) receptor antagonists. Drugs targeting only one pathological condition have generated only limited efficacy. Thus, combining two or more therapeutic interventions into one molecule is believed to provide higher benefit for the treatment of AD. In the presented study, we designed, synthesized, and biologically evaluated 15 novel fluoren-9-amine derivatives. The in silico prediction suggested both the oral availability and permeation through the blood–brain barrier (BBB). An initial assessment of the biological profile included determination of the cholinesterase inhibition and NMDA receptor antagonism at the GluN1/GluN2A and GluN1/GluN2B subunits, along with a low cytotoxicity profile in the CHO-K1 cell line. Interestingly, compounds revealed a selective butyrylcholinesterase (BChE) inhibition pattern with antagonistic activity on the NMDARs. Their interaction with butyrylcholinesterase was elucidated by studying enzyme kinetics for compound 3c in tandem with the in silico docking simulation. The docking study showed the interaction of the tricyclic core of new derivatives with Trp82 within the anionic site of the enzyme in a similar way as the template drug tacrine. From the kinetic analysis, it is apparent that 3c is a competitive inhibitor of BChE.

Nosocomial infections, which greatly increase morbidity among hospitalized patients, together with growing antibiotic resistance still encourage many researchers to search for novel antimicrobial compounds. Picolinium salts with different lengths of alkyl chains (C12, C14, C16) were prepared by Menshutkin-like reaction and evaluated with respect to their biological activity, i.e., lipophilicity and critical micellar concentration. Picolinium salts with C14 and C16 side chains achieved similar or even better results when in terms of antimicrobial efficacy than benzalkoniums; notably, their fungicidal efficiency was substantially more potent. The position of the methyl substituent on the aromatic ring does not seem to affect antimicrobial activity, in contrast to the effect of length of the N-alkyl chain. Concurrently, picolinium salts exhibited satisfactory low cytotoxicity against mammalian cells, i.e., lower than that of benzalkonium compounds, which are considered as safe.

The neuropeptides, orexin A and orexin B (also known as hypocretins), are produced in hypothalamic neurons and belong to ligands for orphan G protein-coupled receptors. Generally, the primary role of orexins is to act as excitatory neurotransmitters and regulate the sleep process. Lack of orexins may lead to sleep disorder narcolepsy in mice, dogs, and humans. Narcolepsy is a neurological disorder of alertness characterized by a decrease of ability to manage sleep-wake cycles, excessive daytime sleepiness, and other symptoms, such as cataplexy, vivid hallucinations, and paralysis. Thus, the discovery of orexin receptors, modulators, and their causal implication in narcolepsy is the most important advance in sleep-research. The presented work is focused on the evaluation of compounds L1⁻L11 selected by structure-based virtual screening for their ability to modulate orexin receptor type 2 (OX2R) in comparison with standard agonist orexin-A together with their blood-brain barrier permeability and cytotoxicity. We can conclude that the studied compounds possess an affinity towards the OX2R. However, the compounds do not have intrinsic activity and act as the antagonists of this receptor. It was shown that L4 was the most potent antagonistic ligand to orexin A and displayed an IC50 of 2.2 µM, offering some promise mainly for the treatment of insomnia.