Complexation of alkaline earth metal cations with fluorescent tertiary-amide lower-rim calix[4]arene derivative bearing two phenanthridine moieties was studied experimentally (UV spectrophotometry, fluorimetry, isothermal microcalorimetry, NMR spectroscopy) and computationally (classical molecular dynamics and DFT calculations) at 25 °C. The complexation reactions were studied in acetonitrile, methanol, and ethanol, whereby the solvent effect on cation-binding processes was particularly addressed. The complex stability constants and standard reaction thermodynamic quantities (Gibbs energies, enthalpies, and entropies) were determined. The receptor exhibited particularly high affinity towards alkaline earth metal cations in acetonitrile, with peak affinity for Ca²⁺. The stability of all complexes was significantly lower in ethanol and methanol, where the most stable complex was formed with Sr²⁺. The decrease in cation-binding abilities was a consequence of the differences in solvation of the reactants and products of the complexation reactions (involving inclusion of the solvent molecule in the calixarene cone), cation charge density, as well as the cation–ligand binding site compatibility. The reactions were enthalpically controlled in acetonitrile, whereas in methanol and ethanol, the binding processes were endothermic and thus entropy driven. The results of ¹H NMR measurements, MD simulations, and DFT calculations provided an insight into the structure of the complexes and the corresponding adducts with solvent molecules, as well as the structural aspects behind the differences in complexation thermodynamics. Due to the significant increase in its fluorescence upon cation binding, the studied calixarene derivative was proven to be a promising luminescent sensor for alkaline earth metal cations.

Complexation of alkaline earth metal cations with fluorescent tertiary-amide lower-rim calix[4]arene derivative bearing two phenanthridine moieties was studied experimentally (UV spectrophotometry, fluorimetry, isothermal microcalorimetry, NMR spectroscopy) and computationally (classical molecular dynamics and DFT calculations) at 25 °C. The complexation reactions were studied in acetonitrile, methanol, and ethanol, whereby the solvent effect on cation-binding processes was particularly addressed. The complex stability constants and standard reaction thermodynamic quantities (Gibbs energies, enthalpies, and entropies) were determined. The receptor exhibited particularly high affinity towards alkaline earth metal cations in acetonitrile, with peak affinity for Ca2+. The stability of all complexes was significantly lower in ethanol and methanol, where the most stable complex was formed with Sr2+. The decrease in cation-binding abilities was a consequence of the differences in solvation of the reactants and products of the complexation reactions (involving inclusion of the solvent molecule in the calixarene cone), cation charge density, as well as the cation-ligand binding site compatibility. The reactions were enthalpically controlled in acetonitrile, whereas in methanol and ethanol the binding processes were endothermic, and thus entropy driven. The results of 1H NMR measurements, MD simulations, and DFT calculations provided an insight into the structure of the complexes and the corresponding adducts with solvent molecules, as well as on the structural aspects behind the differences in complexation thermodynamics. Due to the significant increase of its fluorescence upon cation binding, the studied calixarene derivative was proven to be a promising luminescent sensor for alkaline earth metal cations.

Alzheimer’s disease is a progressive neurodegenerative disorder marked by declining cognitive function. While early-stage treatment focuses on acetylcholinesterase (AChE) inhibition, butyrylcholinesterase (BChE) activity increases as the disease progresses, contributing to cholinergic deficits and neuroinflammation. This shift in enzyme dominance presents a compelling rationale for developing BChE-specific inhibitors as a potential therapeutic avenue. This study explores small, three-membered rings, scaffolds offering potential for interaction with the enzyme’s active site, as building blocks for novel BChE inhibitors. Employing a computational approach based on quantum–chemical multiligand simultaneous molecular docking, we virtually fitted these compounds into the BChE active site to predict binding affinity and key interactions. Our calculations extend beyond simple shape matching by incorporating accurate electronic properties, leading to more reliable predictions of binding strength and stability. The goal was not immediate identification of potent inhibitors, but a systematic assessment of how these rings interact with BChE. This foundational knowledge will inform the design and synthesis of larger, more complex molecules with enhanced binding affinity and selectivity, ultimately aiming to develop compounds to inhibit BChE activity and potentially slow Alzheimer’s progression.

DFT and MD calculations reveal that cation coordination within 1,2- and 1,3-alternate calix[4]arene binding sites varies with ion size and charge density, resulting in endo - and exo -complexes, while solvation also strongly affects their structures.

Background and purpose: Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) are crucial enzymes implicated in various neurological disorders, including Alzheimer’s disease. Developing selective inhibitors for either enzyme is one of the key therapeutic strategies. This study aimed to synthesize and evaluate a novel series of peptidomimetics for their ability to inhibit both human AChE and BChE, with a focus on identifying compounds exhibiting joint inhibitory activity or selectivity for BChE. Experimental approach: Eleven peptidomimetics were synthesized using the Ugi four-component reaction. In vitro enzyme inhibition assays were performed to determine the dissociation constants (Ki) for both human AChE (hAChE) and human BChE (hBChE). Principal component analysis was employed to analyse the inhibition data and map compound selectivity. To investigate the molecular interactions between the peptidomimetics and the BChE active site, quantum-chemical docking simulations were conducted. Key results: All synthesized compounds exhibited reversible, micromolar inhibition of both hAChE and hBChE. Two compounds demonstrated significant BChE selectivity, with 279- and 169-fold higher preference for BChE, respectively. Principal component analysis revealed distinct clusters correlating with preferential binding to either enzyme. Docking simulations supported these findings, highlighting key stabilizing interactions (primarily π-π stacking) between the peptidomimetics and BChE, explaining superior selective and joint inhibitory activity. Conclusion: This work demonstrates the successful synthesis and characterization of novel peptidomimetics with varying degrees of hAChE and hBChE inhibition, including compounds with notable BChE selectivity. The combination of experimental data and computational modelling provides valuable insights into the structural basis of enzyme inhibition and establishes a foundation for rational design of more potent and selective cholinesterase inhibitors based on the designed scaffold.