Ring Substituents Research Articles

Spectroscopical and Molecular Studies of Four Manganese(I) PhotoCORMs with Bioinspired Ligands Containing Non-Coordinated Phenol Groups.

Carbonyl compounds are widely explored in medicinal inorganic chemistry and have drawn attention due to their signaling functions in homeostasis. Carbon-monoxide-releasing molecules (CORMs) were developed with the purpose of keeping the CO inactive until its release in the intracellular environment, considering its biological relevance. However, for therapeutic applications, the mechanisms of photorelease and which electronic and structural variations influence its rates must be fully understood. In this work, four ligands containing a pyridine, a secondary amine, and a phenolic group with different substituents were used to prepare new Mn(I) carbonyl compounds. Structural and physicochemical characterization of these complexes was carried out and confirmed the proposed structures. X-ray diffractometry structures obtained for the four organometallic compounds revealed that the substituents in the phenolic ring promote only negligible distortions in their geometry. Furthermore, UV-Vis and IR kinetics showed the direct dependence of the electron-withdrawing or donating ability of the substituent group, indicating an influence of the phenol ring on the CO release mechanism. These differences in properties were also supported by theoretical studies at the DFT, TD-DFT, and bonding situation analyses (EDA-NOCV). Two methods were used to determine the CO release constants (kCO,old and kCO,new), where Mn-HbpaBr (1) had the greatest kCO by both methods (Kco,old = 2.36 × 10-3 s-1 and kCO,new = 2.37 × 10-3 s-1). Carbon monoxide release was also evaluated using the myoglobin assay, indicating the release of 1.248 to 1.827 carbon monoxides upon light irradiation.

Protocol for structure determination of unknowns by EI mass spectrometry. II. Diagnostic ions in one ring alicyclic, heterocyclic, and aromatic compounds

Electron ionization (EI) mass spectra of saturated carbocyclic hydrocarbons containing a single ring with three or more members are discussed followed by the examination of their unsaturated analogs, including aromatic hydrocarbons. Mass spectrometry characteristics of heterocyclic compounds for each cycle size with one, two, three, and more hetero-atoms in a ring are considered along with their mono- and polyunsaturated analogs. An effect of the (a) size of a cycle; (b) number, nature, and location of elements in a ring; (c) position and nature of ring substituents; and (d) nature and location of unsaturation on the dissociation is revealed. Characteristic dissociation directions of these compounds and diagnostically important ions in their spectra are identified. Basic dissociation rules for alicyclic, heterocyclic, and aromatic compounds under EI are established for further use in the analysis of complex chemicals containing these structural elements.

Synthesis of Novel Benzenesulfonamide-Bearing Functionalized Imidazole Derivatives as Novel Candidates Targeting Multidrug-Resistant Mycobacterium abscessus Complex.

Infections caused by drug-resistant (DR) Mycobacterium abscessus (M. abscessus) complex (MAC) are an important public health concern, particularly when affecting individuals with various immunodeficiencies or chronic pulmonary diseases. Rapidly growing antimicrobial resistance among MAC urges us to develop novel antimicrobial candidates for future optimization. Therefore, we have designed and synthesized benzenesulfonamide-bearing functionalized imidazole or S-alkylated derivatives and evaluated their antimicrobial activity using multidrug-resistant M. abscessus strains and compared their antimycobacterial activity using M. bovis BCG and M. tuberculosis H37Ra. Benzenesulfonamide-bearing imidazole-2-thiol compound 13, containing 4-CF3 substituent in benzene ring, showed strong antimicrobial activity against the tested mycobacterial strains and was more active than some antibiotics used as a reference. Furthermore, an imidazole-bearing 4-F substituent and S-methyl group demonstrated good antimicrobial activity against M. abscessus complex strains, as well as M. bovis BCG and M. tuberculosis H37Ra. In summary, these results demonstrated that novel benzenesulfonamide derivatives, bearing substituted imidazoles, could be further explored as potential candidates for the further hit-to-lead optimization of novel antimycobacterial compounds.

Thiourea-Based Tritopic Halogen-Bonding Acceptors.

A series of thiourea-based tritopic receptor molecules were synthesized to be used as building blocks for halogen-bonded assemblies. Here, 16 new receptor molecules were synthesized from two different 2,4,6-trialkyl-1,3,5-tris(bromomethyl)benzene starting materials via tris(isothiocyanatomethyl)benzene intermediates. The alkyl substituents in the benzene ring proved to be important for isothiocyanate group formation instead of competing thiocyanate group. The synthesis route allowed us to synthesize the isothiocyanate intermediates and further the receptor molecules without the typically used and highly toxic thiophosgene. The synthesized receptor molecules were used to study their halogen-bond acceptor properties with diiodotetrafluorobenzene donors by single-crystal X-ray diffraction method. We were able to obtain five new crystal structures of halogen-bonded complexes, in which all receptors showed two to four accepted C-I⋅⋅⋅S halogen bonds. The observed halogen bonds were highly directional and showed large variation in C=S⋅⋅⋅I acceptor angles, indicating flexible acceptor properties of sulfur.

Unveiling substituent effects in [3+2] cycloaddition reactions of benzonitrile N-oxide and benzylideneanilines from the molecular electron density theory perspective

The zw- type [3+2] cycloaddition (32CA) reactions of benzonitrile N-oxide with a series of substituted benzylideneanilines have been studied within the Molecular Electron Density Theory (MEDT) at the B3LYP/6-31G(d) computational level. The presence of dimethylamino and methoxy substituents in the aromatic rings of benzylideneaniline makes the reaction more facile relative to the unsubstituted one, while the electron withdrawing nitro substituents relatively induce minimal changes in the energy profile complying with the experimentally observed reaction rates. The presence of non-bonding electron density at the nitrogen atom and the formation of pseudoradical centre at the carbon atom of benzonitrile N-oxide characterise the difference in electronic structure of the TSs relative to the reagents, while the topological analysis of the electron localization function (ELF) and the atoms-in-molecules (AIM) reveal no covalent bond formation at the early TSs. The present MEDT study analyses the experimentally observed substituent effects and complete regioselectivity in the studied 32CA reactions.

CHEMICAL PROPERTIES AND APPLICATIONS OF NITROPYRIDINES

Background. Pyridines are one of the most common heterocycles, the derivatives of which are widely used in pharmaceuticals, agrochemistry, and also in the production of new materials. Therefore, a comprehensive study of the chemical behavior of various pyridine derivatives will continue to be an urgent task of organic chemistry. This literature review is devoted to the systematization and analysis of the chemical properties of pyridine nitro derivatives, starting from the first half of the 20th century and up to the present. The paper considers both reactions proceeding through the nitro group (reduction under the action of various chemical agents, substitution, condensation) and reactions through the pyridine cycle. The main areas of application of nitropyridines are also shown.
 Purpose. Generalize and systematize the main types of reactions characteristic of nitropyridines, show the features of their chemical properties associated with the transformation of the nitro group, its effect on the mobility of substituents in the pyridine ring, as well as on the activity of the heterocycle as a whole.
 Materials and methods. To achieve the goal of the study, a review of the scientific literature was made on the main types of chemical reactions characteristic of pyridine nitro derivatives and the most significant areas of their application.
 Results. This paper summarizes the results of experimental studies on the chemical properties and application of nitropyridines from the beginning of the last century to the present.
 Conclusion. Thus, as a result of the analysis of sources devoted to the chemical properties and application of nitropyridines, a brief literature review was compiled, including the main types of reactions characteristic of the compounds under study, and their main areas of application were identified.

Deconstructive Functionalization of Unstrained Cycloalkanols via Electrochemically Generated Aromatic Radical Cations.

Herein we report an electrochemical approach for the deconstructive functionalization of cycloalkanols, where various alcohols, carboxylic acids, and N-heterocycles are employed as nucleophiles. The method has been demonstrated across a broad range of cycloalkanol substrates, including various ring sizes and substituents, to access useful remotely functionalized ketone products (36 examples). The method was demonstrated on a gram scale via single-pass continuous flow, which exhibited increased productivity in relation to the batch process.

Design, Synthesis, and Characterization of Novel Bis-Uracil Chitosan Hydrogels Modified with Zinc Oxide Nanoparticles for Boosting Their Antimicrobial Activity

A new series of hydrogels was successfully prepared by incorporating various substituted bisuracil (R-BU) linkages between chitosan Schiff's base chains (R-BU-CsSB) and between chitosan chains (R-BU-Cs). After protection of the amino groups of chitosan by benzaldehyde, yielding chitosan Schiff's base (CsSB), the reaction with epichlorohydrin was confined on the -OH on C6 to produce epoxy chitosan Schiff's base (ECsSB), which was reacted with R-BU to form R-BU-CsSB hydrogels, and finally, the bioactive amino groups of chitosan were restored to obtain R-BU-Cs hydrogels. Further, some R-BU-Cs-based ZnO nanoparticle (R-BU-Cs/ZnONPs) composites were also prepared. Appropriate techniques such as elemental analysis, FTIR, XRD, SEM, and EDX were used to verify their structures. Their inhibition potency against all the tested microbes were arranged as: ZnONPs bio-composites > R-BU-Cs hydrogels > R-BU-CsSB hydrogels > Cs. Their inhibition performance against Gram-positive bacteria was better than Gram-negative ones. Their minimum inhibitory concentration (MIC) values decreased as a function of the negative resonance effect of the substituents in the aryl ring of R-BU linkages in the hydrogels. Compared with Vancomycin, the ZnONPs bio-composites showed superior inhibitory effects against most of the tested Gram-negative bacteria, all inspected Gram-positive ones, and all investigated fungi.

Study of the photoreaction of new triazene derivatives in solution and in polymer binder

• New aryltriazenes are synthesized and fully characterized in solution by means of different analytical techniques. • The photoreactivity depends on the kind and position of the chemical substituents of the phenyl ring and on the solvent used. • The photoproducts are evaluated using GC-MS and they depends on the solvent used. • The light induced reaction of the nitro derivative is performed in polymer matrices. • The reactivity changes with the polymer used. Triazenes are molecular systems that undergo a photolysis with the evolution of molecular nitrogen. A set of aryltriazene bearing different substituents are synthesized and characterized. The photoreaction is studied in solution by means of UV-vis spectroscopy showing a large dependence of required doses and UV-vis spectrum evolution on the substituent position and character. The structural changes upon the photolysis are also probed using vibrational spectroscopy (IR and Raman). Moreover, GC-MS spectroscopy is employed to retrieve the structure of the main photoproducts. The most promising derivative, in terms of stability and band position is incorporated in different polymer matrices, both thermosetting and thermoplastic; its photoreaction is studied in correlation with the polymer structure.

Intramolecular OHO Hydrogen Bonding in Dibenzoylmethane Enol: Raman Spectroscopic and Quantum Chemical Study

In the present work, the intramolecular O-H···O hydrogen bonding in 3-hydroxy-1,3-diphenylprop-2-en-1-one (keto-enol form of dibenzoylmethane, DBM) was investigated. For this purpose, the Raman spectra of polycrystalline samples of ordinary (H-DBM) and deuterated (D-DBM) 3-hydroxy-1,3-diphenylprop-2-en-1-one in the temperature range of 5–300 K were measured. It was found that low-temperature hydrogen bonding is extremely strong, the proton and deuteron are located in the midpoint of the O···O segment, and their ground and first excited vibrational states are located above the barrier U0 between the local minima. The vibrational frequencies, in this case, are 1543 and 1709 cm−1 for the proton and 1045 and 1087 cm−1 for the deuteron. As the temperature rises and the barrier height increases in H-DBM, the zero-point vibrational state of the proton begins to move into one of the local minima at T > 50 K, while the excited state remains in the broad single-well potential. The same is observed in D-DBM, but with a significant temperature delay. Compounds with donor (−OCH3) and acceptor (−NO2) substituents in the phenyl ring were also synthesized and their spectra were obtained. Both results confirm existing ideas about the nature of the extremely strong hydrogen bond. The quantum-chemical calculation of the vibrational spectrum of H-DBM and D-DBM is consistent with the experimental results.

Enantioseparation of β-Blockers Using Silica-Immobilised Eremomycin Derivatives as Chiral Stationary Phases in HPLC

The regularities of chromatographic retention and separation enantioselectivity of the selected β-blockers (propranolol, pindolol, alprenolol, atenolol, oxprenalol, metoprolol, clenbuterol, sotalol, pronethalol, salbutamol, and labetalol) were studied with eight chiral stationary phases (CSPs) in polar ionic mode (PIM) elution system. A range of novel CSPs was prepared by immobilisation of macrocyclic glycopeptide antibiotic eremomycin (E-CSP); structurally related antibiotics chloreremomycin (Chloro-E-CSP) and semi-synthetic oritavancin (O-CSP); and five eremomycin derivatives including amide- (Amide-E-CSP), adamantyl-2-amide- (Adamantylamide-E-CSP), eremomycin aglycon (EAg-CSP), eremosaminyl eremomycin aglycon (EEA-CSP), and des-eremosamynyl eremomycin (DEE-CSP) onto microspherical silica (Kromasil, particle size 5 micron, pore size 11 nm). The effect of different functional groups in eremomycin structure on chiral recognition of β-blockers was studied. The original E-CSP revealed moderate enantioseparation for all studied β-blockers. The presence of a free carboxylic group in a chiral selector molecule is found to be critical for the general retention of enantiomers as no separation enantioselectivity was recorded for Amide-E-CSP and Adamantyl-E-CSP. Modification of the aromatic system of eremomycin by the introduction of a chloro- substituent in the aromatic ring (Chloro-E-CSP) or a hydrophobic 4’-chlorobiphenylmethyl substituent to the disaccharide sugar residue (O-CSP) resulted in decreased enantioselectivity. The best enantioseparation of β-blockers was obtained for CSPs with eremosaminyl eremomycin aglycon and des-eremosamynyl eremomycin as chiral selectors.

Influence of Substituents in a Six-Membered Chelate Ring of HG-Type Complexes Containing an N→Ru Bond on Their Stability and Catalytic Activity.

An efficient approach to the synthesis of olefin metathesis HG-type catalysts containing an N→Ru bond in a six-membered chelate ring was proposed. For the most part, these ruthenium chelates can be prepared easily and in high yields based on the interaction between 2-vinylbenzylamines and Ind II (the common precursor for Ru-complex synthesis). It was demonstrated that the increase of the steric volume of substituents attached to the nitrogen atom and in the α-position of the benzylidene fragment leads to a dramatic decrease in the stability of the target ruthenium complexes. The bulkiest iPr substituent bonded to the nitrogen atom or to the α-position does not allow the closing of the chelate cycle. N,N-Diethyl-1-(2-vinylphenyl)propan-1-amine is a limiting case; its interaction with Ind II makes it possible to isolate the corresponding ruthenium chelate in a low yield (5%). Catalytic activity of the synthesized complexes was tested in RCM reactions and compared with α-unsubstituted catalysts obtained previously. The structural peculiarities of the final ruthenium complexes were thoroughly investigated using XRD and NMR analysis, which allowed making a reliable correlation between the structure of the complexes and their catalytic properties.

Fluorohydroxylation and Hydration Reactions of para-Quinone Methides Promoted by Selectfluor

Selectfluor-promoted vicinal fluorohydroxylation and hydration reaction of para-quinone methides (p-QMs) were described, affording vicinal fluorohydrins and ketone/ether products in high yields. The hydration products were highly controlled by the electronic properties of substituents in the aromatic ring, and simultaneously, the amount of Selectfluor was completely different during the synthesis of ketone/ether products. This reaction also represents the first fluorohydroxylation of p-QMs, and the wide range of p-QMs makes the vicinal fluorohydroxylation of great significance.

Tuning Photochemical and Photophysical Properties of P(V) Phthalocyanines.

The ability of P(V) phthalocyanines (Pcs) for efficient singlet oxygen (SO) generation was demonstrated for the first time by the example of unsubstituted and α- and β-octabutoxy-substituted P(V)Pcs with hydroxy, methoxy and phenoxy ligands in the apical positions of the octahedral P centre. Variation of substituents in Pc ring and P(V) axial ligands allows careful tuning of photophysical and photochemical properties. Indeed, a combination of BuO groups in the β-positions of the Pc ring and PhO groups as axial ligands provides significant SO generation quantum yields up to 90%; meanwhile, the values of SO generation quantum yields for others investigated compounds vary from 27 to 55%. All the complexes, except α-substituted P(V)Pc, demonstrate fluorescence with moderate quantum yields (10-16%). The introduction of electron-donating butoxy groups, especially in the α-position, increases the photostability of P(V)Pcs. Moreover, it has been shown in the example of β-BuO-substituted P(V) that the photostability depends on the nature of axial ligands and increases in the next row: OPh < OMe < OH. The presence of oxy/hydroxy axial ligands on the P(V) atom makes it possible to switch the photochemical and photophysical properties of P(V)Pcs by changing the acidity of the media.

Primary Structure of Glycans by NMR Spectroscopy.

Glycans, carbohydrate molecules in the realm of biology, are present as biomedically important glycoconjugates and a characteristic aspect is that their structures in many instances are branched. In determining the primary structure of a glycan, the sugar components including the absolute configuration and ring form, anomeric configuration, linkage(s), sequence, and substituents should be elucidated. Solution state NMR spectroscopy offers a unique opportunity to resolve all these aspects at atomic resolution. During the last two decades, advancement of both NMR experiments and spectrometer hardware have made it possible to unravel carbohydrate structure more efficiently. These developments applicable to glycans include, inter alia, NMR experiments that reduce spectral overlap, use selective excitations, record tilted projections of multidimensional spectra, acquire spectra by multiple receivers, utilize polarization by fast-pulsing techniques, concatenate pulse-sequence modules to acquire several spectra in a single measurement, acquire pure shift correlated spectra devoid of scalar couplings, employ stable isotope labeling to efficiently obtain homo- and/or heteronuclear correlations, as well as those that rely on dipolar cross-correlated interactions for sequential information. Refined computer programs for NMR spin simulation and chemical shift prediction aid the structural elucidation of glycans, which are notorious for their limited spectral dispersion. Hardware developments include cryogenically cold probes and dynamic nuclear polarization techniques, both resulting in enhanced sensitivity as well as ultrahigh field NMR spectrometers with a 1H NMR resonance frequency higher than 1 GHz, thus improving resolution of resonances. Taken together, the developments have made and will in the future make it possible to elucidate carbohydrate structure in great detail, thereby forming the basis for understanding of how glycans interact with other molecules.

Fluorescent boron difluoride curcuminoides as perspective materials for bio-visualization

Curcuminoids of boron difluoride, 1-aryl(hetaryl)-5-phenylpenta-2,4-dien-1-onates of boron difluoride, have been synthesized. A comparative study of the electronic structure, luminescent properties and their potential for applications in bio-imaging has been carried out. The influence of the electronic structure of α-substituents on the luminescence of compounds was studied by the methods of stationary and time-resolved luminescence spectroscopy and DFT modeling. The introduction of π-donor substituents leads to a noticeable bathochromic shift and an increase in the Stokes shift in the luminescence spectra. On going from σ-donor substituents in the phenyl ring to π-donor substituents, the luminescence quantum yield increases from 0.03 to 0.22. The maximum Stokes shift and high quantum yield of luminescence is exhibited by the complex with a stilbene substituent, which has the longest π-system and the maximum efficiency of charge transfer. Dyes are able to penetrate into the cells of the model cell line and accumulate, moreover, accumulation occurs mainly in the cytoplasm of cells. The compounds penetrate into the cells by 12 h of incubation without damaging it’s structure and without causing rapid cell death. The submicromolar range of non-toxic concentrations during long-term incubation for a model cell line was determined, which is a characteristic of fluorescent imaging. Due to uniform distribution in the cytoplasm of cells dye with naphtyl substituent is promising for visualization of the cell cytoplasm. This leader compound has the lowest cytotoxicity for cells from the synthesized series of dyes, which makes it promising for further studies as a fluorescent imaging agent.The leader compound has the lowest cytotoxicity for cells from the synthesized series of dyes, which makes it promising for further studies as a fluorescent imaging agent.

Permeability of New Antifungal Fluconazole Derivatives through a Lipophilic Membrane: Experiment and Modeling.

Relationships between the structures of molecules and their properties form the basis of modern chemistry and lay the foundation for structure-based drug design. Being the main two determinants of bioavailability, solubility and permeability of drugs are widely investigated experimentally and predicted from physicochemical parameters and structural descriptors. In the present study, we measure the passive diffusion permeability of a series of new fluconazole derivatives with triazole and thiazolo-pyrimidine moieties connected by different linker bridges through the PermeaPad barrier-a relatively new biomimetic lipophilic membrane that has been increasingly used in recent years. The permeability coefficients of new derivatives are shown to be dependent both on the structure of the linker fragment and on the substituent in the phenyl ring of the thiazolo-pyrimidine moiety. The impact of the compound ionization state on the permeability is revealed. Reliable correlations of the permeability with the antifungal activity and distribution coefficient are found. In addition, the solubility-diffusion approach is shown to be able to successfully predict the permeability of the studied derivatives. The obtained results can be considered another step in the development of permeability databases and design of schemes for in vitro permeability prediction.

Synthesis of 2-aminopropyl benzopyran derivatives as potential agents against triple-negative breast cancer.

Synthesis of three series of 2-aminopropyl derivatives containing a benzopyran nucleus was performed to evaluate their performance against triple-negative breast cancer cell lines (MDA-MB-231 and MDA-MB-436) and normal breast epithelial cells (MCF10A). For the three series, the cytotoxic activity was as follows: N-methylated derivatives (tertiary amines) 5b, 6b, and 7b > secondary amine benzopyrans 5, 6, and 7 > quaternary amine salts 5c, 6c, and 7c > free phenolic derivatives 5a, 6a, and 7a. The structure-activity relationship showed the importance of the presence of an amine group and a p-fluorobenzyloxy substituent in the chromanol ring (IC50 values from 1.5 μM to 58.4 μM). In addition, 5a, 5b, 6a, and 7b displayed slight selectivity towards tumor cells. Compounds 5, 5a, 5b, 6, 6a, 6c, 7, and 7b showed apoptotic/necrotic effects due to, at least in part, an increase in reactive oxygen species generation, whereas 5b, 5c, 6b, 7a, and 7c caused cell cycle arrest in the G1 phase. Further cell-based mechanistic studies revealed that 5a, 6a, and 7b, which were the most promising compounds, downregulated the expression of Bcl-2, while 5b downregulated the expression of cyclins CCND1 and CCND2. Therefore, 2-aminopropyl benzopyran derivatives emerge as new hits and potential leads for developing useful agents against breast cancer.

Towards control of excitonic coupling in DNA-templated Cy5 aggregates: the principal role of chemical substituent hydrophobicity and steric interactions.

Understanding and controlling exciton coupling in dye aggregates has become a greater focus as potential applications such as coherent exciton devices, nanophotonics, and biosensing have been proposed. DNA nanostructure templates allow for a powerful modular approach. Using DNA Holliday junction (HJ) templates variations of dye combinations and precision dye positions can be rapidly assayed, as well as creating aggregates of dyes that could not be prepared (either due to excess or lack of solubility) through alternative means. Indodicarbocyanines (Cy5) have been studied in coupled systems due to their large transition dipole moment, which contributes to strong coupling. Cy5-R dyes were recently prepared by chemically modifying the 5,5'-substituents of indole rings, resulting in varying dye hydrophobicity/hydrophilicity, steric considerations, and electron-donating/withdrawing character. We utilized Cy5-R dyes to examine the formation and properties of 30 unique DNA templated homodimers. We find that in our system the sterics of Cy5-R dyes play the determining factor in orientation and coupling strength of dimers, with coupling strengths ranging from 50-138 meV. The hydrophobic properties of the Cy5-R modify the percentage of dimers formed, and have a secondary role in determining the packing characteristics of the dimers when sterics are equivalent. Similar to other reports, we find that positioning of the Cy5-R within the HJ template can favor particular dimer interactions, specifically oblique or H-type dimers.

Binding interactions of hydrophobically-modified flavonols with β-glucosidase: fluorescence spectroscopy and molecular modelling study.

Natural flavonoids are capable of inhibiting glucosidase activity, so they can be used for treating diabetes mellitus and hypertension. However, molecular-level details of their interactions with glucosidase enzymes remain poorly understood. This paper describes the synthesis and spectral characterization of a series of fluorescent flavonols and their interaction with the β-glucosidase enzyme. To tune flavonol-enzyme interaction modes and affinity, we introduced different polar halogen-containing groups or bulky aromatic/alkyl substituents in the peripheral 2-aryl ring of a flavonol moiety. Using fluorescence spectroscopy methods in combination with molecular docking and molecular dynamics simulations, we examined the binding affinity and identified probe binding patterns, which are critical for steric blockage of the key catalytic residues of the enzyme. Using a fluorescent assay, we demonstrated that the binding of flavonol 2e to β-glucosidase decreased its enzymatic activity up to 3.5 times. In addition, our molecular docking and all-atom molecular dynamics simulations suggest that the probe binding is driven by hydrophobic interactions with aromatic Trp and Tyr residues within the catalytic glycone binding pockets of β-glucosidase. Our study provides a new insight into structure-property relations for flavonol-protein interactions, which govern their enzyme binding, and outlines a framework for a rational design of new flavonol-based potent inhibitors for β-glucosidases.