Theoretical study on intramolecular hydrogen bonds of flavonoid cocrystals.

This study investigates the role of intramolecular hydrogen bonds in the formation of cocrystals involving flavonoid molecules, focusing on three active pharmaceutical ingredients (APIs): chrysin (CHR), isoliquiritigenin (ISO), and kaempferol (KAE). These APIs form cocrystals with different cocrystal formers (CCFs) through intramolecular hydrogen bonding. We found that disruption of these intramolecular hydrogen bonds leads to decreased stability compared to molecules with intact bonds. The extrema of molecular electrostatic potential surfaces (MEPS) show that flavonoid molecules with disrupted intramolecular hydrogen bonds have stronger hydrogen bond donors and acceptors than those with intact bonds. Using the artificial bee colony algorithm, dimeric structures of these flavonoid molecules were explored, representing early-stage structures in cocrystal formation, including API-API, API-CCF, and CCF-CCF dimers. It was observed that the number and strength of dimeric interactions significantly increased, and the types of interactions changed when intramolecular hydrogen bonds were disrupted. These findings suggest that disrupting intramolecular hydrogen bonds generally hinders the formation of cocrystals. This theoretical study provides deeper insight into the role of intramolecular hydrogen bonds in the cocrystal formation of flavonoids.

Synthesis, Physicochemical Characterization, and Antimicrobial Evaluation of Halogen-Substituted Non-Metal Pyridine Schiff Bases.

Four synthetic Schiff bases (PSB1 [(E)-2-(((4-aminopyridin-3-yl)imino)methyl)-4,6-dibromophenol], PSB2 [(E)-2-(((4-aminopyridin-3-yl)imino)methyl)-4,6-diiodophenol], PSB3 [(E)-2-(((4-aminopyridin-3-yl)imino)methyl)-4-iodophenol], and PSB4 [(E)-2-(((4-aminopyridin-3-yl)imino)methyl)-4-chloro-6-iodophenol]) were fully characterized. These compounds exhibit an intramolecular hydrogen bond between the hydroxyl group of the phenolic ring and the nitrogen of the azomethine group, contributing to their stability. Their antimicrobial activity was evaluated against various Gram-negative and Gram-positive bacteria, and it was found that the synthetic pyridine Schiff bases, as well as their precursors, showed no discernible antimicrobial effect on Gram-negative bacteria, including Salmonella Typhi (and mutant derivatives), Salmonella Typhimurium, Escherichia coli, and Morganella morganii. In contrast, a more pronounced biocidal effect against Gram-positive bacteria was found, including Bacillus subtilis, Streptococcus agalactiae, Streptococcus pyogenes, Enterococcus faecalis, Staphylococcus aureus, and Staphylococcus haemolyticus. Among the tested compounds, PSB1 and PSB2 were identified as the most effective against Gram-positive bacteria, with PSB2 showing the most potent biocidal effects. Although the presence of reactive oxygen species (ROS) was noted after treatment with PSB2, the primary mode of action for PSB2 does not appear to involve ROS generation. This conclusion is supported by the observation that antioxidant treatment with vitamin C only partially mitigated bacterial inhibition, indicating an alternative biocidal mechanism.

Modulating the ESIPT Mechanism and Luminescence Characteristics of Two Reversible Fluorescent Probes by Solvent Polarity: A Novel Perspective.

As reversible fluorescent probes, HTP-1 and HTP-2 have favourable applications for the detection of Zn2+ and H2S. Herein, the impact of solvent on the excited-state intramolecular proton transfer (ESIPT) of HTP-1 and HTP-2 was comprehensively investigated. The obtained geometric parameters and infrared (IR) vibrational analysis associated with the intramolecular hydrogen bond (IHB) indicated that the strength of IHB for HTP-1 was weakened in the excited state. Moreover, structural torsion and almost no ICT behaviour indicated that the ESIPT process did not occur in HTP-1. Nevertheless, when the 7-nitro-1,2,3-benzoxadiazole (NBD) group replaced the H atom, the IHB strength of HTP-2 was enhanced after photoexcitation, which inhibited the twisting of tetraphenylethylene, thereby opening the ESIPT channel. Notably, hole-electron analysis and frontier molecular orbitals revealed that the charge decoupling effect was the reason for the fluorescence quenching of HTP-2. Furthermore, the potential energy curves (PECs) revealed that HTP-2 was more inclined to the ESIPT process in polar solvents than in nonpolar solvents. With a decrease in solvent polarity, it was more conducive to the ESIPT process. Our study systematically presents the ESIPT process and different detection mechanisms of the two reversible probe molecules regulated by solvent polarity, providing new insights into the design and development of novel fluorescent probes.

Computational Investigation about the Effects of Solvent Polarity and Chalcogen Element Electronegativity on ESIPT Behaviors for the Et2N-Substituted Flavonoid.

Inspired by the outstanding nature of flavonoid derivatives in the fields of chemistry and medicine, in this work we mainly focus on exploring the photo-induced properties of the novel Et2N-substituted flavonoid (ENF) fluorophore theoretically. Considering the potential photo-induced properties in different solvents and the chalcogen atomic electronegativity-associated photoexcitation, by time-dependent density functional theory (TDDFT) methods we primarily explore the intramolecular hydrogen bonding interactions and photo-induced charge redistribution behaviors. Via comparing geometrical data and the infrared (IR) spectral shifts-associated hydroxy moiety of ENF, we confirm that the intramolecular hydrogen bond O-H···O should be enhanced with facilitating an excited-state intramolecular proton-transfer (ESIPT) reaction. Particularly, the charge reorganization around hydrogen bonding moieties further reveals the tendency of ESIPT behavior. Combined with the construction of the potential energy surface and the search for reaction transition states, we finally confirmed the solvent-polarity-regulated behaviors as well as the chalcogen elements' electronegativity-dependent ESIPT mechanisms for the ENF fluorophore. We sincerely wish our work could accelerate the further development and applications of flavonoid derivatives.

Fast Production of Covalent Organic Frameworks for Covalent Enzyme Immobilization with Boosted Enzymatic Catalysis by Solar-Driven Photothermal Effect.

Developing new enzyme-immobilization systems to stabilize their dynamic structures and meanwhile enhance their catalytic activity is of great significance but very challenging. Herein, we design and fabricate a class of robust mesoporous covalent organic frameworks (COFs) via Michael addition-elimination reaction. It is found that highly crystalline COFs can be produced in 10 min, which is attributed to the promoting effect of the intramolecular hydrogen bond activation. The COFs rich in hydroxyl groups can be facilely post-modified by epibromohydrin to covalently immobilize enzymes with both high loading and activity. Furthermore, we create a solar-driven photothermal-promoted strategy by introducing photoactive azo groups to COF carriers, which can boost the enzyme catalytic performance (lipase) with much higher conversion of various racemic substrates and chiral resolution upon solar light irradiation. The heterogeneous biocatalysts also demonstrate exceptional reusability and stability. This work provides a green and energy-efficient approach to facilitate the scale application of enzyme-immobilized biocatalysts.

Atomic electronegativity-dependent intramolecular hydrogen bond and fluorescence characteristics of novel scaffold-based fluorophore: a TD-DFT study.

In this work, fluorescent properties and excited-state intramolecular proton transfer (ESIPT) processes of 2,5-bis(benzo[d]thiazol-2-yl)phenol (BTP) and its derivatives (BOP and BSeP) with different heteroatom atoms (O and Se) have been systematically explored by the density functional theory (DFT) and time-dependent DFT (TD-DFT) methods. The calculated absorption and fluorescence emission peaks agree well with the experimental values in acetonitrile. From the data of structures, topological parameters, reduced density gradient analyses, and infrared (IR) vibrational frequencies, the intramolecular hydrogen bonds (IHBs) of BTP and its derivatives are enhanced upon light-excitation. The potential energy curves show that the ESIPT process occurs in BTP and its derivatives after surmounting 0.167-0.306 eV energy barrier. The strength of intramolecular hydrogen bond, HOMO-LUMO energy gap, and red-shifted value of absorption and fluorescence emission wavelengths are dependent on the electron-withdrawing ability of heteroatom from O to S and Se. We believe that this work can pave the way for developing a new ESIPT-based fluorophore with better luminescent properties.

Intramolecular Hydrogen Bonding in N6-Substituted 2-Chloroadenosines: Evidence from NMR Spectroscopy.

Two forms were found in the NMR spectra of N6-substituted 2-chloroadenosines. The proportion of the mini-form was 11-32% of the main form. It was characterized by a separate set of signals in COSY, 15N-HMBC and other NMR spectra. We assumed that the mini-form arises due to the formation of an intramolecular hydrogen bond between the N7 atom of purine and the N6-CH proton of the substituent. The 1H,15N-HMBC spectrum confirmed the presence of a hydrogen bond in the mini-form of the nucleoside and its absence in the main form. Compounds incapable of forming such a hydrogen bond were synthesized. In these compounds, either the N7 atom of the purine or the N6-CH proton of the substituent was absent. The mini-form was not found in the NMR spectra of these nucleosides, confirming the importance of the intramolecular hydrogen bond in its formation.

Revealing the Reasons for Degeneration of Resonance-Assisted Hydrogen Bond on the Aromatic Platform: Calculations of Ortho-, Meta-, Para-Disubstituted Benzenes, and (Z)-(E)-Olefins.

The energies of the O-H∙∙∙O=C intramolecular hydrogen bonds were compared quantitatively for the series of ortho-disubstituted benzenes and Z-isomers of olefins via a molecular tailoring approach. It was established that the hydrogen bond energy in the former series is significantly less than that in the latter one. The reason for lowering the hydrogen bond energy in the ortho-disubstituted benzenes compared to the Z-isomers of olefins is the decrease in the π-contribution to the total energy of the complex interaction, in which the hydrogen bond per se is enhanced by the resonance effect. By the example of the para- and meta-disubstituted benzenes, as well as E-isomers of olefins, it was explicitly shown that the aromatic ring is a much poorer conductor of the resonance effect compared to the double bond. The hydrogen bond in the ortho-disubstituted benzenes has a lower energy than a typical resonance-assisted hydrogen bond because the aromatic moiety cannot properly assist the hydrogen bond with a resonance effect. Thus, a hydrogen bond on an aromatic platform should fall into a special category, namely an aromaticity-assisted hydrogen bond, which is closer by nature to a simple hydrogen bond rather than to a resonance-assisted one.

Details Matter in Structure-based Drug Design.

Successful structure-based drug design (SBDD) requires the optimization of interactions with the target protein and the minimization of ligand strain. Both factors are often modulated by small changes in the chemical structure which can lead to profound changes in the preferred conformation and interaction preferences of the ligand. We draw from examples of a Roche project targeting phosphodiesterase 10 to highlight that details matter in SBDD. Data mining in crystal structure databases can help to identify these sometimes subtle effects, but it is also a great resource to learn about molecular recognition in general and can be used as part of molecular design tools. We illustrate the use of the Cambridge Structural Database for identifying preferred structural motifs for intramolecular hydrogen bonding and of the Protein Data Bank for deriving propensities for protein-ligand interactions.

Molecular tailoring approach as tool for revealing resonance-assisted hydrogen bond: Case study of Z-pyrrolylenones with the NH⋯OС intramolecular hydrogen bond.

Both the experimental and calculated data reveal that a strong NH⋯OС intramolecular hydrogen bond closing the seven-membered quasi-cycle is formed in the Z-isomers of pyrrolylenones. Comparison of the NH⋯OС intramolecular hydrogen bonds energies in the pyrrolylenones, estimated via the molecular tailoring approach, with the similar data for reference malonaldehydes shows that the resonance-assisted hydrogen bonding occurs in both cases, the hydrogen bond energy being varied mainly within 10-20 kcal/mol. The combined application of function-based and molecular tailoring approaches makes it possible to decompose the NH⋯OС total hydrogen bond energy in the pyrrolylenones into the π- and σ-components. It is established that the contribution of the π-component to the total N(O)H⋯OС hydrogen bond energy in the pyrrolylenones and malonaldehydes is almost the same (6-7 kcal/mol). Comparison of the π-contribution to the total energy of the resonance-assisted hydrogen bonding in the Z-isomer of pyrrolylenones with the energy of the push-pull effect in the E-isomer of pyrrolylenones reveals that the resonance contribution to the total energy of the resonance-assisted hydrogen bond in the former significantly enhances with reference to the net resonance energy in the latter. The appearance of the resonance-assisted hydrogen bond in the pyrrolylenones is possible due to the participation in the interaction of 10 or 14 π-electrons satisfying the Hückel aromaticity rule.

Physicochemical and Theoretical Characterization of a New Small Non-Metal Schiff Base with a Differential Antimicrobial Effect against Gram-Positive Bacteria.

Searching for adequate and effective compounds displaying antimicrobial activities, especially against Gram-positive bacteria, is an important research area due to the high hospitalization and mortality rates of these bacterial infections in both the human and veterinary fields. In this work, we explored (E)-4-amino-3-((3,5-di-tert-butyl-2-hydroxybenzylidene)amino) benzoic acid (SB-1, harboring an intramolecular hydrogen bond) and (E)-2-((4-nitrobenzilidene)amino)aniline (SB-2), two Schiff bases derivatives. Results demonstrated that SB-1 showed an antibacterial activity determined by the minimal inhibitory concentration (MIC) against Staphylococcus aureus, Enterococcus faecalis, and Bacillus cereus (Gram-positive bacteria involved in human and animal diseases such as skin infections, pneumonia, diarrheal syndrome, and urinary tract infections, among others), which was similar to that shown by the classical antibiotic chloramphenicol. By contrast, this compound showed no effect against Gram-negative bacteria (Klebsiella pneumoniae, Escherichia coli, and Salmonella enterica). Furthermore, we provide a comprehensive physicochemical and theoretical characterization of SB-1 (as well as several analyses for SB-2), including elemental analysis, ESMS, 1H and 13C NMR (assigned by 1D and 2D techniques), DEPT, UV-Vis, FTIR, and cyclic voltammetry. We also performed a computational study through the DFT theory level, including geometry optimization, TD-DFT, NBO, and global and local reactivity analyses.

Nuclear magnetic resonance studies on conformation and stability of mastoparan in methanol.

Mastoparan is a small peptide composed of 14 amino acid residues found in wasp venom. It penetrates into cytoplasm through the cell membranes and then binds to a G protein to stimulate the release of histamine. Conformation and its thermal stability of mastoparan from Vespula lewisi (MP) in methanol are investigated by using proton nuclear magnetic resonance (NMR) spectroscopy. On the basis of data on NOESY cross peaks, spin-spin coupling constants between an amide proton (NH) and an α-proton, NH chemical shift analyses, and temperature dependence of integrated intensity of NH resonance lines, we found that MP forms the helix between the 5th and 12th residues at low temperatures and the helix segment is maintained even at 54°C. This conformation is similar to that of MP bound to detergent micelles, and hence, methanol is considered to be appropriate as a membrane mimetic for MP. In connection with the function of the venom peptide, significance of high stability of the helical conformation is discussed.

Intramolecular H-Bond Dynamics of Catechol Investigated by THz High-Resolution Spectroscopy of Its Low-Frequency Modes.

Catechol is an oxygenated aromatic volatile organic compound and a biogenic precursor of secondary organic aerosols. Monitoring this compound in the gas phase is desirable due to its appreciable reactivity with tropospheric ozone. From a molecular point of view, this molecule is attractive since the two adjacent hydroxy groups can interchangeably act as donor and acceptor in an intramolecular hydrogen bonding due to the tunnelling between two symmetrically equivalent structures. Using synchrotron radiation, we recorded a rotationally-resolved Fourier Transform far-infrared (IR) spectrum of the torsional modes of the free and bonded -OH groups forming the intramolecular hydrogen bond. Additionally, the room temperature, pure rotational spectrum was measured in the 70-220 GHz frequency range using a millimeter-wave spectrometer. The assignment of these molecular transitions was assisted by anharmonic high-level quantum-chemical calculations. In particular, pure rotational lines belonging to the ground and the four lowest energy, vibrationally excited states were assigned. Splitting due to the tunnelling was resolved for the free -OH torsional state. A global fit combining the far-IR and millimeter-wave data provided the spectroscopic parameters of the low-energy far-IR modes, in particular those characterizing the intramolecular hydrogen bond dynamics.

Molecular Tailoring Approach for the Estimation of Intramolecular Hydrogen Bond Energy.

Hydrogen bonds (HBs) play a crucial role in many physicochemical and biological processes. Theoretical methods can reliably estimate the intermolecular HB energies. However, the methods for the quantification of intramolecular HB (IHB) energy available in the literature are mostly empirical or indirect and limited only to evaluating the energy of a single HB. During the past decade, the authors have developed a direct procedure for the IHB energy estimation based on the molecular tailoring approach (MTA), a fragmentation method. This MTA-based method can yield a reliable estimate of individual IHB energy in a system containing multiple H-bonds. After explaining and illustrating the methodology of MTA, we present its use for the IHB energy estimation in molecules and clusters. We also discuss the use of this method by other researchers as a standard, state-of-the-art method for estimating IHB energy as well as those of other noncovalent interactions.

The Effect of Intramolecular Hydrogen Bond Type on the Gas-Phase Deprotonation of ortho-Substituted Benzenesulfonic Acids. A Density Functional Theory Study.

Structural factors have been identified that determine the gas-phase acidity of ortho-substituted benzenesulfonic acid, 2-XC6H4-SO3H, (X = -SO3H, -COOH, -NO2, -SO2F, -C≡N, -NH2, -CH3, -OCH3, -N(CH3)2, -OH). The DFT/B3LYP/cc-pVTZ method was used to perform conformational analysis and study the structural features of the molecular and deprotonated forms of these compounds. It has been shown that many of the conformers may contain anintramolecular hydrogen bond (IHB) between the sulfonic group and the substituent, and the sulfonic group can be an IHB donor or an acceptor. The Gibbs energies of gas-phase deprotonation ΔrG0298 (kJ mol-1) were calculated for all compounds. It has been set that in ortho-substituted benzenesulfonic acids, the formation of various types of IHB is possible, having a significant effect on the ΔrG0298 values of gas-phase deprotonation. If the -SO3H group is the IHB donor, then an ion without an IHB is formed upon deprotonation, and the deprotonation energy increases. If this group is an IHB acceptor, then a significant decrease in ΔrG0298 of gas-phase deprotonation is observed due to an increase in IHB strength and the A- anion additional stabilization. A proton donor ability comparative characteristic of the -SO3H group in the studied ortho-substituted benzenesulfonic acids is given, and the ΔrG0298 energies are compared with the corresponding values of ortho-substituted benzoic acids.

Structural Characterization, DFT Calculation, NCI, Scan-Rate Analysis and Antifungal Activity against Botrytis cinerea of (E)-2-{[(2-Aminopyridin-2-yl)imino]-methyl}-4,6-di-tert-butylphenol (Pyridine Schiff Base).

Botrytis cinerea is a ubiquitous necrotrophic filamentous fungal phytopathogen that lacks host specificity and can affect more than 1000 different plant species. In this work, we explored L1 [(E)-2-{[(2-aminopyridin-2-yl)imino]-methyl}-4,6-di-tert-butylphenol], a pyridine Schiff base harboring an intramolecular bond (IHB), regarding their antifungal activity against Botrytis cinerea. Moreover, we present a full characterization of the L1 by NMR and powder diffraction, as well as UV-vis, in the presence of previously untested different organic solvents. Complementary time-dependent density functional theory (TD-DFT) calculations were performed, and the noncovalent interaction (NCI) index was determined. Moreover, we obtained a scan-rate study on cyclic voltammetry of L1. Finally, we tested the antifungal activity of L1 against two strains of Botrytis cinerea (B05.10, a standard laboratory strain; and A1, a wild type strains isolated from Chilean blueberries). We found that L1 acts as an efficient antifungal agent against Botrytis cinerea at 26 °C, even better than the commercial antifungal agent fenhexamid. Although the antifungal activity was also observed at 4 °C, the effect was less pronounced. These results show the high versatility of this kind of pyridine Schiff bases in biological applications.

Structural and Energetic Insights on Two Dye Compounds: 1-Acetyl-2-Naphthol and 2-Acetyl-1-Naphthol.

The energy involved in the structural switching of acyl and hydroxyl substituents in the title compounds was evaluated combining experimental and computational studies. Combustion calorimetry and Knudsen effusion techniques were used to determine the enthalpies of formation, in the crystalline state, and of sublimation, respectively. The gas-phase enthalpy of formation of both isomers was derived combining these two experimental data. Concerning the computational study, the G3(MP2)//B3LYP composite method was used to optimize and determine the energy of the isomers in the gaseous state. From a set of hypothetical reactions it has been possible to estimate the gas-phase enthalpy of formation of the title compounds. The good agreement between the experimental and computational gas-phase enthalpies of formation of the 1-acetyl-2-naphthol and 2-acetyl-1-naphthol isomers, provided the confidence for extending the computational study to the 2-acetyl-3-naphthol isomer. The structural rearrangement of the substituents in position 1 and 2 in the naphthalene ring and the energy of the intramolecular hydrogen bond are the factors responsible for the energetic differences exhibited by the isomers. The gas phase tautomeric keto ↔ enol equilibria of the o-acetylnaphthol isomers were analyzed using the Boltzmann's distribution.

Discovery of novel selective Janus kinase 2 (JAK2) inhibitors bearing a 1H-pyrazolo[3,4-d]pyrimidin-4-amino scaffold.

Janus kinases (JAKs) regulate various cancers and immune responses and are targets for the treatment of cancers and immune diseases. A new series of 1H-pyrazolo[3,4-d]pyrimidin-4-amino derivatives were synthesized and optimized by introducing a functional 3,5-disubstituted-1H-pyrazole moiety into the C-3 moiety of pyrazole template, and then were biologically evaluated as potent Janus kinase 2 (JAK2) inhibitors. Among these molecules, inhibitors 11f, 11g, 11h and 11k displayed strong activity and selectivity against the JAK2 kinase, with IC50 values of 7.2 nM, 6.5 nM, 8.0 nM and 9.7 nM, respectively. In particular, the cellular inhibitory assay and western blot analysis further support the JAK2 selectivity of compound 11g also in cells. Furthermore, compound 11g also exhibited potent inhibitory activity in lymphocytes proliferation assay and delayed hypersensitivity assay. Taken together, the novel JAK2 selective inhibitors discovered in this study may be potential lead compounds for new drug discovery via further development of more potent and selective JAK2 inhibitors.

Synchrotron-Radiation Vacuum-Ultraviolet Circular-Dichroism Spectroscopy for Characterizing the Structure of Saccharides.

Circular-dichroism (CD) spectroscopy is a powerful tool for analyzing the structures of chiral molecules and biomolecules. The development of CD instruments using synchrotron radiation has greatly expanded the utility of this method by extending the spectra to the vacuum-ultraviolet (VUV) region below 190 nm and thereby yielding information that is unobtainable by conventional CD instruments. This technique is especially advantageous for monitoring the structure of saccharides that contain hydroxy and acetal groups with high-energy transitions in the VUV region. Combining VUVCD spectra with theoretical calculations provides new insight into the contributions of anomeric hydroxy groups and rotational isomers of hydroxymethyl groups to the dynamics, intramolecular hydrogen bonds, and hydration of saccharides in aqueous solution.

Influence of Hydroxyl Functional Group on the Structure and Stability of Xanthone: A Computational Approach.

The present work addresses computational research focused on the energetic and structural properties of four isomers monohydroxyxanthone, using the G3(MP2)//B3LYP method, in order to evaluate the influence of the hydroxyl (-OH moiety) functional group on the xanthone molecule. The combination of these computational results with previous experimental data of these compounds enabled the determination of their enthalpies, entropies and Gibbs energies of formation, in the gaseous phase, and consequently to infer about the relative thermodynamic stability of the four isomers. Other issues were also addressed for the hydroxyxanthone isomers, namely the conformational and the tautomeric equilibrium analysis of the optimized molecular structures, the frontier orbitals, and the electrostatic potential energy maps. Complementarily, an energetic study of the intramolecular O - H ⋯ O hydrogen bond for 1-hydroxanthone was also performed.