Enol Form Research Articles

TD-DFT analysis of the photo-ring-opening reaction of the flav-3-en-2-ol in acetonitrile solution: Functional choice and effect of solvated hydrogen bond

Of the forty hybrid functionals supported by Gaussian 16, only fourteen functionals with small contributions from the exact Hartree-Fock exchange demonstrated the breaking of the C2-O1 bond of flav-3-en-2-ol: TPSSh, O3LYP, τHCTHhyb, B3LYP, B3P86, B3PW91, B971, B972, X3LYP, B98, APF, APFD, mPW1LYP, and mPW3PBE. TPSSh and O3LYP gave rise to a cis-2-hydroxychalcone transition accompanied by ground-state intramolecular proton transfer (GSIPT), and the remaining twelve functionals selected showed a return to the flav-3-en-2-ol with the recovery of the C2-O1 bond. The strong H-bond of acetonitrile with flav-3-en-2-ol has a striking effect on the consequences of the excitation in comparison with a single flav-3-en-2-ol molecule: optimization of the S1 excited state of the solvated complex leads to the breaking of the C2-O1 bond by O3LYP functional only. However, upon relaxation of the excited enol form, this bond was recovered, and a return to the flav-3-en-2-ol occurred. Nevertheless, the O3LYP functional gives a theoretical model consistent with the experiment: the H-bond of flav-3-en-2-ol with the acetonitrile molecule is a switch in the reaction path. If this H-bond is present at the excitation moment, then the flav-3-en-2-ol molecule undergoes a C2-O1 bond cleavage but recovers upon relaxation. If this H-bond is absent, then the flav-3-en-2-ol molecule transforms into the enol form which goes further into cis-2-hydroxychalcone. The excitation of the solvated complex causes a pronounced strengthening of this intermolecular H-bond. GSIPT is caused by a change in the polarization of the enol form during its electronic relaxation, as a result of which the proton begins to experience a stronger attraction to the opposite part of the molecule.

Effect of ESIPT-Induced Photoisomerization of Keto-Enamine Linkages on the Photocatalytic Hydrogen Evolution Performance of Covalent Organic Frameworks.

Photoexcitation of keto-enamine allows intramolecular proton transfer from C-NH to C=O, leading to tautomerization, while the photogenerated isomers are excluded from the study of photocatalytic applications. Herein, we demonstrate the photoisomerization of keto-enamine linkages on covalent organic frameworks (COFs) induced by excited-state intramolecular proton transfer (ESIPT). Partial enolization generates partially enolized photoisomers with a mixture of keto (C=O) and enol (OH) forms, conferring extended π-conjugation with an increase in electron density. The spatially separated D-A configuration is thus rebuilt with the enol-imine-linked branch as a donor and the keto-enamine-linked branch as an acceptor, and in turn, the photoinduced charges transfer between the two adjacent branches with a long lifetime. We further prove that the partially enolized photoisomer is a key transition instead of the keto-enamine form as an excited-state model to understand the photocatalytic behaviors. Therefore, ESIPT-induced photoisomerization must be considered for rationally designing keto-enamine-linked COFs with enhanced photocatalytic activity. Also, our study points toward the importance of controlling excited-state structures for long-lived separated charges, which is of particular interest for optoelectronic applications.

Topological analysis and reactivity study of monomeric and dimeric forms of 2-methyl-4(1H)-quinolone: a computational study.

Quinolone derivatives have gathered major attention largely due to their wonderful biological activities. Quinolones are a class of molecules that are derived from quinolines and also extracted from natural sources. Most of these quinolones have significant medicinal properties ranging from antiallergenic and anticancer to antimicrobial activities. Some bacteria produce several 2-alkyl-4(1H)-quinolones. In past years, a variety of methods have been reported for the synthesis of quinolone derivatives. In this present work, structural, wave functional, and electronic properties of monomeric and dimeric forms of 2-methyl-4(1H)-quinolone are investigated. From the calculated binding energies, it was found that the formation of dimers is thermodynamically favorable. The analysis of reactivity parameters confirms that the keto form is more reactive than the enol form and keto-keto dimer is more reactive than compared to all monomeric and dimeric forms of our studied compound. Geometry optimizations of monomers and dimers of studied molecules were carried out using the B3LYP-D3(BJ)/ma-def2-TZVPP level of theory. The highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) energies were calculated using the B3LYP/def2-TZVP level of theory. All DFT calculations were done with the ORCA 5.0.3 program. The reactivity parameters such as ionization potential, electron affinity, global hardness, global softness, electronegativity, chemical potential, and electrophilicity index were calculated. The nature of intermolecular interactions within the dimers was studied using topological analysis such as atoms in molecule (AIM) and reduced density gradient (RDG) surface analyses. To visualize the electron delocalization in the dimer electron localization function (ELF) and localized orbital locator (LOL) studies were also performed. The analyses such as AIM, RDG, ELF, and LOL were carried out by the multifunctional wavefunction analysis program Multiwfn 3.8.

Investigation on the stability of the Enol Tautomer of Favipiravir and its derivatives by DFT, QTAIM, NBO, NLO and 1H-NMR

Relative stability energies of enol and keto forms of Favipiravir drug (6-fluoro-3-hydroxy-2-pyrazine carboxamide) and its twelve derivatives were theoretically envisaged using the B3LYP/6-311 + G(3df,2p)//B3LYP/6-311 + G(d,p) level of theory. Influence of the nature of the substituted groups on the geometric structures, IMHB, vibrational frequencies, dipole moments, and global reactivity descriptors was systematically studied. The enol form was found to be more stable than the keto form, regardless of the nature of the substituted group, by an average of 12.5 and 5.4 kcal/mol in the gas phase and in the aqueous solution, respectively. The role of the IMHB strength in the stability of the enol form compared with the keto form was investigated in terms of QTAIM and NBO analysis and 1H NMR chemical shifts. The NLO properties at CAM-B3LYP with 6-311 + G(d,p) basis set of the two forms and their derivatives were also used to explain the relative stability.

Complexes on the Base of a Proton Transfer Capable Pyrimidine Derivative: How Protonation and Deprotonation Switch Emission Mechanisms.

A rare example of pyrimidine-based ESIPT-capable compounds, 2-(2-hydroxyphenyl)-4-(1H-pyrazol-1-yl)-6-methylpyrimidine (HLH), was synthesized (ESIPT─excited state intramolecular proton transfer). Its reactions with zinc(II) salts under basic or acidic conditions afforded a dinuclear [Zn2LH2Cl2] complex and an ionic (H2LH)4[ZnCl4]2·3H2O solid. Another ionic solid, (H2LH)Br, was obtained from the solution of HLH acidified with HBr. In both ionic solids, the H+ ion protonates the same pyrimidinic N atom that accepts the O-H···N intramolecular hydrogen bond in the structure of free HLH, which breaks this hydrogen bond and switches off ESIPT in these compounds. This series of compounds which includes neutral HLH molecules and ionic (LH)- and (H2LH)+ species allowed us to elucidate the impact of protonation and coordination coupled deprotonation of HLH on the photoluminescence response and on altering the emission mechanism. The neutral HLH compound exhibits yellow emission as a result of the coexistence of two radiative decay channels: (i) T1 → S0 phosphorescence of the enol form and (ii) anti-Kasha S2 → S0 fluorescence of the keto form, which if feasible due to the large S2-S1 energy gap. However, owing to the efficient nonradiative decay through an energetically favorable conical intersection, the photoluminescence quantum yield of HLH is low. Protonation or deprotonation of the HLH ligand results in the significant blue-shift of the emission bands by more than 100 nm and boosts the quantum efficiency up to ca. 20% in the case of [Zn2LH2Cl2] and (H2LH)4[ZnCl4]2·3H2O. Despite both (H2LH)4[ZnCl4]2·3H2O and (H2LH)Br have the same (H2LH)+ cation in the structures, their emission properties differ significantly, whereas (H2LH)Br shows dual emission associated with two radiative decay channels: (i) S1 → S0 fluorescence and (ii) T1 → S0 phosphorescence, (H2LH)4[ZnCl4]2·3H2O exhibits only fluorescence. This difference in the emission properties can be associated with the external heavy atom effect in (H2LH)Br, which leads to faster intersystem crossing in this compound. Finally, a huge increase in the intensity of the phosphorescence of (H2LH)Br on cooling leads to pronounced luminescence thermochromism (violet emission at 300 K, sky-blue emission at 77 K).

A Combination of Computational and Experimental Studies to Correlate Electronic Structure and Reactivity of Donor–Acceptor Singlet Carbenes

AbstractMost of the reactivities of donor–acceptor (D–A) singlet carbenes are similar to metal carbenoids. However, the lone pair at the carbenoid carbon, coordinated with metal, is free in D–A carbene thereby making it nucleophilic as well. Herein, DFT-optimized structural features of D–A carbene has been investigated and is compared with rhodium carbenoid. It was observed that, when a D–A carbene reacts with cyclic-1,3-diones in different ethereal solvents, it is the lone pair at the sp2 orbital of the carbene that abstracts the proton from the enol form (of the cyclic-1,3-diones) to form a benzylic carbocation and an enolate. Subsequently, the carbocation undergoes nucleophilic attack by O of the ether solvents and then by the enolate to afford the desired ether-linked products. Accordingly, herein the reaction in THF, which otherwise had failed to work as a substrate in reported amino etherification reactions, worked well. DFT-calculated orbital energy levels and reaction profile support this reverse reactivity of singlet carbenes. Furthermore, HOMO–LUMO calculations indicated that electron-rich arenes in D–A carbene stabilizes the LUMO and destabilizes the HOMO which increases yield. Additionally, a library of 37 enol ether and 39 ether-linked compounds of potential medicinal relevance have been synthesized with good to excellent yields using numerous cyclic-1,3-diones.

Theoretical studies on the photo protective mechanism of curcuminoids

In this work, the deactivation pathways of curcuminoids after photoexcitation was studied by employing density functional theory to explore their UVA radiation screening capacity. A comprehensive computational characterization of the excited-state processes of curcumin, demethoxycurcumin, and bis-demethoxycurcumin was done. The molecules exist in diketo and enol forms which are in equilibrium and interconvertible through keto-enol tautomerism. The enolic forms of each of the studied molecules have eight geometric cis–trans isomers as a result of torsion rotation about three different carbon–carbon double bonds across the aliphatic chain. For each geometric isomer, sixteen possible rotamers are found to exist due to rotation about five different carbon–carbon single bond rotations, also across the skeleton of the aliphatic chain. Upon photoexcitation, the studied molecules follow three main pathways of radiationless decay: (a) rotamerism and interconversion between rotamers of comparable energies which are in equilibrium, (b) interconversion between the cis–trans geometrical isomers where an efficient vibrational relaxation path is formed at ∼90° during torsion rotation about carbon–carbon double bond, and (c) excited state intramolecular proton transfer in a single O–H stretching vibration through a cyclic intramolecular hydrogen bonded ring formed at the centre of the molecule giving back the original structure. The absorption and emission spectra of the molecules were also simulated where the theoretically obtained absorption and emission maxima are close to the reported experimental values.

Surfactant mediated modulation of photophysics and self-assembly process of a small, substituted phenol

5-(tert-Butyl)-2-hydroxy-1,3- isophthalaldehyde (5-tBHI) exhibits a large Stokes shifted emission spectrum, irrespective of excitation wavelength in aqueous solution and thus can be useful in bio-imaging. It is imperative to understand the binding of 5-tBHI in micelles as micelle represent the simplest mimic of biological membrane. Hence, the interaction of 5-tBHI with cationic surfactant cetyltrimethylammonium bromide (CTAB), anionic surfactant sodium dodecyl sulfate (SDS), and neutral surfactant Triton X-100 (TX-100) was investigated. This help us elucidate the interplay of hydrophobicity and pH to modulate the ground and excited state intra/inter-molecular proton transfer processes of the probe. The absorption and fluorescence spectra of 5-tBHI have been found to be highly sensitive towards hydrophobicity and electrostatic interactions. However, no particular trend was observed, suggesting an incomplete encapsulation of the probe in the micelles. The observation from the steady state spectra could not be rationalized completely based on the time resolved fluorescence decays in the nanosecond-picosecond regime, suggesting that the processes are ultrafast in nature. Subsequently, analyses of fluorescent transients in femtosecond-picosecond regime provided a better explanation to match well with the steady state phenomena. It was found that pH has a dominant role to guide the direction of the two-state keto-enol tautomerisation. However, the effect of hydrophobicity can not be neglected as it pushes the equilibrium to the enol form. Furthermore, Fluorescence Lifetime Imaging Microscopy (FLIM), supported by SEM images, provide a pictorial idea of how the aggregation of the probe in neat water is affected by the nature of the surfactants. It further shows that SDS, with an acidic local pH favours the aggregation process, over CTAB and TX-100.

α-(Aminomethyl)acrylates as acceptors in radical-polar crossover 1,4-additions of dialkylzincs: insights into enolate formation and trapping.

We demonstrate that α-(aminomethyl)acrylates are suitable acceptors for 1,4-additions of dialkylzincs in aerobic conditions. The air-promoted radical-polar crossover process involves the 1,4-addition of an alkyl radical followed by homolytic substitution at the zinc atom of dialkylzinc. Coordination of the nitrogen atom to zinc enables this SH2 process which represents a rare example of alkylzinc-group transfer to a tertiary α-carbonyl radical. The zinc enolate thus formed readily undergoes β-fragmentation unless it is trapped by electrophiles in situ. Enolates of substrates having free N-H bonds undergo protodemetalation to provide ultimately the 1,4-addition adduct. In the presence of carbonyl acceptors, aldol condensation occurs providing overall a tandem 1,4-addition-aldol process. When a tert-butanesulfinyl moiety is present on the nitrogen atom, these electrophilic substitution reactions occur with good levels of chiral induction, paving the way to enantioenriched β2-amino acids and β2,2-amino acids.

Zinc-Mediated C–H Metalations in Modern Organic Synthesis

AbstractC–H Deprotometalations have long occupied a key role in modern organic synthesis in both the research laboratory and pharmaceutical and fine chemical manufacture, thanks to readily accessible reagents and well-established procedures. Typically, organolithiums are the reagent of choice thanks to high reactivity and ease of use but these are incompatible with base- and nucleophile-sensitive functional groups. In comparison, organozinc base complexes offer a milder approach to deprotonative C–H functionalisations, and compatibility with a wide range of functionalities which would be problematic when using the alternative organolithium or organomagnesium reagents has now been demonstrated. Here, we review the current state of the art in zinc-mediated C–H metalations at substituted arenes, heteroarenes, and Csp3–H sites.1 Introduction2 Csp2–H Functionalisation Using Zinc Bases2.1 Functionalised Arenes2.2 Heterocycles3 Csp3–H Functionalisation Using Zinc Bases3.1 Zinc Enolate Formation: Traditional Approach3.2 Zinc Enolate Formation via Zinc Bases3.3 Non-Enolic Csp3–H Zincations4 Conclusion

Ultrafast internal conversion and photochromism in gas-phase salicylideneaniline.

Salicylideneaniline (SA) is an archetypal system for excited-state intramolecular proton transfer (ESIPT) in non-planar systems. Multiple channels for relaxation involving both the keto and enol forms have been proposed after excitation to S1 with near-UV light. Here, we present transient absorption measurements of hot gas-phase SA, jet-cooled SA, and SA in Ar clusters using cavity-enhanced transient absorption spectroscopy (CE-TAS). Assignment of the spectra is aided by simulated TAS spectra, computed by applying time-dependent complete active space configuration interaction (TD-CASCI) to structures drawn from nonadiabatic molecular dynamics simulations. We find prompt ESIPT in all conditions followed by the rapid generation of the trans keto metastable photochrome state and fluorescent keto state in parallel. Increasing the internal energy increases the photochrome yield and decreases the fluorescent yield and fluorescent state lifetime observed in TAS. In Ar clusters, internal conversion of SA is severely hindered, but the photochrome yield is unchanged. Taken together, these results are consistent with the photochrome being produced via the vibrationally excited keto population after ESIPT.

PLP-Dependent Enzyme Methionine γ-Lyase: Insights into the Michaelis Complex from Molecular Dynamics and Free Energy Simulations.

Methionine γ-lyase (MGL) breaks down methionine, with the help of its cofactor pyridoxal-5'-phosphate (PLP), or vitamin B6. Methionine depletion is damaging for cancer cells but not normal cells, so MGL is of interest as a therapeutic protein. To increase our understanding and help engineer improved activity, we focused on the reactive, Michaelis complex between MGL, covalently bound PLP, and substrate Met. is not amenable to crystallography, as it proceeds to products. Experimental activity measurements helped exclude a mechanism that would bypass . We then used molecular dynamics and alchemical free energy simulations to elucidate its structure and dynamics. We showed that the PLP phosphate has a pKa strongly downshifted by the protein, whether Met is present or not. Met binding affects the structure surrounding the reactive atoms. With Met, the Schiff base linkage between PLP and a nearby lysine shifts from a zwitterionic, keto form to a neutral, enol form that makes it easier for Met to approach its labile, target atom. The Met ligand also stabilizes the correct orientation of the Schiff base, more strongly than in simulations without Met, and in agreement with structures in the Protein Data Bank, where the Schiff base orientation correlates with the presence or absence of a co-bound anion or substrate analogue in the active site. Overall, the Met ligand helps organize the active site for the enzyme reaction by reducing fluctuations and shifting protonation states and conformational populations.

First-Principles Study of the Dispersion Effects in the Structures and Keto-Enol Tautomerization of Curcumin.

Noncovalent interactions, such as dispersion, play a significant role in the stability of flexible molecules, such as curcumin. This study revealed the importance of dispersion correction in the structure and keto-enol tautomerization of curcumin, which has rarely been addressed in computational studies. We rigorously constructed all possible unique curcumin conformers in the enol and keto forms within the first-principles framework. Regardless of the different environments, we carefully explained the agreement between the computational geometry (in the gas phase) and the experimental measurement (in the polymorph) by using dispersion correction. The calculation results for the aqueous solution of conformational abundance, thermochemistry, and reaction kinetics support the experimental observations after considering the dispersion correction. The study also suggests a water-catalyzed mechanism for keto-enol tautomerization, where dispersion correction plays a role in decreasing the energy barrier and making the keto form thermochemically and kinetically favorable. Our results could be helpful in future computational studies to find a method for increasing the aqueous solubility of curcumin; hence, the potential of curcumin as a multifunctional medicine can be fully achieved.

Lewis acidity and substituent effects influence aldehyde enolization and C–C coupling in beta zeolites

The Claisen-Schmidt condensation between propanal and benzaldehyde was used a model aldol reaction to assess the reactivity of tetravalent framework Lewis acid sites (Ti, Zr, Sn, Hf) in hydrophobic beta zeolites (M-*BEA) and determine rates of enolization and carbon–carbon (C–C) bond formation along with selectivities among cross- and self-condensation products. Rates of enolate formation during liquid phase reactions (393 K) span nearly 100-fold, depending on the identity of the metal heteroatom, and correlate with enthalpies for adsorption of pyridine in liquid-filled pores of M-*BEA, as measured by isothermal titration calorimetry. Comparisons among adsorption enthalpies suggest that tetrahedrally substituted Zr and Hf are more effective Lewis acids than Sn and Ti for coordinating aldehydes within these environments. Ratios of initial rates of C–C coupling between propanal and benzaldehyde compared to propanal self-condensation were less than unity for all M-*BEA catalysts. These selectivity patterns reflect the combination of electronic and steric effects imposed by the larger aromatic substituent at the carbonyl carbon atom and its concerted interactions with the Lewis acid site, which causes rates for nucleophilic attack of enolates to benzaldehyde to be far less than those to propanal.

Cu(II), Ni(II) and Co(II) Complexes of Malonic Acid Dihydrazide with Bis-BrSalicylhydrazone

New complexes of Cu(II), Ni(II), and Co(II) with N1,N3-bis(5-bromo-2-hydroxybenzylidene)-malonohydrazide (LH4) have been synthesized. It was shown that, in the synthesized Cu(II) and Co(II) complexes with the LH4 ligand, coordination occurs according to the Schiff base type, while in the Ni(II) complex the oxygen atom of the amide (hydrazide) group in the enol form and the nitrogen atom of the azomethine group take part in the coordination groups. Based on the data of IR, electron spectroscopy, EPR, thermogravimetry and elemental analysis of the obtained complexes, the octahedral coordination of Cu(II) ions and the binuclear structure of the complexes are assumed. It was established that all obtained compounds have high bactericidal and fungicidal activity. After, the activities of the studied ligand and its metal complexes against various cancer proteins including breast, colon, and lung cancer were compared.

Dangling Water Molecules Bridge for ESIPT in Aggregated TMP: A Theoretical Study.

We present a theoretical study on the occurrence of excited-state proton transfer in an aggregated structure of 2-(benzo[d]thiazol-2-yl)-6-methoxyphenol (TMP) exclusively in water among polar solvents, as reported in a recent experiment (Bhattacharyya, A. New J. Chem. 2019, 43, 15087). Our extensive investigation of the TMP monomer and dimer implementing density functional theory (DFT) and time-dependent density functional theory (TDDFT) methods, in three different solvents, namely, water, methanol, and dimethyl sulfoxide (DMSO), with explicit inclusion of solvent molecules demonstrated the existence of both enol and keto forms of the TMP dimer in the excited state, but only in water; this confirmed the experimental emission spectra completely and simultaneously validated the aggregation-induced emission phenomenon. Further analysis of various parameters such as potential energy scan (PES) of the hydroxyl (O-H) bond involved in hydrogen bonding, frontier molecular orbitals (FMOs), molecular electrostatic potential (MEP), and infrared (IR) stretching frequencies of both the monomer and dimer forms of TMP in different solvents clearly indicated the geometry of the dimer, with the arrangement of the solvent molecules to be the sole reason for the excited-state charge transfer. The bridging alignment of water molecules in between the stacked units of the TMP dimer results in intermolecular interactions, ultimately leading to intermolecular proton transfer in the excited state.

Synthesis, characterization, DFT calculations and biological activity of new Schiff base complexes

Schiff bases ligand (HL) was produced by condensing 4-aminobenzohydrazide with N-(4-chlorophenyl)-2-(4-formylphenoxy)acetamide. Cobalt (II), nickel (II), and copper (II) acetate and ligand are reacted to form 1:1 complexes. By using electronic spectra, magnetic susceptibility measurements, infrared data from 1H NMR, and XRD studies, the ligand and its metal complexes have been characterized. According to the spectrum data, the ligand functions as a monobasic bidentate, coordinating with the nitrogen atom of azomethine (−CN−) group and the oxygen atom of carbonyl group in enol form. An octahedral structure has been proposed for Co(II), Ni(II), and Cu(II) complexes according to magnetic and electronic spectrum analysis. Using the DFT method, the computational investigations of the ligand and its metal complexes showed the bond lengths, bond angles, and quantum chemical parameters. To determine the thermal stability and mode of thermal degradation of hydrazone ligand and its complexes, thermogravimetric analysis was approved out on the samples. Two calculated method, Horowitz-Metzger and Coats-Redfern, were used to calculate the characteristics of the composites' thermal degradation mechanisms at each step, including their breakdown kinetics. The ligand and its complexes were investigated for their cytotoxicity in vitro compared to human amnion (WISH) and epitheliod carcinoma (Hela). The Ni(II) complex showed highly inhibition against (WISH) growth (IC50 = 18.28±1.8 μM) with relationship to the produced chemicals and other common medications. The interaction between the ligand and its complexes with the genetic tumor (3hb5) receptor was examined using docking experiments.

On the photobehaviour of curcumin in biocompatible hosts: The role of H-abstraction in the photodegradation and photosensitization.

Curcumin (CUR) is a naturally occurring pigment extensively studied due to its therapeutic activity and delivered by suitable nanocarriers to overcome poor solubility in aqueous media. The significant absorption of CUR in the visible blue region has prompted its use as a potential phototherapeutic agent in treating infectious and cancer diseases, although the mechanism underlying the phototoxic effects is still not fully understood. This contribution investigates the photobehaviour of CUR within polymeric micelles, microemulsions, and zein nanoparticles, chosen as biocompatible nanocarriers, and human serum albumin as a representative biomolecule. Spectroscopic studies indicate that in all host systems, the enolic tautomeric form of CUR is converted in a significant amount of the diketo form because of the perturbation of the intramolecular hydrogen bond. This leads to intermolecular H-abstraction from the host components by the lowest excited triplet state of CUR with the formation of the corresponding ketyl radical, detected by nanosecond laser flash photolysis. This radical is oxidized by molecular oxygen, likely generating peroxyl and hydroperoxyl radical species, unless in Zein, reasonably due to the poor availability of oxygen in the closely packed structure of this nanocarrier. In contrast, no detectable formation of singlet oxygen was revealed in all the systems. Overall these results highlight the key role of the H-abstraction process over singlet oxygen sensitization as a primary photochemical pathway strictly dictated by the specific features of the microenvironment, providing new insights into the photoreactivity of CUR in biocompatible hosts that can also be useful for a better understanding of its phototoxicity mechanism.

Complexation of Fluorofenidone by Cucurbit[7]uril and β-Cyclodextrin: Keto-Enol Tautomerization to Enhance the Solubility.

This study is designed to compare drug encapsulation by cucurbit[7]uril and β-cyclodextrin, using fluorofenidone as a model drug. Single-crystal X-ray diffraction analysis was employed to successfully determine the crystal structures of fluorofenidone·H+@cucurbit[7]uril Form, fluorofenidone@cucurbit[7]uril Form, and fluorofenidone@β-cyclodextrin Form. Keto-enol tautomerization of fluorofenidone mediated by cucurbit[7]uril in acid solution is confirmed by crystal structures, pH titration, and nuclear magnetic resonance experiments. However, β-cyclodextrin cannot cause the keto-enol tautomerization of fluorofenidone under similar conditions. The phase solubility study demonstrates that cucurbit[7]uril has a much higher solubilization capacity for fluorofenidone than β-cyclodextrin in 0.1 M HCl since the Kc values of fluorofenidone with cucurbit[7]uril and β-cyclodextrin were 1223.97 ± 452.68 and 78.49 ± 10.56 M-1, respectively. Excellent solubility can be attributed to the keto-enol tautomerization of fluorofenidone under the conditions of cucurbit[7]uril in acid solution. The enol form of fluorofenidone is encapsulated by cucurbit[7]uril by hydrogen bonding interaction and hydrophobic interaction to increase binding affinity. Rat pharmacokinetic studies demonstrate that the area under the plasma concentration-time curve from time 0 to 7 h value of fluorofenidone@cucurbit[7]uril complex is 1.70-fold greater than that of free fluorofenidone, and the mean residence time from time 0 to 7 h is slightly prolonged from 1.29 to 1.76 h (P < 0.01) after oral administration. However, no significant difference is found between fluorofenidone and fluorofenidone@β-cyclodextrin complex. This work indicates that the induction of keto-enol tautomerization of drugs using macrocyclic molecules has the potential to be an effective method to improve their solubility and bioavailability, providing valuable insights for the application of macrocyclic molecules in the biomedical field.

Enzymatic evaluation of chromenone derivatives from Flemingia philippinensis as viral neuraminidase (H3N2) inhibitors

The chromenones (1–6) from F. philippinensis displayed significant inhibition against the viral neuraminidase of H3N2. All the target chromenones including the new compound 5 have a triketone skeleton consisting of 2-acetyl-1,3-cyclohexanedione, which provides a being stable structure as exocyclic keto and enol form itself. The most potent inhibitor was identified as chromenone 1 (IC50 = 4.6 µM), but a subtle change in the functionality markedly affected the inhibitory potency (IC50 = 4.6 ∼ 28.5 µM) and mode. In particular, chromenones (1 and 4) with the exocyclic enol form exhibited the competitive mode, whereas the keto forms (2, 3, 5, and 6) were noncompetitive. The competitive inhibitor, chromenone 1, was proved to interact in a reversible simple slow-binding mode, according to the respective parameters: Kiapp = 2.38 µM, k3 = 0.0013 µM−1min−1, and k4 = 0.0031 min−1. The binding interactions of the competitive (1 and 4) and noncompetitive (2 and 3) inhibitors at the catalytic and allosteric sites, respectively, were predicted by the molecular docking method.