ABSTRACT
α-glucosidase, a pharmacological target for type 2 diabetes mellitus (T2DM), is present in the intestinal brush border membrane and catalyzes the hydrolysis of sugar linkages during carbohydrate digestion. Since α-glucosidase inhibitors (AGIs) modulate intestinal metabolism, they may influence oxidative stress and glycolysis inhibition, potentially addressing intestinal dysfunction associated with T2DM. Herein, we report on a study of an ortho-carbonyl substituted hydroquinone series, whose members differ only in the number and position of methyl groups on a common scaffold, on radical-scavenging activities (ORAC assay) and correlate them with some parameters obtained by density functional theory (DFT) analysis. These compounds' effect on enzymatic activity, their molecular modeling on α-glucosidase, and their impact on the mitochondrial respiration and glycolysis of the intestinal Caco-2 cell line were evaluated. Three groups of compounds, according their effects on the Caco-2 cells metabolism, were characterized: group A (compounds 2, 3, 5, 8, 9, and 10) reduces the glycolysis, group B (compounds 1 and 6) reduces the basal mitochondrial oxygen consumption rate (OCR) and increases the extracellular acidification rate (ECAR), suggesting that it induces a metabolic remodeling toward glycolysis, and group C (compounds 4 and 7) increases the glycolysis lacking effect on OCR. Compounds 5 and 10 were more potent as α-glucosidase inhibitors (AGIs) than acarbose, a well-known AGI with clinical use. Moreover, compound 5 was an OCR/ECAR inhibitor, and compound 10 was a dual agent, increasing the proton leak-driven OCR and inhibiting the maximal electron transport flux. Additionally, menadione-induced ROS production was prevented by compound 5 in Caco-2 cells. These results reveal that slight structural variations in a hydroquinone scaffold led to diverse antioxidant capability, α-glucosidase inhibition, and the regulation of mitochondrial bioenergetics in Caco-2 cells, which may be useful in the design of new drugs for T2DM and metabolic syndrome.
Subject(s)
Antioxidants , Energy Metabolism , Glycoside Hydrolase Inhibitors , Hydroquinones , alpha-Glucosidases , Humans , Caco-2 Cells , alpha-Glucosidases/metabolism , Glycoside Hydrolase Inhibitors/pharmacology , Glycoside Hydrolase Inhibitors/chemistry , Antioxidants/pharmacology , Antioxidants/chemistry , Antioxidants/metabolism , Hydroquinones/pharmacology , Hydroquinones/chemistry , Energy Metabolism/drug effects , Glycolysis/drug effects , Mitochondria/metabolism , Mitochondria/drug effectsABSTRACT
Avian influenza poses a severe threat to poultry production and global food security, prompting the development of vaccination programs in numerous countries. Modified live virus (MLV) vaccines, with their potential for mass application, offer a distinct advantage over existing options. However, concerns surrounding reversion, recombination, and unintended transmission have hindered the progress of MLV development for avian influenza in poultry. To address these concerns, we engineered reassortment-impaired, non-transmissible, safe, immunogenic, and protective MLVs through the rearrangement of internal gene segments and additional modifications to the surface gene segments HA and NA. The unique peptide marker aspartic acid-arginine-proline-alanine-valine-isoleucine-alanine-asparragine (DRPAVIAN) was incorporated into HA, while NA was modified to encode the chicken interleukin-18 (ckIL18) gene (MLV-H9N2-IL). In vitro, the MLV-H9N2 and MLV-H9N2-IL candidates demonstrated stability and virus titers comparable to the wild-type H9N2 strain. In chickens, the MLV-H9N2 and MLV-H9N2-IL candidates did not transmit via direct contact. Co-infection studies with wild-type virus confirmed that the altered HA and NA segments exhibited fitness disadvantages and did not reassort. Vaccinated chickens showed no clinical signs upon vaccination, all seroconverted, and the inclusion of ckIL18 in the MLV-H9N2-IL vaccine enhanced neutralizing antibody production. A significant decrease in viral loads post-challenge underscored the protective effect of the MLVs. The MLV-H9N2-IL vaccine, administered via drinking water, proved immunogenic in chickens in a dose-dependent manner, generating protective levels of neutralizing antibodies upon aggressive homologous virus challenge. In summary, this study lays the groundwork for safe MLVs against avian influenza suitable for mass vaccination efforts.
ABSTRACT
Antimicrobial resistance is a major global health problem, and, among Gram-positive bacteria, methicillin-resistant Staphylococcus aureus (MRSA) represents a serious threat. MRSA causes a wide range of infections, including bacteremia, which, due to the limited use of ß-lactams, is difficult to treat. This study aimed to analyze 51 MRSA isolates collected in 2018 from samples of patients with bacteremia from two hospitals of the Metropolitan Health Service of Santiago, Chile, both in their resistance profile and in the identification of virulence factors. In addition, genomic characterization was carried out by the WGS of an isolate that was shown to be the one of greatest concern (N°. 42) due to its intermediate resistance to vancomycin, multiple virulence factors and being classified as ST8 PVL-positive. In our study, most of the isolates turned out to be multidrug-resistant, but there are still therapeutic options, such as tetracycline, rifampicin, chloramphenicol and vancomycin, which are currently used for MRSA infections; however, 18% were PVL positive, which suggests greater virulence of these isolates. It was determined that isolate N°42 is grouped within the USA300-LV strains (ST8, PVL+, COMER+); however, it has been suggested that, in Chile, a complete displacement of the PVL-negative ST5 clone has not occurred.
ABSTRACT
Platelets are the critical target for preventing and treating pathological thrombus formation. However, despite current antiplatelet therapy, cardiovascular mortality remains high, and cardiovascular events continue in prescribed patients. In this study, first results were obtained with ortho-carbonyl hydroquinones as antiplatelet agents; we found that linking triphenylphosphonium cation to a bicyclic ortho-carbonyl hydroquinone moiety by a short alkyl chain significantly improved their antiplatelet effect by affecting the mitochondrial functioning. The mechanism of action involves uncoupling OXPHOS, which leads to an increase in mitochondrial ROS production and a decrease in the mitochondrial membrane potential and OCR. This alteration disrupts the energy production by mitochondrial function necessary for the platelet activation process. These effects are responsive to the complete structure of the compounds and not to isolated parts of the compounds tested. The results obtained in this research can be used as the basis for developing new antiplatelet agents that target mitochondria.
Subject(s)
Blood Platelets , Hydroquinones , Membrane Potential, Mitochondrial , Organophosphorus Compounds , Platelet Aggregation Inhibitors , Humans , Blood Platelets/metabolism , Blood Platelets/drug effects , Hydroquinones/pharmacology , Hydroquinones/chemistry , Membrane Potential, Mitochondrial/drug effects , Mitochondria/metabolism , Mitochondria/drug effects , Organophosphorus Compounds/pharmacology , Organophosphorus Compounds/chemistry , Oxidative Phosphorylation/drug effects , Platelet Activation/drug effects , Platelet Aggregation/drug effects , Platelet Aggregation Inhibitors/pharmacology , Platelet Aggregation Inhibitors/chemistry , Reactive Oxygen Species/metabolismABSTRACT
Infectious salmon anaemia virus (ISAV) is a pathogen that causes disease and large mortality in farm-raised Salmo salar L., being considered as a major problem in the salmon industry. However, despite its relevance, there are still numerous knowledge gaps on virus entry and early stages of infection. Previous studies suggested that virus entry into cells occurs via endocytosis, with no description of specific mechanisms. However, it remains unknown if the endocytosis induced by ISAV is a clathrin-dependent or clathrin-independent process. This study aimed to identify cellular mechanisms allowing ISAV entry into Atlantic Salmon head kidney (ASK) cells. Our results showed that ISAV can be found in coated pits and membrane ruffles, the latter being induced by a rearrangement of actin filaments promoted by ISAV infection. Additionally, it was determined that ISAV stimulate the uptake of extracellular fluid in a multiplicity of infection (MOI)-dependent manner. When the clathrin-mediated endocytic pathway was pharmacologically inhibited, ISAV infection was significantly reduced but not entirely inhibited. Similarly, when the Na+/H+ exchanger (NHE), a key component of macropinocytosis, was inhibited, ISAV infection was negatively affected. Our results suggest that ISAV enters cells via both clathrin-mediated endocytosis and most likely macropinocytosis.
Subject(s)
Fish Diseases , Isavirus , Orthomyxoviridae Infections , Animals , Endocytosis , Clathrin , Orthomyxoviridae Infections/veterinaryABSTRACT
Current influenza A vaccines fall short, leaving both humans and animals vulnerable. To address this issue, we have developed attenuated modified live virus (MLV) vaccines against influenza using genome rearrangement techniques targeting the internal gene segments of FLUAV. The rearranged M2 (RAM) strategy involves cloning the M2 ORF downstream of the PB1 ORF in segment 2 and incorporating multiple early stop codons within the M2 ORF in segment 7. Additionally, the IgA-inducing protein (IGIP) coding region was inserted into the HA segment to further attenuate the virus and enhance protective mucosal responses. RAM-IGIP viruses exhibit similar growth rates to wild type (WT) viruses in vitro and remain stable during multiple passages in cells and embryonated eggs. The safety, immunogenicity, and protective efficacy of the RAM-IGIP MLV vaccine against the prototypical 2009 pandemic H1N1 strain A/California/04/2009 (H1N1) (Ca/04) were evaluated in Balb/c mice and compared to a prototypic cold-adapted live attenuated virus vaccine. The results demonstrate that the RAM-IGIP virus exhibits attenuated virulence in vivo. Mice vaccinated with RAM-IGIP and subsequently challenged with an aggressive lethal dose of the Ca/04 strain exhibited complete protection. Analysis of the humoral immune response revealed that the inclusion of IGIP enhanced the production of neutralizing antibodies and augmented the antibody-dependent cellular cytotoxicity response. Similarly, the RAM-IGIP potentiated the mucosal immune response against various FLUAV subtypes. Moreover, increased antibodies against NP and NA responses were observed. These findings support the development of MLVs utilizing genome rearrangement strategies in conjunction with the incorporation of immunomodulators. IMPORTANCE: Current influenza vaccines offer suboptimal protection, leaving both humans and animals vulnerable. Our novel attenuated MLV vaccine, built by rearranging FLUAV genome segments and incorporating the IgA-inducing protein, shows promising results. This RAM-IGIP vaccine exhibits safe attenuation, robust immune responses, and complete protection against lethal viral challenge in mice. Its ability to stimulate broad-spectrum humoral and mucosal immunity against diverse FLUAV subtypes makes it a highly promising candidate for improved influenza vaccines.
ABSTRACT
Influenza A virus (FLUAV) infects a wide range of hosts and human-to-swine spillover events are frequently reported. However, only a few of these human viruses have become established in pigs and the host barriers and molecular mechanisms driving adaptation to the swine host remain poorly understood. We previously found that infection of pigs with a 2:6 reassortant virus (hVIC/11) containing the hemagglutinin (HA) and neuraminidase (NA) gene segments from the human strain A/Victoria/361/2011 (H3N2) and internal gene segments of an endemic swine strain (sOH/04) resulted in a fixed amino acid substitution in the HA (A138S, mature H3 HA numbering). In silico analysis revealed that S138 became predominant among swine H3N2 virus sequences deposited in public databases, while 138A predominates in human isolates. To understand the role of the HA A138S substitution in the adaptation of a human-origin FLUAV HA to swine, we infected pigs with the hVIC/11A138S mutant and analyzed pathogenesis and transmission compared to hVIC/11 and sOH/04. Our results showed that the hVIC/11A138S virus had an intermediary pathogenesis between hVIC/11 and sOH/04. The hVIC/11A138S infected the upper respiratory tract, right caudal, and both cranial lobes while hVIC/11 was only detected in nose and trachea samples. Viruses induced a distinct expression pattern of various pro-inflammatory cytokines such as IL-8, TNF-α, and IFN-ß. Flow cytometric analysis of lung samples revealed a significant reduction of porcine alveolar macrophages (PAMs) in hVIC/11A138S-infected pigs compared to hVIC/11 while a MHCIIlowCD163neg population was increased. The hVIC/11A138S showed a higher affinity for PAMs than hVIC/11, noted as an increase of infected PAMs in bronchoalveolar lavage fluid (BALF), and showed no differences in the percentage of HA-positive PAMs compared to sOH/04. This increased infection of PAMs led to an increase of granulocyte-monocyte colony-stimulating factor (GM-CSF) stimulation but a reduced expression of peroxisome proliferator-activated receptor gamma (PPARγ) in the sOH/04-infected group. Analysis using the PAM cell line 3D4/21 revealed that the A138S substitution improved replication and apoptosis induction in this cell type compared to hVIC/11 but at lower levels than sOH/04. Overall, our study indicates that adaptation of human viruses to the swine host involves an increased affinity for the lower respiratory tract and alveolar macrophages.
Subject(s)
Influenza A Virus, H3N2 Subtype , Influenza A virus , Humans , Animals , Swine , Influenza A Virus, H3N2 Subtype/genetics , Macrophages, Alveolar , Amino Acids , Hemagglutinins , NoseABSTRACT
The piscine orthomyxovirus called infectious salmon anemia virus (ISAV) is one of the most important emerging pathogens affecting the salmon industry worldwide. The first reverse genetics system for ISAV, which allows the generation of recombinant ISA virus (rISAV), is an important tool for the characterization and study of this virus. The plasmid-based reverse genetics system for ISAV includes the use of a novel fish promoter, the Atlantic salmon internal transcribed spacer region 1 (ITS-1). The salmon, viral, and mammalian genetic elements included in the pSS-URG vectors allow the expression of the eight viral RNA segments. In addition to four cytomegalovirus (CMV)-based vectors that express the four proteins of the ISAV ribonucleoprotein complex, the eight pSS-URG vectors allowed the generation of infectious rISAV in salmon cells.
Subject(s)
Fish Diseases , Isavirus , Orthomyxoviridae Infections , Orthomyxoviridae , Animals , Isavirus/genetics , DNA, Complementary/genetics , Cell Line , Orthomyxoviridae/genetics , RNA, Viral/genetics , Orthomyxoviridae Infections/veterinary , Salmon/genetics , Mammals/geneticsABSTRACT
Synthesis, the complete 1H- and 13C-NMR assignments, and the long-range C,H coupling constants (nJC,H) of some hydrogen-deficient carbazolequinones, assessed by a J-HMBC experiment, are reported. In these molecules, the protons, used as entry points for assignments, are separated by several bonds with non-protonated atom carbons. Therefore, the use of long-range NMR experiments for the assignment of the spectra is mandatory; we used HSQC and HMBC. On the other hand, the measured heteronuclear (C,H) coupling constants 2J to 5J) allow us to choose the value of the long-range delay used in the HMBC experiment less arbitrarily in order to visualize a desired correlation in the spectrum. The chemical shifts and the coupling constant values can be used as input for assignments in related chemical structures.
Subject(s)
Carbon , Protons , Magnetic Resonance Spectroscopy , Carbon/chemistry , Hydrogen/chemistry , Magnetic Resonance ImagingABSTRACT
Mitochondrial Complex I plays a crucial role in the proliferation, chemoresistance, and metastasis of breast cancer (BC) cells. This highlights it as an attractive target for anti-cancer drugs. Using submitochondrial particles, we identified FRV-1, an ortho-carbonyl quinone, which inhibits NADH:duroquinone activity in D-active conformation and reduces the 3ADP state respiration dependent on Complex I, causing mitochondrial depolarization, ATP drop, increased superoxide levels, and metabolic remodeling towards glycolysis in BC cells. Introducing methyl groups at FRV-1 structure produced analogs that acted as electron acceptors at the Complex I level or increased the inhibitory effect of FCCP-stimulated oxygen consumption rate, which correlated with their redox potential, but increased toxicity on RMF-621 human breast fibroblasts was observed. FRV-1 was inactive in the naphthoquinone oxidoreductase 1 (NOQ1)-positive BC cell line, MCF7, but the sensitivity was recovered by dicoumarol, a NOQ1 inhibitor, suggesting that FRV-1 is a NOQ1 substrate. Importantly, FRV-1 selectively inhibited the proliferation, migration, and invasion of NQO1 negative BC cell, MDA-MB-231, in an OXPHOS- and ROS-dependent manner and sensitized it to the BH3 mimetic drug venetoclax. Overall, FRV-1 is a novel Complex I inhibitor in D-active conformation, blocking possibly the re-activation to A-state, producing selective anti-cancer effects in NQO1-negative BC cell lines.
ABSTRACT
INTRODUCTION: The use of triphenylphosphonium cation (TPP+) linked to phenolic compounds by alkyl chains has a significant relevance as a mitochondrial delivery strategy in biomedicine because it affects mitochondrial bioenergetics in models of noncommunicable diseases such as cancer and cardiovascular-related conditions. Studies indicate that a long alkyl chain (10-12 carbon) increases the mitochondrial accumulation of TPP+-linked drugs. In contrast, other studies show that these compounds are consistently toxic to micromolar concentrations (as observed in platelets). In the present study, we evaluated the in vitro effect of three series of triphenylphosphonium-linked acyl hydroquinones derivates on the metabolism and function of human platelets using 3-9 carbons for the alkyl linker. Those were assessed to determine the role of the length of the alkyl chain linker on platelet toxicity. METHODS: Human platelets were exposed in vitro to different concentrations (2-40 µM) of every compound; cellular viability, phosphatidylserine exposition, mitochondrial membrane potential (ΔΨm), intracellular calcium release, and intracellular ROS generation were assessed by flow cytometry. An in silico energetic profile was generated with Umbrella sampling molecular dynamics (MD). RESULTS AND CONCLUSIONS: There was an increase in cytotoxic activity directly related to the length of the acyl chain and lipophilicity, as seen by three techniques, and this was consistent with a decrease in ΔΨm. The in silico energetic profiles point out that the permeability of the mitochondrial membrane may be involved in the cytotoxicity of phosphonium salts. This information may be relevant for the design of new TPP+ -based drugs with a safe cardiovascular profile.
Subject(s)
Antineoplastic Agents , Hydroquinones , Humans , Hydroquinones/pharmacology , Mitochondria/metabolism , Mitochondrial Membranes/metabolism , Antineoplastic Agents/pharmacology , Energy Metabolism , Organophosphorus Compounds/pharmacology , Organophosphorus Compounds/metabolism , Membrane Potential, MitochondrialABSTRACT
The electrochemical behavior of N-methyl- and N-benzyl-4-piperidone curcumin analogs were studied experimentally and theoretically. The studied compounds present different substituents at the para position in the phenyl rings (-H, -Br, -Cl, -CF3, and -OCH3). We assessed their electrochemical behavior by differential pulse and cyclic voltammetry, while we employed density functional theory (DFT) M06 and M06-2x functionals along with 6-311+G(d,p) basis set calculations to study them theoretically. The results showed that compounds suffer a two-electron irreversible oxidation in the range of 0.72 to 0.86 V, with surface concentrations ranging from 1.72 × 10-7 to 5.01 × 10-7 mol/cm2. The results also suggested that the process is diffusion-controlled for all compounds. M06 DFT calculations showed a better performance than M06-2x to obtain oxidation potentials. We found a good correlation between the experimental and theoretical oxidation potential for N-benzyl-4-piperidones (R2 = 0.9846), while the correlation was poor for N-methyl-4-piperidones (R2 = 0.3786), suggesting that the latter suffer a more complex oxidation process. Calculations of the BDEs for labile C-H bonds in the compounds suggested that neither of the two series of compounds has a different tendency for a proton-coupled electron transfer (PCET) oxidation process. It is proposed that irreversible behavior is due to possible dimerization of the compounds by Shono-type oxidation.
Subject(s)
Curcumin , Piperidones , Electrons , Oxidation-Reduction , Electron TransportABSTRACT
Infectious salmon anemia virus (ISAV) is the etiological agent of infectious salmon anemia. It belongs to the genus isavirus, one of the genera of the Orthomyxoviridae family, as does Influenzavirus A. The ISAV genome comprises eight negative-sense single-stranded RNA segments that code for at least 10 proteins. Although some ISAV strains can reach 100% mortality rates, the factors that determine isavirus infectivity remain unknown. However, some studies suggest that segments 5 and 6 are responsible for the different degrees of virulence and infectivity among ISAV subtypes, unlike the influenza A virus, where most segments are involved in the virus infectivity. In this work, synthetic reassortant viruses for the eight segments of ISAV were generated by reverse genetics, combining a highly virulent virus, ISAV 752_09 (HPR7b), and an avirulent strain, SK779/06 (HPR0). We characterized the rescued viruses and their capacity to replicate and infect different cell lines, produce plaques in ASK cells, and their ability to induce and modulate the cellular immune response in vitro. Our results show that the majority of ISAV segments are involved in at least one of the analyzed characteristics, segment 5 being one of the most important, allowing HPR0 viruses, among other things, to produce plaques and replicate in CHSE-214 cells. We determined that segments 5 and 6 participate in different stages of the viral cycle, and their compatibility is critical for viral infection. Additionally, we demonstrated that segment 2 can modulate the cellular immune response. Our results indicate a high degree of genetic compatibility between the genomic segments of HPR7b and HPR0, representing a latent risk of reassortant that would give rise to a new virus with an unknown phenotype.
Subject(s)
Fish Diseases , Isavirus , Orthomyxoviridae Infections , Salmo salar , Animals , Isavirus/genetics , Orthomyxoviridae Infections/veterinary , Phylogeny , Salmo salar/genetics , Sequence Analysis, DNAABSTRACT
A prospective study of the dye properties of non-toxic lawsone thiophenyl derivatives, obtained using a green synthetic methodology allowed for the description of their bathochromic shifts in comparison to those of lawsone, a well-known natural pigment used as a colorant that recently also has aroused interest in dye-sensitized solar cells (DSSCs). These compounds exhibited colors close to red, with absorption bands in visible and UV wavelength range. The colorimetric study showed that these compounds exhibited a darker color than that of lawsone within a range of colors depending on the substituent in the phenyl ring. Computational calculations employing Density Functional Theory (DFT) and Time-Dependent Density Functional Theory (TD-DFT), showed that the derivatives have lower excitation energies than lawsone, while the alignment of their frontier orbitals regarding the conduction bands of TiO2 and ZnO and the redox potential of the electrolyte I-/I3- suggests that they could be employed as sensitizers. The study of the interactions of the lawsone and a derivative with a TiO2 surface model by different anchoring modes, showed that the adsorption is thermodynamically favored. Natural bond orbital (NBO) analysis indicates a two-center bonding (BD) O-Ti as the main interaction of the dyes with TiO2.
ABSTRACT
The ISAV has a genome composed of eight segments of (-)ssRNA, segment 6 codes for the hemagglutinin-esterase protein, and has the most variable region of the genome, the highly polymorphic region (HPR), which is unique among orthomyxoviruses. The HPR has been associated with virulence, infectivity and pathogenicity. The full length of the HPR is called HPR0 and the strain with this HPR is avirulent, in contrast to strains with deleted HPR that are virulent to varying degrees. The molecular mechanism that gives rise to the different HPRs remains unclear. Here, we studied in vitro the evolution of reassortant recombinant ISAV (rISAV) in Atlantic salmon head kidney (ASK) cells. To this end, we rescued and cultivated a set of rISAV with different segment 6-HPR genotypes using a reverse genetics system and then sequencing HPR regions of the viruses. Our results show rapid multiple recombination events in ISAV, with sequence insertions and deletions in the HPR, indicating a dynamic process. Inserted sequences can be found in four segments of the ISAV genome (segments 1, 5, 6, and 8). The results suggest intra-segmental heterologous recombination, probably by class I and class II template switching, similar to the proposed segment 5 recombination mechanism.
Subject(s)
Isavirus/genetics , Isavirus/pathogenicity , Recombination, Genetic , Animals , Cell Line , Fish Diseases/virology , Genotype , Hemagglutinins, Viral/genetics , Orthomyxoviridae Infections/virology , Salmo salar , Sequence Analysis, DNA , Viral Fusion Proteins/genetics , Virulence/geneticsABSTRACT
We designed and synthesized in water, using conventional heating and microwave irradiation, new thio-derivatives of 2-hydroxy-1,4-naphthoquinone, a naturally occurring pigment known as lawsone or hennotannic acid, thus improving their antiplatelet activity with relevance to their potential future use in thrombus formation treatment. The structure-activity relationship showed that the thiophenyl moiety enhances the antiplatelet activity. Moreover, the position and nature of the substituent at the phenyl ring have a key effect on the observed biological activity. Compound 4 (2-((4-bromophenyl)thio)-3-hydroxynaphthalene-1,4-dione) was the most active derivative, presenting IC50 values for platelet aggregation inhibition of 15.03 ± 1.52 µM for TRAP-6, and 5.58 ± 1.01 µM for collagen. Importantly, no cytotoxicity was observed. Finally, we discussed the structure-activity relationships of these new lawsone thio-derivatives on inhibition of TRAP-6- and collagen-induced platelet aggregation.
ABSTRACT
Intramolecular hydrogen bond (IMHB) interactions have attracted considerable attention due to their central role in molecular structure, chemical reactivity, and interactions of biologically active molecules. Precise correlations of the strength of IMHB's with experimental parameters are a key goal in order to model compounds for drug discovery. In this work, we carry out an experimental (NMR) and theoretical (DFT) study of the IMHB in a series of structurally similar o-carbonyl hydroquinones. Geometrical parameters, as well as Natural Bond Orbital (NBO) and Quantum Theory of Atoms in Molecules (QTAIM) parameters for IMHB were compared with experimental NMR data. Three DFT functionals were employed to calculated theoretical parameters: B3LYP, M06-2X, and ωB97XD. O H distance is the most suitable geometrical parameter to distinguish among similar IMHBs. Second order stabilization energies ΔEij(2) from NBO analysis and hydrogen bond energy (EHB) obtained from QTAIM analysis also properly distinguishes the order in strength of the studied IMHB. ΔEij(2) from NBO give values for the IMHB below 30 kcal/mol, while EHB from QTAIM analysis give values above 30 kcal/mol. In all cases, the calculated parameters using ωB97XD give the best correlations with experimental ¹H-NMR chemical shifts for the IMHB, with R² values around 0.89. Although the results show that these parameters correctly reflect the strength of the IMHB, when the weakest one is removed from the analysis, arguing experimental considerations, correlations improve significantly to values around 0.95 for R².