In symptomatic patients on as-needed inhaled corticosteroids-formoterol, VAS asthma is associated with small airways resistance.

OBJECTIVES: Impulse oscillometry (IOS) can demonstrate small airways disease even when spirometry values are normal. However, it is unknown if the absence of symptoms excludes increased small airways resistance in asthma patients. We aimed to correlate symptoms (assessed through visual analogue scales) with measures of small airways resistance in patients with asthma and to determine whether less symptomatic patients have increased small airways resistance. METHODS: We conducted a single center, prospective cohort study. We included controlled asthma patients on as-needed inhaled corticosteroids-formoterol. Patients were evaluated on their symptom VASs, Spirometry and IOS (with R5-R20% measuring small airways resistance) which were measured both in periods when they were less symptomatic and symptomatic. Symptoms were assessed using MASK-air®, an mHealth app that includes a daily monitoring questionnaire with validated VASs. We correlated MASK-air VASs with small airways resistance. RESULTS: We assessed 29 patients. There was a significant correlation between VAS asthma and R5-R20% in symptomatic periods (r = 0.43; 95% CI = 0.13;0.68, p = 0.019), but not in less symptomatic periods (0.04; 95% CI-0.40;0.46; p = 0.825). In less symptomatic periods, patients presenting with low VAS asthma (VAS < 30) displayed a lower median R5-R20% than the remainder (0.26 versus 0.35), as well as a lower R5% (0.13 versus 0.15) (p < 0.001). In 68.9% of less symptomatic patients, R5-R20 values remained higher than normal values. CONCLUSION: In symptomatic patients on as-needed inhaled corticosteroids-formoterol, VAS asthma was associated with small airways resistance. However, even if these patients are less symptomatic, small airways resistance may be higher than normal. Since SAD significantly affects asthma control, patients should be carefully followed-up, even in less symptomatic periods.

Preparation of Mixed Bis-N-Heterocyclic Carbene Rhodium(I) Complexes.

A series of mixed bis-NHC rhodium(I) complexes of type RhCl(η2-olefin)(NHC)(NHC') have been synthesized by a stepwise reaction of [Rh(µ-Cl)(η2-olefin)2]2 with two different NHCs (NHC = N-heterocyclic carbene), in which the steric hindrance of both NHC ligands and the η2-olefin is critical. Similarly, new mixed coumarin-functionalized bis-NHC rhodium complexes have been prepared by a reaction of mono NHC complexes of type RhCl(NHC-coumarin)(η2,η2-cod) with the corresponding azolium salt in the presence of an external base. Both synthetic procedures proceed selectively and allow the preparation of mixed bis-NHC rhodium complexes in good yields.

Therapeutic potential of coumarin bearing metal complexes: Where are we headed?

The successfully application of some metallodrugs such as salvarsan, silver sulfadiazine and cisplatin in modern medicine launched the biological investigation of organometallic and metal-organic complexes. The availability and tunability of various ligands including N-heterocycles, phosphines, N-heterocyclic carbenes present an extended research area to chemists. In recent years, the preparation of the metal complexes of bioactive organic compounds is a new strategy. Coumarin derivatives are one of the classes of compounds used for this purpose, and many complexes of coumarin derivatives were prepared for enhanced biological activity, especially anticancer and antimicrobial. In this paper, we discuss the current situation of this topic.

Water Soluble Coumarin Quaternary Ammonium Chlorides: Synthesis and Biological Evaluation.

In the present study, coumarin-bearing three pyridinium and three tetra-alkyl ammonium salts were synthesized. The compounds were fully characterized by 1 H- and 13 C-NMR, LC/MS and IR spectroscopic methods and elemental analyses. The cytotoxic properties of all compounds were tested against human liver cancer (HepG2), human colorectal cancer (Caco-2) and non-cancer mouse fibroblast (L-929) cell lines. Some compounds performed comparable cytotoxicity with standard drug cisplatin. Antibacterial properties of the compounds were tested against Gram-negative Escherichia coli and Gram-positive Bacillus subtilis bacteria, but the compounds did not have any antibacterial effect against both bacteria. Enzyme inhibitory properties of all compounds were tested on the activities of human carbonic anhydrase I and II, and xanthine oxidase. All compounds inhibited both enzymes more effectively than standard drugs, acetazolamide and allopurinol, respectively. The biological evaluation results showed that ionic and water soluble coumarin derivatives are promising structures for further investigations especially on enzyme inhibition field.

Catechol-bearing imidazolium and benzimidazolium chlorides as promising antimicrobial agents.

Catechol-containing imidazolium (four) and benzimidazolium chlorides (eight) were synthesized to evaluate their antimicrobial properties. All the compounds were fully characterized using 1 H and 13 C nuclear magnetic resonance, liquid chromatography-mass spectrometry, infrared spectroscopic methods, and elemental analyses. Antimicrobial activities of the compounds were tested against the bacteria Escherichia coli, Pseudomonas aeruginosa, Acinetobacter baumannii, Klebsiella pneumoniae, Staphylococcus aureus, methicillin-resistant S. aureus (MRSA), Enterococcus faecalis, and the fungal strains Candida albicans and Candida glabrata, and promising results were achieved. The two most important benzyl-substituted benzimidazolium chlorides, 3l and 3k, showed comparable activity to vancomycin against MRSA.

Microwave-assisted synthesis of 1-substituted-1H-benzimidazolium salts: Non-competitive inhibition of human carbonic anhydrase I and II.

A series of 1-substituted-1H-benzimidazolium p-toluenesulfonate salts were synthesized in good yields by the reaction of 1-substituted benzimidazole derivatives and p-toluenesulfonic acid under microwave irradiation. Two iodide salts were synthesized by the anion exchange reaction of the corresponding p-toluenesulfonate salt and NaI. All compounds were characterized by 1 H NMR, 13 C NMR, IR, LC-MS spectroscopic methods, and elemental analyses. The crystal structure of 1-methoxyethyl-1H-benzimidazolium p-toluenesulfonate 2d showed that cation and anion are interconnected by N-H···O and C-H···O hydrogen bonds. All compounds were examined as inhibitor of human carbonic anhydrase (hCA) I and II, and all of them inhibited hCA I and hCA II. Kinetic investigation results revealed that these compounds inhibit hCA I and hCA II in a non-competitive manner. The iodide salts had higher inhibitory activity than their corresponding p-toluenesulfonate salts.

Synthesis, characterization and antimicrobial activities of novel silver(I) complexes with coumarin substituted N-heterocyclic carbene ligands.

Eight new coumarin substituted silver(I) N-heterocyclic carbene (NHC) complexes were synthesized by the interaction of the corresponding imidazolium or benzimidazolium chlorides and Ag2O in dichloromethane at room temperature. Structures of these complexes were established on the basis of elemental analysis, (1)H NMR, (13)C NMR, IR and mass spectroscopic techniques. The antimicrobial activities of carbene precursors and silver NHC complexes were tested against standard strains: Enterococcus faecalis, Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa and the fungi Candida albicans and Candida tropicalis. Results showed that all the compounds inhibited the growth of the all bacteria and fungi strains and some complexes performed good activities against different microorganisms. Among all the compounds, the most lipophilic complex bis[1-(4-methylene-6,8-dimethyl-2H-chromen-2-one)-3-(naphthalene-2-ylmethyl)benzimidazol-2-ylidene]silver(I) dichloro argentate (5e) was found out as the most active one.

Functionalized imidazolium and benzimidazolium salts as paraoxonase 1 inhibitors: Synthesis, characterization and molecular docking studies.

Paraoxonase (PON) is a key enzyme in metabolism of living organisms and decreased activity of PON1 was acknowledged as a risk for atherosclerosis and organophosphate toxicity. The present study describes the synthesis, characterization, PON1 inhibitory properties and molecular docking studies of functionalized imidazolium and benzimidazolium salts (1a-5g). The structures of all compounds were elucidated by IR, NMR, elemental analysis and structures of compounds 2b and 2c were characterized by single-crystal X-ray diffraction. Compound 1c, a coumarin substituted imidazolium salt showed the best inhibitory effect on the activity of PON1 with good IC50 value (6.37 µM). Kinetic investigation was evaluated for this compound and results showed that this compound is competitive inhibitor of PON1 with Ki value of 2.39 µM. Molecular docking studies were also performed for most active compound 1c and one of least active compound 2c in order to determine the probable binding model into active site of PON1 and validation of the experimental results.

In vitro inhibition effect of some coumarin compounds on purified human serum paraoxonase 1 (PON1).

Human serum paraoxonase 1 (PON1; EC 3.1.8.1) is a high-density lipoprotein associated, calcium-dependent enzyme that hydrolyses aromatic esters, organophosphates and lactones and can protect the low-density lipoprotein against oxidation. In this study, in vitro effect of some hydroxy and dihydroxy ionic coumarin derivatives (1-20) on purified PON1 activity was investigated. Among these compounds, derivatives 11-20 are water soluble. In investigated compounds, compounds 6 and 13 were found the most active (IC50 = 35 and 34 µM) for PON1, respectively. The present study has demonstrated that PON1 activity is very highly sensitive to studied coumarin derivatives.

Some coumarins and benzoxazinones as potent paraoxonase 1 inhibitors.

In this study, we aimed to investigate the effect of some coumarin and benzoxazinone derivatives on the activity of human PON1. Human serum paraoxonase 1 was purified from fresh human serum blood by two-step procedures that are ammonium sulfate precipitation (60-80%) and then hydrophobic interaction chromatography (Sepharose 4B, L-tyrosine and 1-napthylamine). The enzyme was purified 232-fold with a final specific activity of 27.1 U/mg. In vitro effects of some previously synthesized ionic coumarin or benzoxazinone derivatives (1-21) on purified PON1 activity were investigated. Compound 14 (1-(2,3,4,5,6)-pentamethylbenzyl-3-(6,8-dimethyl-2H-chromen-2-one-4-yl))benzimidazolium chloride was found out as the strongest inhibitor (IC50 = 7.84 µM) for PON1 among the compounds. Kinetic investigation and molecular docking study were evaluated for one of the most active compounds (compound 12) and obtained data showed that this compound is competitive inhibitor of PON1 and interact with Leu262 and Ser263 in the active site of PON1. Moreover, coumarin derivatives were found out as the more potent inhibitors for PON1 than benzoxazinone derivatives.

Coumarin or benzoxazinone based novel carbonic anhydrase inhibitors: synthesis, molecular docking and anticonvulsant studies.

Among many others, coumarin derivatives are known to show human carbonic anhydrase (hCA) inhibitory activity. Since hCA inhibition is one of the underlying mechanisms that account for the activities of some antiepileptic drugs (AEDs), hCA inhibitors are expected to have anti-seizure properties. There are also several studies reporting compounds with an imidazole and/or benzimidazole moiety which exert these pharmacological properties. In this study, we prepared fifteen novel coumarin-bearing imidazolium and benzimidazolium chloride, nine novel benzoxazinone-bearing imidazolium and benzimidazolium chloride derivatives and evaluated their hCA inhibitory activities and along with fourteen previously synthesized derivatives we scanned their anticonvulsant effects. As all compounds inhibited purified hCA isoforms I and II, some of them also proved protective against Maximal electroshock seizure (MES) and ScMet induced seizures in mice. Molecular docking studies with selected coumarin derivatives have revealed that these compounds bind to the active pocket of the enzyme in a similar fashion to that previously described for coumarin derivatives.

Synthesis, characterization, and tyrosinase inhibitory properties of benzimidazole derivatives.

1-Alkylbenzimidazole and 1,3-dialkyl benzimidazolium salts were synthesized and characterized by the data of IR, 1H NMR, 13C NMR spectra and elemental analyses. These compounds were investigated as tyrosinase inhibitors. Tyrosinase has been purified from banana by affinity chromatography on a Sepharose 4B gel conjugated with L-tyrosine-p-aminobenzoic acid. All the synthesized compounds inhibited the tyrosinase activity. Among the compounds studied, 1,4-di(1H-benzo[d]imidazol-1-yl)butane was found to be the most active tyrosinase inhibitor (IC50 0.31 mM).

Synthesis and carbonic anhydrase inhibitory properties of novel coumarin derivatives.

A newly series of water-soluble 1-alkyl-3-(4-methyl-7, 8-dihydroxy-2H-chromen-2-one) benzimidazolium chloride salts (3a-j) were synthesized and their inhibitory effects on the activity of purified human carbonic anhydrase (hCA) I and II were evaluated. hCA I and II from human erythrocytes were purified by a simple one step procedure by using Sepharose 4B-L-tyrosine-sulphanilamide affinity column. The result showed that all the synthesized compounds were inhibited the CA isoenzymes activity. Among them, 3g and 3j were found to be most active (IC(50) = 22.09 µM and 20.33 µM) for hCA I and hCA II, respectively.

Efficiency enhancement with chloride to iodide ion exchange of benzimidazolium salt as a redox mediator.

The new benzimidazolium derivative (SM-1) salt with ion exchange from the (SM-0) was fabricated and characterized by proton-nuclear magnetic resonance (1H-NMR), carbon-nuclear magnetic resonance (13C-NMR), Fourier-transform infrared spectroscopy (FT-IR), electrospray ionization (EIS-MS), thermal analysis (TG), cyclic voltammetry (CV), and ultraviolet-visible spectroscopy (UV-vis), for electrolytes (liquid or dried) in the DSSC charge transportation mechanism. Also, the influence of ion exchange from chloride to iodine in the synthesized electrolytes, compared to other electrolytes (conventional or commercial), was investigated about DSSC performance efficiency. When using as a liquid electrolyte (SM-1), the power conversion efficiency (ƞ) of the working DSSC device was recorded as 1.980% and it was observed that the performances of DSSCs increased up to 56% when comparing dried electrolyte for SM-1 without conventional redox material (I-/I3 -). In the future, different molecular modifications of this type of benzimidazole derivatives or mixtures with conventional redox couples may further improve the performance of DSSC devices.

Water-soluble silver(i) complexes with N-donor benzimidazole ligands containing an imidazolium core: stability and preliminary biological studies.

Herein, we report the synthesis, characterisation and preliminary biological evaluation of two novel silver(i) complexes of type [AgL2](NO3)3 (3 and 4) with ionic N-donor benzimidazoles. The complexes have been synthesized by the reaction of 1.5 equivalents of silver nitrate and N-donor benzimidazoles containing an imidazolium core at the 2-position (1 and 2) in ethanol. The X-ray analysis of 4 shows that it has two free imidazolium cores and the charge is balanced with three nitrate anions. A study by the combination of NMR, IR, LC-MS and elemental analysis techniques also suggests that the complexes have this structure both in the solid-state and solution. The complexes are highly soluble and stable in water. Cytotoxicity evaluation against four cancerous human cells and one non-cancerous human cell revealed that the complexes have no significant anti-growth effect. However, the complexes showed a remarkable antimicrobial effect at normalized minimum inhibitory concentrations (normalized MICs) in the range of 33-268 µM against a panel of microorganisms consisting of Gram-negative and Gram-positive bacteria, and fungi.

Iridium(i) complexes bearing hemilabile coumarin-functionalised N-heterocyclic carbene ligands with application as alkyne hydrosilylation catalysts.

A set of iridium(i) complexes of formula IrCl(κC,η2-IRCouR')(cod) or IrCl(κC, η2-BzIRCouR')(cod) (cod = 1,5-cyclooctadiene; Cou = coumarin; I = imidazolin-2-carbene; BzI = benzimidazolin-2-carbene) have beeen prepared from the corresponding azolium salt and [Ir(µ-OMe)(cod)]2 in THF at room temperature. The crystalline structures of 4b and 5b show a distorted trigonal bipyramidal configuration in the solid state with a coordinated coumarin moiety. In contrast, an equilibrium between this pentacoordinated structure and the related square planar isomer is observed in solution as a consequence of the hemilability of the pyrone ring. Characterization of both species by NMR was achieved at the low and high temperature limits, respectively. In addition, the thermodynamic parameters of the equilibrium, ΔHR and ΔSR, were obtained by VT 1H NMR spectroscopy and fall in the range 22-33 kJ mol-1 and 72-113 J mol-1 K-1, respectively. Carbonylation of IrCl(κC,η2-BzITolCou7,8-Me2)(cod) resulted in the formation of a bis-CO derivative showing no hemilabile behaviour. The newly synthesised complexes efficiently catalyze the hydrosilylation of alkynes at room temperature with a preference for the ß-(Z) vinylsilane isomer.

New coumarin derivatives as carbonic anhydrase inhibitors.

In the current study, a series of 4-chloromethyl-7-hydroxy-coumarin derivatives containing imidazolium, benzimidazolium, bisbenzimidazolium and quaternary ammonium salts were synthesized, characterized and the inhibition effects of the derivatives on human carbonic anhydrases (hCA I and hCA II) were investigated as in vitro. Structures of these coumarins were confirmed by FT-IR, (1)H NMR, (13)C NMR and LC-MS analyses. Structure activity relationship study showed that 3d (IC50: 79 µM for hCA I and 88 µM for hCA II) performed higher inhibitory activity than others.