Antifungal Activity and Stability of Fluconazole Emulsion Containing Ionic Liquids Explained by Intermolecular Interactions.

This research reports accelerated stability experiments, the evaluation of intermolecular interactions, and antifungal assays for fluconazole emulsions prepared using ultrasound (US) and magnetic stirring (MS) in the presence of ionic liquids derived from 1,n-(3-methylimidazolium-1-yl)alkane bromide ([CnMIM]Br; n = 12 or 16). The goals of the investigation are to quantify the stability, identify the forces that drive the formation and stability, and determine the antifungal activity of fluconazole-containing emulsions, and corroborate the data from our previous results that indicated that the emulsion based on [C16MIM]Br seemed to be more stable. In this study, accelerated stability experiments evidenced a considerable stability for the [C16MIM]Br emulsions at two temperatures (25 and 37 °C)­the instability index increased in the following order: US40% < US20% < MS. The 1H NMR data showed that the ILs interacts differently with medium-chain triglycerides (MCT). Two distinct interaction mechanisms were also observed for [C12MIM]Br and [C16MIM]Br with fluconazole, in which the latter formed more compact mixed aggregates than the former. The result was corroborated by diffusion data, which showed that ILs suffered a decrease in diffusion in the presence of fluconazole. The antifungal assay showed that emulsions containing ILs displayed superior activity compared with fluconazole alone. The emulsions also showed potent activity in inhibiting a resistant species (C. glabrata­CG34) to FLZ. All emulsions showed weak irritant potential in HET-CAM assay.

Investigating ESIPT and donor-acceptor substituent effects on the photophysical and electrochemical properties of fluorescent 3,5-diaryl-substituted 1-phenyl-2-pyrazolines.

This paper describes the synthesis, structural study, and evaluation of electrochemical and photophysical properties by UV-Vis absorption and fluorescence emission analysis (solution and solid-state) of a series of eight 3,5-aryl-substituted 1-phenyl-2-pyrazolines (5), where 3-aryl = 2-OH-C6H4 (5a-g) or Ph (5h), and 5-aryl = Ph (a, h), 1-naphthyl (b), 4-Br-C6H4 (c), 4-F-C6H4 (d), 4-OCH3-C6H4(e), 4-NO2-C6H4 (f), 4-(N(CH3)2)-C6H4(g). The UV-Vis absorption properties of 2-pyrazolines were evaluated in DCM, MeCN, AcOEt, EtOH, and DMSO as the solvent and showed a fluorescence shift for the polar aprotic solvents. The steady-state fluorescence emission exhibited a band in the blue region when excited at the least energetic transition of each compound, although the excited-state intramolecular proton (ESIPT) effect was not detected. In the solid state, compounds presented similar behavior regarding absorption and emission properties compared to the solution assays. With the electrochemical analyses performed for the synthesized 2-pyrazolines, it was possible to conclude that the redox potentials were influenced by the electronic and steric effects of the substituents on the aryl rings and, according to the electronic nature of the substituents, which electron-donating groups were favored. Finally, the TD-DFT analyses revealed that all compounds had delocalized electron density throughout the 2-pyrazolines unit and were not influenced by the substituent bonded at C-5. Nonetheless, LUMO orbital analysis showed that only derivatives 5b and 5f have this localized density over the substituents.

Photophysical, photostability, and ROS generation properties of new trifluoromethylated quinoline-phenol Schiff bases.

A new series of ten examples of Schiff bases, namely (E)-2-(((2-alkyl(aryl/heteroaryl)-4-(trifluoromethyl)quinolin-6-yl)imino)methyl)phenols 3, was easily synthesized with yields of up to 91% from the reactions involving a series of 2-(R-substituted) 6-amino-4-(trifluoromethyl)quinolines 1 and 4(5)-R1-substituted salicylaldehydes 2 - in which alkyl/aryl/heteroaryl for 2-R-substituents are Me, Ph, 4-MeC6H4, 4-FC6H4, 4-NO2C6H4, and 2-furyl, and R1-substituents are 5-NEt2, 5-OCH3, 4-Br, and 4-NO2. Complementarily, the Schiff bases showed low to good quantum fluorescence yield values in CHCl3 (Φf = 0.12-0.80), DMSO (Φf = 0.20-0.75) and MeOH (Φf = 0.13-0.85). Higher values of Stokes shifts (SS) were observed in more polar solvents (DMSO; 65-150 nm and MeOH; 65-130 nm) than in CHCl3 (59-85 nm). Compounds 3 presented good stability under white-LED irradiation conditions and moderate ROS generation properties were observed.

Antimicrobial and Toxicity Evaluation of Imidazolium-Based Dicationic Ionic Liquids with Dicarboxylate Anions.

Imidazolium-based dicationic ILs (DILs) presenting antimicrobial activity and relatively low toxicity are highly desirable and are envisioned for use in live tissue to prevent bacterial or fungal infections. In this context, we present here DILs with dicarboxylate anions [Cn(MIM)2[Cn(MIM)2][CO2-(CH2)mCO2], in which n = 4, 6, 8, and 10, and m = 0, 1, 2, 3, 4, and 5. The results showed that DILs with an alkyl chain spacer of ten carbons were active against yeasts and the bacterial strains tested. However, most of the DILs were cytotoxic and toxic at 1 mM. By contrast, DILs with alkyl chains possessing less than ten carbons were active against some specific Candidas and bacteria (mainly S. aureus), and they showed moderate cytotoxicity. The best activity against Gram-positive bacteria was observed for [C4(MIM)2][Pim] toward MRSA. For the DILs described herein, their level of toxicity against C. elegans was lower than that of most of the mono- and dicationic IL analogs with other anions. Our results showed that the presence of carboxylate anions reduces the toxicity of DILs compared to DILs containing halide anions, which is particularly significant to the means of designing biologically active compounds in antimicrobial formulations.

Synergic effects of ultrasound and ionic liquids on fluconazole emulsion.

The aim of this work was to evaluate the influence of US on the properties of the fluconazole emulsions prepared using imidazolium-based ILs ([Cn C1im]Br). The effects of the preparation method (mechanical stirring or US), US amplitude, alkyl chain length (of [C12C1im]Br or [C16C1im]Br), and IL concentration on the physicochemical properties were evaluated. Properties such as droplet size, span index, morphology, viscosity encapsulation efficiency, and drug release profile were determined. The results showed that US-prepared emulsions had a smaller droplet size and smaller polydispersity (Span) than those prepared by mechanical stirring. Additionally, the results showed that emulsions prepared with [C16C1im]Br and US had spherical shapes and increased stability compared to emulsions prepared by MS, and also depended on the IL concentration. The emulsion prepared by US at 40% amplitude had increased encapsulation efficiency. US provided a decrease in the viscosity of emulsions containing [C12C1im]Br; however, in general, all emulsions had viscosity close to that of water. Emulsions containing [C16C1im]Br had the lowest viscosities of all the emulsions. The emulsions containing the IL [C16C1im]Br had more controlled release and a lower cumulative percentage of drug release. The IL concentration required to prepare these emulsions was lower than the amount of conventional surfactant required, which highlights the potential synergic effects of ILs and US in preparing emulsions of hydrophobic drugs.

Biological assays of BF2-naphthyridine compounds: Tyrosinase and acetylcholinesterase activity, CT-DNA and HSA binding property evaluations.

The present work reports the biological assays between synthetic BF2-naphtyridine complexes and four proteins: human serum albumin (HSA), calf-thymus DNA (CT-DNA), tyrosinase and acetylcholinesterase enzymes via spectroscopic analysis at physiological conditions, combined with molecular docking simulations. The BF2-complexes presented spontaneous and moderate binding ability to HSA through the ground-state association (static fluorescence quenching mechanism). The main binding site is Sudlow's site I (subdomain IIA) and the binding does not perturb significantly both secondary and surface structure of HSA. Despite BF2-complexes showed good binding ability with HSA, these compounds presented weak intercalative ability with CT-DNA (the most conventional and simple model to preliminary studies), except in the case of 1 h, which suggested that the presence of electronic donor groups in both aromatic ring moieties of BF2-complex structure can increase the intercalative ability for DNA strands. Competitive binding displacement assays in the presence of methyl green and molecular docking calculations indicated that the studied compounds interact preferentially in the major groove of DNA. In addition, the assayed compounds presented the ability to activate or inhibit both tyrosinase (the decontrolled activity can induce melanoma carcinoma) or AChE (involved in reactions related to the function of neurotransmitters) enzymes.

Physicochemical characterization, released profile, and antinociceptive activity of diphenhydraminium ibuprofenate supported on mesoporous silica.

The thermal, physical, and morphological properties of diphenhydraminium ibuprofenate ([DIP][IBU]) adsorbed onto mesoporous silica (SiO2-60 Šand SiO2-90 Å) from solution were determined. The thermal, physical, and morphological properties of [DIP][IBU] supported on silica were determined. The adsorption of [DIP][IBU] on the pores and surface of silica was proven by N2 adsorption/desorption isotherms. Additionally, release profiles were determined for all systems, and the antinociceptive activity of neat [DIP][IBU] and [DIP][IBU] supported on silica were determined. The interaction of [DIP][IBU] and silica was dependent on pore size, with the formation of a [DIP][IBU] monolayer on SiO2-60 and a multilayer on SiO2-90. The release profile was sustained and slow and dependent on the pore size of the silica, in which the smaller the pore size, the faster the release. The nociceptive evaluation showed that [DIP][IBU] presents a greater (99.21 ±â€¯0.85%) antinociceptive effect than the ibuprofen (46 ±â€¯4.3%). Additionally, [DIP][IBU] on SiO2-60 (90 ±â€¯5.8%) had a greater antinociceptive effect than on SiO2-90 (73 ±â€¯13.2%), which indicates that in vivo tests are in accordance with the in vitro experiments.

Synthesis of N-Pyrrolyl(furanyl)-Substituted Piperazines, 1,4-Dizepanes, and 1,4-Diazocanes.

The synthetic potential of 5-bromo-1,1,1-trifluoro-4-methoxypent-3-en-2-one toward the catalyst-free synthesis of N-pyrrolyl(furanyl)-piperazines, 1,4-diazepanes, and 1,4-diazocanes through a telescoped protocol is reported. This three-component one-pot method provided 23 examples with high chemo- and regioselectivity at yields up to 96%.

Chemo- and regioselective reactions of 5-bromo enones/enaminones with pyrazoles.

Reaction of 5-bromo enones with pyrazoles provided a series of unexpected N,O-aminal derivatives, through a 1,4-conjugated addition at the ß-carbon of the 5-bromo enones instead of the expected nucleophilic substitution of the bromine. This reaction also furnished the 1,3-regioisomer of the pyrazole. A similar reaction of pyrazoles using 5-bromo enaminones furnished only N-alkylated pyrazoles-with high regioselectivity and at good yields-through nucleophilic substitution of the bromine.

Effect of slight structural changes on the gelation properties of N-phenylstearamide supramolecular gels.

Supramolecular gels present several applications in which the gelator properties are closely dependent on their structure and solvent. Despite this, there are few studies on the effect of the gelation ability of gelators with slight molecular changes. Therefore, N-arylestearamides (in which aryl = phenyl (1), 4-tolyl (2) and 4-acetylphenyl (3)) were evaluated in different solvents. The critical gelefication concentration (CGC) values indicated that the substituents can significantly affect the concentration at which the supramolecular gels are formed, mainly in non-aromatic solvents (e.g. cyclohexane, acetonitrile and DMSO). From UV-Vis and DSC data, we verified that the gel-sol and sol-gel transitions (Tgel-sol and Tsol-gel) increase in the order of 1 < 2 < 3. Organogel strength was evaluated for 1-3 as a function of concentration and solvent type using rheology data. Gel strength is concentration-dependent and a strength order was found in acetonitrile, cyclohexane and DMSO, in which: 1 ∼ 2 > 3. Dynamic viscoelastic measurements as a function of temperature sweeps indicate a predominantly enthalpic contribution to the elasticity of the organogels formed from 1-3. Temperature-dependent 1H NMR indicates that NHO interactions may be responsible for the molecular association of molecules into 1D fibers, while 3D fibers were formed from van der Waals interactions.

Impact of Anions on the Partition Constant, Self-Diffusion, Thermal Stability, and Toxicity of Dicationic Ionic Liquids.

Partition constants (KD°), molecular dynamics (T1, T2, and DOSY measurements), thermal stability, and toxicity of dicationic ionic liquids (ILs) were determined. The dicationic ILs derived from 1,n-bis(3-methylimidazolim-1-yl)octane, [BisOct(MIM)2][2X] (in which X = Cl, Br, NO3, SCN, BF4, and NTf2), were evaluated to verify the influence of anion structure on the IL properties. A monocationic IL [Oct(MIM)][Br] was also monitored for comparison. In general, the solubility of the ILs followed the anion free energy of hydration (ΔG°hyd). The thermokinetic and thermodynamic functions of activation of the ILs were determined via thermogravimetric data, and it was observed that polyatomic anions influence the decomposition mechanism of these IL structures. Furthermore, [Oct(MIM)][Br] had a decomposition rate greater than that of the dicationic analogue, and the thermodynamic parameters of activation data corroborate these results. Finally, the dicationic ILs did not indicate toxic effects (LD50 > 40 mM).

Heteroassembly Ability of Dicationic Ionic Liquids and Neutral Active Pharmaceutical Ingredients.

Extensive investigation of interactions and aggregation properties of IL + API systems is necessary to apply ionic liquids (ILs) with different hydrophobic characteristics to drug delivery or in active pharmaceutical ingredient (API) formulations. Therefore, this study aims to investigate the heteroassembly between dicationic ILs ([BisOct(MIM)2][2X], in which X is Br or BF4, and [BisOct(BnIM)2][2Br]), both in the absence and the presence of neutral APIs (salicylic acid, ibuprofen, and paracetamol) with different functional groups. Isothermal titration calorimetry results demonstrate that IL-API associations occur at very low concentrations of IL. These results were reinforced by electrospray ionization mass spectrometry with variable collision-induced dissociation, in which the IL dication interactions with APIs were detected. The strength of the dication-API interaction was determined from E cm,1/2 data. The aggregation parameters (cac, ΔG agg °, and K) between ILs and APIs were evaluated by conductivity. The 1H NMR data showed that differences in chemical shifts provided relevant insights about interaction sites in both components.

Insights on the Similarity of Supramolecular Structures in Organic Crystals Using Quantitative Indexes.

The quest for concepts of isostructurality in organic crystals has been long and mostly based on geometric data, even with the development of modern software. This field of study is of great interest to the pharmaceutical industry and for the prediction of crystal structures. Despite this, there is still no methodology that provides broad quantitative and comparable similarity data between two complete crystalline structures. The present study demonstrated that the similarity between two crystalline structures could be estimated from the similarity between the two "supramolecular clusters". Quantitative indexes for similarity comparisons of crystal structures were shown using nine 5-aryl-1-(1,1-dimethylethyl)-1H-pyrazoles as a model. This proposal includes the quantitative data of a geometric parameter (I D), a contact area parameter (I C), and an energetic parameter (I G). The proposed indexes exhibited good perspective regarding the similarity data and distinct regions of similarity. The range of similarity was set at I X ≥ 0.80, 0.80 > I X > 0.60, and I X ≤ 0.60 (X = D, C, or G). Indexes with a value near 1.0 indicate systems with isostructural, isocontact, and isoenergetic behavior. The results indicated that supramolecular structures with high similarity must have high values for all three indexes (I D, I C, and I G).

Synthesis, Crystal Structure, and Supramolecular Understanding of 1,3,5-Tris(1-phenyl-1H-pyrazol-5-yl)benzenes.

Understanding the supramolecular environment of crystal structures is necessary to facilitate designing molecules with desirable properties. A series of 12 novel 1,3,5-tris(1-phenyl-1H-pyrazol-5-yl)benzenes was used to assess the existence of planar stacking columns in supramolecular structures of pyrazoles. This class of molecules with different substituents may assist in understanding how small structural changes affect the supramolecular environment. The obtained compounds did not present the formation of planar stacking interactions between benzenes in solid or liquid states. This supposition was indicated by single crystal diffraction, Density Functional Theory (DFT) and quantum theory of atoms in molecules (QTAIM) calculations, and concentration-dependent liquid-state ¹H nuclear magnetic resonance (NMR). NMR showed that chemical shifts of benzene and pyrazole hydrogens confirm that planar stacking interactions are not formed in solution. The crystalline structures presented different molecular conformations. The molecular structures of 5 and 9b are in a twisted conformation, while compound 7 showed a conformation analogous to a calyx form.

Synthesis, effect of substituents on the regiochemistry and equilibrium studies of tetrazolo[1,5-a]pyrimidine/2-azidopyrimidines.

An efficient synthesis methodology for a series of tetrazolo[1,5-a]pyrimidines substituted at the 5- and 7-positions from the cyclocondensation reaction [CCC + NCN] was developed. The NCN corresponds to 5-aminotetrazole and CCC to ß-enaminone. Two distinct products were observed in accordance with the ß-enaminone substituent. When observed in solution, the compounds can be divided into two groups: (a) precursor compounds with R = CF3 or CCl3, which leads to tetrazolo[1,5-a]pyrimidines in high regioselectivity with R at the 7-position of the heterocyclic ring; and (b) precursor compounds with R = aryl or methyl, which leads to a mixture of compounds, tetrazolo[1,5-a] pyrimidines (R in the 5-position of the ring) and 2-azidopyrimidines (R in the 4-position of the ring), which was attributed to an equilibrium of azide-tetrazole. In the solid state, all compounds were found as 2-azidopyrimidines. The regiochemistry of the reaction and the stability of the products are discussed on the basis of the data obtained by density functional theory (DFT) for energetic and molecular orbital (MO) calculations.

Regiochemistry of cyclocondensation reactions in the synthesis of polyazaheterocycles.

The syntheses of several polyazaheterocycles are demonstrated. The cyclocondensation reactions between ß-enaminodiketones [CCl3C(O)C(=CNMe2)C(O)-CO2Et] and aromatic amidines resulted in glyoxalate-substituted pyrido[1,2-a]pyrimidinone, thiazolo[3,2-a]pyrimidinone and pyrimido[1,2-a]benzimidazole. Pyrazinones and quinoxalinones were obtained through the reaction of these glyoxalates with ethylenediamine and 1,2-phenylenediamine derivatives. On the other hand, the reaction of glyoxalates with amidines did not lead to the formation of imidazolones, but rather N-acylated products were obtained. All the products were isolated in good yields. DFT-B3LYP calculations provided HOMO/LUMO coefficients, charge densities, and the stability energies of the intermediates, and from these data it was possible to explain the regiochemistry of the products obtained. Additionally, the data were a useful tool for elucidating the reaction mechanisms.

Synthesis of novel trifluoromethyl-substituted spiro-[chromeno[4,3-d]pyrimidine-5,1'-cycloalkanes], and evaluation of their analgesic effects in a mouse pain model.

Herein we report the synthesis of twelve 2,5-substituted 4-(trifluoromethyl)-spirochromeno[4,3-d]pyrimidines (7-10), as well as an evaluation of their analgesic effect in a mouse pain model. The nine new chromeno[4,3-d]pyrimidines (7-9) were synthesized from the cyclocondensation reactions of three 2,2,2-trifluoro-1-(4-methoxyspiro[chromene-2,1'-cycloalkane]-3-yl)ethanones (3) containing 5-, 6- and 7-membered spirocycloalkanes, with some well-known amidine salts (4-6) [NH2CR(NH)]-in which R=Me, Ph, and NH2-at yields of 60-95%. Subsequently, three new 2-(pyrrol-1-yl)-4-(trifluoromethyl)-chromeno[4,3-d]pyrimidines (10) were obtained through a Clauson-Kaas reaction between the respective 2-(amino)-4-(trifluoromethyl)-chromeno[4,3-d]pyrimidines (9) and 2,5-dimethoxy-tetrahydrofuran. The analgesic evaluation showed that these 4-(trifluoromethyl)chromeno[4,3-d]pyrimidines (100mg/kg, p.o.) and Ketoprofen (100mg/kg, p.o.) significantly reduced capsaicin-induced spontaneous nociception. Moreover, the 2-pyrrolyl-spirocyclohexane derivative 10b (100 and 300mg/kg, p.o.) had an anti-allodynic effect comparable to Ketoprofen (100 and 300mg/kg, p.o.) in the arthritic pain model, without causing locomotor alterations in the mice. These results suggest that the compound 10b is a promising molecule for new analgesic drugs in the treatment of pathological pain, such as in arthritis.

Synthesis and antinociceptive activity of new 2-substituted 4-(trifluoromethyl)-5,6-dihydrobenzo[h]quinazolines.

A useful synthetic route for an initial new series of 2-substituted 4-(trifluoromethyl)-5,6-dihydrobenzo[h]quinazolines (3), as well as an evaluation of their analgesic effect in a mice pain model, is reported. Five new quinazolines were formed from the cyclocondensation reactions of 2,2,2-trifluoro-1-(1-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)ethanone (1) with some well-known amidine salts [NH2CR(=NH)] (2), in which R=H, Me, Ph, NH2 and SMe, at a 40-70% yield. Subsequently, due to the importance of the pyrrole nucleus, a 2-(pyrrol-1-yl)quinazoline (4) was obtained through a Clauson-Kaas reaction from the respective 2-(amino)quinazoline, in a reaction with 2,5-dimethoxy-tetrahydrofuran. The analgesic evaluation demonstrated that four 5,6-dihydrobenzo[h]quinazolines (compounds of 3c (R=Ph), 3d (R=NH2), 3e (R=SMe), and 4 (R=pyrrol-1-yl); 100mg/kg, p.o.) and ketoprofen (100mg/kg, p.o.) significantly reduced the spontaneous nociception in a capsaicin-induced test. Moreover, in comparison with ketoprofen (100 and 300mg/kg, p.o.), compound 3c (30-300mg/kg, p.o.) showed an anti-hyperalgesic action in an arthritic pain model without locomotor alterations in the mice, suggesting that quinazoline 3c is a promising prototype scaffold for new analgesic drugs in the treatment of pathological pain such as that in arthritis.

Sonochemical heating profile for solvents and ionic liquid doped solvents, and their application in the N-alkylation of pyrazoles.

The heating profile for 25 solvents was determined in ultrasonic probe equipment at amplitudes of 20%, 25%, and 30%. Each solvent was heated in accordance with its boiling point. The effect of vapor pressure, surface tension, and viscosity of the solvents in dissipated ultrasonic power (Up) was evaluated. Multiple regression analysis of these solvent properties and dissipated Up reveals that solvent viscosity is the property that most strongly affected dissipated Up. Experimentation involving acetonitrile doped with [BMIM][BF4] indicated faster heating than MeCN. Aprotic polar solvents such as DMSO, DMF, and MeCN were tested in the N-alkylation of pyrazoles under ultrasonic conditions. After 5min at 90°C, the reactants had been totally converted into product in these solvents. Solvents, with low dissipated Up (e.g., toluene) were tested. Conversions were lower compared to those of aprotic polar solvents. When the reactions were done in hexane, no conversion to product was observed. To check the effect of doping in solvents with low Up, [BMIM][BF4], DMSO, and DMF were selected. The conversions for toluene doped with [BMIM][BF4], DMSO, and DMF were 100%, 59%, and 25%, respectively. These conversions were greater than when done in just toluene (46%). Thus, [BMIM][BF4] was the best polar doping solvent, followed by DMSO. DMF was not considered to be a satisfactory doping solvent. No conversion was observed for reactions in the absence of base performed in DMSO, DMF, and MeCN doped with [BMIM][BF4].

Regioselectively Controlled Synthesis of N-Substituted (Trifluoromethyl)pyrimidin-2(1H)-ones.

A simple and regioselectively controlled method for the preparation of both 1,4- and 1,6-regioisomers of 1-substituted 4(6)-trifluoromethyl-pyrimidin-2(1H)-ones is described. Both regioisomers were synthesized from the cyclocondensation reaction of 4-substituted 1,1,1-trifluoro-4-methoxybut-3-en-2-ones: with nonsymmetric ureas for the 1-substituted 4-(trifluoromethyl)pyrimidin-2(1H)-ones (1,4-isomer) and with nonsymmetric 1-substituted 2-methylisothiourea sulfates for the synthesis of 1-substituted 6-(trifluoromethyl)pyrimidin-2(1H)-ones (1,6-isomer). Each method furnished only the respective isomer in very good yields. The structure of the products was assigned based on the (1)H and (13)C NMR as well as 2D HMBC spectral analysis.