Inclusion complex of ketoconazole and p-sulfonic acid calix[6]arene improves antileishmanial activity and selectivity against Leishmania amazonensis and Leishmania infantum.

Many previous studies presented the effectiveness of ketoconazole (KTZ) against leishmaniasis. However, the bioavailability and therapeutic efficacy of free KTZ are limited due to its low aqueous solubility. In this study, an inclusion complex (IC6HKTZ) was prepared with p-sulfonic acid calix[6]arene (CX6SO3H) to improve the solubility and efficacy of KTZ against Leishmania amazonensis and Leishmania infantum promastigotes. A linear increase in KTZ solubility as a function of CX6SO3H concentration was verified using the phase-solubility diagram. The resulting diagram was classified as AL-type and a 1:1 host-guest stoichiometry was assumed to prepare IC6HKTZ by freeze-drying. FTIR, TG/DSC, XRD, and solid-state 13C NMR spectroscopy analyses were performed to confirm the formation of IC6HKTZ. The solubility enhancement of KTZ by 120.00 µM CX6SO3H was about 95 times. The IC50 values of IC6HKTZ and free KTZ were 3.95 and 14.35 µM for Leishmania amazonensis and 6.74 and 17.47 µM for Leishmania infantum, respectively. The viability of DH82 macrophages was not affected by CX6SO3H. These results show that CX6SO3H is a new supramolecular carrier system that improves antileishmanial activities to KTZ for the treatment of cutaneous and visceral leishmaniasis.

Structural Elucidation and Free Radical Scavenging Activity of a new o-Orsellinic Acid Derivative Isolated from the Lichen Cladonia rappii.

Rappiidic acid, a new o-orsellinic acid derivative, was isolated from the lichen Cladonia rappii. Its capability to scavenge reactive oxygen species (ROS) and reactive nitrogen species (RNS) was investigated and compared with resveratrol and (+)-usnic acid. Usnic acid at 100 µM was the most efficient ROS scavenger, exhibiting activity 3-fold higher than that of resveratrol. At the same concentration, rappidic acid scavenged 23.1% of ROS formed, demonstrating that this compound is twice as active as resveratrol. Both compounds were shown to be poor RNS scavengers.

Theoretical and experimental study of inclusion complexes formed by isoniazid and modified ß-cyclodextrins: 1H NMR structural determination and antibacterial activity evaluation.

Me-ß-cyclodextrin (Me-ßCD) and HP-ß-cyclodextrin (HP-ßCD) inclusion complexes with isoniazid (INH) were prepared with the aim of modulating the physicochemical and biopharmaceutical properties of the guest molecule, a well-known antibuberculosis drug. The architectures of the complexes were initially proposed according to NMR data Job plot and ROESY followed by density functional theory (DFT) calculations of (1)H NMR spectra using the PBE1PBE functional and 6-31G(d,p) basis set, including the water solvent effect with the polarizable continuum model (PCM), for various inclusion modes, providing support for the experimental proposal. An analysis of the (1)H NMR chemical shift values for the isoniazid (H6',8' and H5',9') and cyclodextrins (H3,5) C(1)H hydrogens, which are known to be very adequately described by the DFT methodology, revealed them to be extremely useful, promptly confirming the inclusion complex formation. An included mode which describes Me-ßCD partially enclosing the hydrazide group of the INH is predicted as the most favorable supramolecular structure that can be used to explain the physicochemical properties of the encapsulated drug. Antibacterial activity was also evaluated, and the results indicated the inclusion complexes are a potential strategy for tuberculosis treatment.

Benzocaine complexation with p-sulfonic acid calix[n]arene: experimental ((1) H-NMR) and theoretical approaches.

The aim of this work was to study the interaction between the local anesthetic benzocaine and p-sulfonic acid calix[n]arenes using NMR and theoretical calculations and to assess the effects of complexation on cytotoxicity of benzocaine. The architectures of the complexes were proposed according to (1) H NMR data (Job plot, binding constants, and ROESY) indicating details on the insertion of benzocaine in the cavity of the calix[n]arenes. The proposed inclusion compounds were optimized using the PM3 semiempirical method, and the electronic plus nuclear repulsion energy contributions were performed at the DFT level using the PBE exchange/correlation functional and the 6-311G(d) basis set. The remarkable agreement between experimental and theoretical approaches adds support to their use in the structural characterization of the inclusion complexes. In vitro cytotoxic tests showed that complexation intensifies the intrinsic toxicity of benzocaine, possibly by increasing the water solubility of the anesthetic and favoring its partitioning inside of biomembranes.

Experimental and theoretical NMR determination of isoniazid and sodium p-sulfonatocalix[n]arenes inclusion complexes.

In this work the inclusion complex formation of isoniazid with sodium p-sulfonatocalix[n]arenes is reported aiming to improve the physicochemical and biopharmaceutical properties of isoniazid a first line antibuberculosis drug. The architectures of the complexes were proposed according to NMR data Job plot indicating details on the insertion of the isoniazid in the calix[n]arenes cavities. DFT theoretical NMR calculations were also performed for sodium p-sulfonatocalix[4]arene complex with isoniazid, with various modes of complexation being considered, to provide support for the experimental proposal. A comparison between experimental and theoretical ¹H NMR chemical shifts profiles allowed for the inclusion complex characterization confirming the isoniazid inclusion mode which is preferentially through the hydrazide moiety. The remarkable agreement between experimental and theoretical NMR profiles adds support to their use in the structural characterization of inclusion compounds. Antibacterial activity was evaluated and the results indicated the inclusion complexes as a potential strategy for tuberculosis treatment.

Synthesis of lipophilic genistein derivatives and their regulation of IL-12 and TNF-α in activated J774A.1 cells.

Genistein modulates inflammatory responses in part by reducing the production of the pro-inflammatory cytokines IL-12, TNF-α, and nitric oxide, by activated macrophages in response to lipopolysaccharide stimulus. Previous studies have shown that synthetic lipophilic genistein glycosides were significantly more active than hydrophilic glycosides. The aims of this study were to synthesize and to evaluate the effect of novel lipophilic genistein derivatives on IL-12, TNF-α, and nitric oxide production by J774A.1 cells. The results show that the modification of genistein enables the generation of non-cytotoxic compounds with increased IL-12 inhibition. However, these derivatives failed to inhibit TNF-α. The nitric oxide production was notably inhibited by the monoester (2, 3) and monoether (6, 7) compounds in a dose-dependent manner.

Synthesis and phytotoxic activity of ozonides.

The [4 + 3] cycloaddition of the proper furans with the oxyallyl cation, generated in situ from 2,4-dibromopentan-3-one, produced a series of 8-oxabicyclo [3.2.1]oct-6-en-3-ones. Exposure of the oxabicycles to ozone afforded the corresponding 8,9,10,11-tetraoxatricyclo[5.2.1.1 (2,6)]undecan-4-ones in variable yields (7-100%). The phytotoxic properties of these ozonides (or 1,2,4-trioxolanes) and their oxabicycle precursors were evaluated as the ability to interfere with the growth of Sorghum bicolor and Cucumis sativus seedlings. Among oxabicycles, the highest inhibitory activity was shown by compounds possessing a alpha,beta-unsaturated carbonyl moiety. A differential sensitivity of the two crops was evident with ozonides. The most active compounds were also tested against the weed species Ipomoea grandifolia and Brachiaria decumbens. To the best of our knowledge, this is the first article describing ozonides as potential herbicides.

Development and pharmacological evaluation of ropivacaine-2-hydroxypropyl-beta-cyclodextrin inclusion complex.

Ropivacaine (RVC) is an enantiomerically pure local anesthetic (LA) largely used in surgical procedures, which presents physico-chemical and therapeutic properties similar to those of bupivacaine (BPV), but associated to less systemic toxicity. This study focuses on the development and pharmacological evaluation of a RVC in 2-hydroxypropyl-beta-cyclodextrin (HP-beta-CD) inclusion complex. Phase-solubility diagrams allowed the determination of the association constant between RVC and HP-beta-CD (9.46 M(-1)) and showed an increase on RVC solubility upon complexation. Release kinetics revealed a decrease on RVC release rate and reduced hemolytic effects after complexation (onset at 3.7 mM and 11.2mM for RVC and RVC HP-beta-CD, respectively) were observed. Differential scanning calorimetry (DSC), scanning electron microscopy (SEM) and X-ray analysis (X-ray) showed the formation and the morphology of the complex. Nuclear magnetic resonance (NMR) and job-plot experiments afforded data regarding inclusion complex stoichiometry (1:1) and topology. Sciatic nerve blockade studies showed that RVC HP-beta-CD was able to reduce the latency without increasing the duration of motor blockade, but prolonging the duration and intensity of the sensory blockade (p<0.001) induced by the LA in mice. These results identify the RVC HP-beta-CD complex as an effective novel approach to enhance the pharmacological effects of RVC, presenting it as a promising new anesthetic formulation.

Comparison of GC and HPLC for the quantification of organic acids in coffee.

A GC and an HPLC method for the quantification of organic acids OAs in coffee have been compared. The GC procedure, employing trimethylsilyl derivatives, was found to be very tedious. The HPLC method, which employed an ion exchange column using a flow gradient of water containing 1% phosphoric acid and UV detection (210 nm), was found to be much simpler for the quantification of eight organic acids (oxalic, succinic, fumaric, malic, tartaric, citric, quinic and fumaric acids) in four representative coffee samples. The HPLC procedure was more convenient than that described in the literature since no pre-purification was required for quantification of the OAs.