LC-MS/MS method for the determination of a semi-synthetic phenolic antioxidant 2,6-diisobornyl-4-methylphenol in rats after different administration routes.

IBP (2,6-diisobornyl-4-methylphenol) is a small drug molecule with antioxidant properties considered to be a promising neuro-, cardio-, and retinoprotective agent. In this study, a bioanalytical LC-MS/MS method for its determination in rat plasma was developed using 11H-indeno[1,2-b]quinoxalin-11-one oxime as an internal standard (IS). The analytes were extracted from plasma by liquid-liquid extraction technique using isopropyl alcohol:chloroform mixture (1:5, v/v) followed by evaporation and reconstitution of the residues in acetonitrile. The chromatographic separation was carried out on the EC Nucleodur C8 ec column (150 × 4.6 mm, 5 µm) under an isocratic elution mode using acetonitrile and water containing 0.1% (v/v) formic acid (97:3, v/v) as a mobile phase at a flow rate of 0.55 mL/min (40 °C). The IS and IBP were eluted at 3.79 ± 0.02 and 6.30 ± 0.02 min, respectively. The total analysis time was 7.00 min. Multiple reaction monitoring was used to conduct the MS/MS detection in the negative ion mode with transitions at m/z 245.9 â†’ 214.9 (IS) and 379.2 â†’ 256.0 (IBP). Validation studies of the developed method revealed good linearity over the range of 10-5,000 ng/mL. Within- and between-run accuracy was in the range of 92-110%, while within- and between-run precision was below 8%. Additionally, low matrix effects and high recovery (above 98%) were observed. IBP remained stable in rat plasma at room temperature for 4 h, at -80 °C for 21 days, over three freeze-thaw cycles, under vacuum concentrator (45 °C, dried residues) and auto-sampler (15 °C, processed samples) temperatures for 1 h and 24 h, respectively. Subsequently, the validated LC-MS/MS method has been successfully applied to quantitate IBP in actual plasma samples after a single oral, intramuscular, and subcutaneous dose of IBP (10 mg/kg in the peach oil) to rats. Pharmacokinetic studies show that more rapid and complete IBP absorption with a satisfactory excretion rate were observed after oral administration route compared to the intramuscular and subcutaneous ones.

Synthesis and Antimicrobial Activity of Sulfenimines Based on Pinane Hydroxythiols.

The widespread presence of multidrug-resistant pathogenic microorganisms challenges the development of novel chemotype antimicrobials, insensitive to microbial tools of resistance. To date, various monoterpenoids have been shown as potential antimicrobials. Among many classes of molecules with antimicrobial activity, terpenes and terpenoids are an attractive basis for the design of antimicrobials because of their low toxicity and availability for various modifications. In this work, we report on the synthesis of sulfenimines from chiral trifluoromethylated and non-fluorinated pinane-type thiols. Final compounds were obtained with yields of up to 81%. Among the 13 sulfenimines obtained, 3 compounds were able to repress the growth of both bacteria (S. aureus, both MSSA and MRSA; P. aeruginosa) and fungi (C. albicans) with an MIC of 8-32 µg/mL. Although compounds exhibited relatively high cytotoxicity (the therapeutic index of 3), their chemotype can be used as a starter point for the development of disinfectants and antiseptics for targeting multidrug-resistant pathogens.

Synthesis of Trifluoromethylated Monoterpene Amino Alcohols.

For the first time, monoterpene trifluoromethylated ß-hydroxy-benzyl-O-oximes were synthesized in 81-95% yields by nucleophilic addition of the Ruppert-Prakash reagent (TMSCF3) to the corresponding ß-keto-benzyl-O-oximes based on (+)-nopinone, (-)-verbanone and (+)-camphoroquinone. Trifluoromethylation has been determined to entirely proceed chemo- and stereoselective at the C=O rather than C=N bond. Trifluoromethylated benzyl-O-oximes were reduced to the corresponding α-trifluoromethyl-ß-amino alcohols in 82-88% yields. The structure and configuration of the compounds obtained have been established.

Isobornylchalcones as Scaffold for the Synthesis of Diarylpyrazolines with Antioxidant Activity.

The pyrazoline ring is defined as a "privileged structure" in medicinal chemistry. A variety of pharmacological properties of pyrazolines is associated with the nature and position of various substituents, which is especially evident in diarylpyrazolines. Compounds with a chalcone fragment show a wide range of biological properties as well as high reactivity which is primarily due to the presence of an α, ß-unsaturated carbonyl system. At the same time, bicyclic monoterpenoids deserve special attention as a source of a key structural block or as one of the pharmacophore components of biologically active molecules. A series of new diarylpyrazoline derivatives based on isobornylchalcones with different substitutes (MeO, Hal, NO2, N(Me)2) was synthesized. Antioxidant properties of the obtained compounds were comparatively evaluated using in vitro model Fe2+/ascorbate-initiated lipid peroxidation in the substrate containing brain lipids of laboratory mice. It was demonstrated that the combination of the electron-donating group in the para-position of ring B and OH-group in the ring A in the structure of chalcone fragment provides significant antioxidant activity of synthesized diarylpyrazoline derivatives.

Synthesis and Antioxidant Activity of Carane and Pinane Based Sulfenimines and Sulfinimines.

The synthesis of sulfenimines and sulfinimines has been carried out with 10-hydroxyisocamphylthiol. The configuration of the compounds has been deduced by methods of NMR, DFT calculations and X-ray diffraction analysis. The cytotoxic, antioxidant and membrane-protective activity of the synthesized compounds as well as of the previously obtained sulfenimines and sulfinimines based on 4-caranethiol have been determined.

Synthesis and Antioxidant Ability of Novel Derivatives Based on para-Coumaric Acid Containing Isobornyl Groups.

A series of novel esters and amides was synthesized on the basis of para-coumaric acid containing isobornyl groups in ortho-positions relative to the phenolic hydroxy group. Antioxidant properties of the obtained compounds were evaluated and compared on in vitro models: radical-scavenging ability, antioxidant activity on a substrate containing the lipids of animal brain, cytotoxicity of red blood cells, antioxidant and membrane-protective properties on the model of oxidative red blood cells hemolysis. Statistically significant relationship was established between the antioxidant activity of the studied compounds in model system containing animal lipids and the parameters reflecting their antioxidant properties on the model of H2 O2 -induced hemolysis of red blood cells. It was determined that an amide with a morpholine fragment has the highest antioxidant activity. The specified derivative significantly surpassed the reference substances (parent acid, BHT) and was not inferior to the effective antioxidant 2,6-diisobornyl-4-methylphenol in terms of its properties.

Novel Aminomethyl Derivatives of 4-Methyl-2-prenylphenol: Synthesis and Antioxidant Properties.

4-Methyl-2-prenylphenol (1) was synthesized from para-cresol and prenol, natural alcohol under the conditions of heterogeneous catalysis. A series of nine new aminomethyl derivatives with secondary and tertiary amino groups were obtained on the basis of compound 1. A comparative evaluation of their antioxidant properties was carried out using in vitro models. It was established that Mannich base with octylaminomethyl group has radical-scavenging activity, high Fe2+ -chelation ability as well as the ability to inhibit oxidative hemolysis of red blood cells.

Caryophyllane Thiols, Vinyl Thioethers, Di- and Bis-Sulfides: Antioxidant and Membrane Protective Activities.

Caryophyllane thioterpenoids were synthesized in 23 - 81% yields. The antioxidant properties of the obtained compounds in various model systems were found. It was revealed that 4,5-epoxycaryophyll-9-ylmethanethiol has the greatest antioxidant activity. The isomerism of sesquiterpenic fragments was shown to have a significant effect on the biological activity of the compounds.

Synthesis and membrane-protective activity of novel derivatives of α-mangostin at the C-4 position.

A series of new C-4-derivatives of α-mangostin has been synthesized with the use of Mannich reaction and alkylation with 4-bromomethyl-2,6-dialkylphenols. It has been shown on a model of H2O2-induced erythrocyte hemolysis that the Mannich bases containing morpholinomethyl and piperidinomethyl fragments differ from parent α-mangostin by their high antioxidant and membrane-protective activity.