Unraveling the Mechanism of Platelet Aggregation Suppression by Thioterpenoids: Molecular Docking and In Vivo Antiaggregant Activity.

Natural monoterpenes and their derivatives are widely considered the effective ingredients for the design and production of novel biologically active compounds. In this study, by using the molecular docking technique, we examined the effects of two series of "sulfide-sulfoxide-sulfone" thioterpenoids containing different (e.g., bornane and pinane) monoterpene skeletons on the platelet's aggregation. Our data revealed that all the synthesized compounds exhibit inhibitory activities on platelet aggregation. For example, compound 1 effectively inhibited platelet activation and demonstrated direct binding with CD61 integrin, a well-known platelet GPIIb-IIIa receptor on platelets. We further examined the antiaggregant activity of the most active compound, 1, in vivo and compared its activity with that of acetylsalicylic acid and an oral GPIIb-IIIa blocker, orbofiban. We found that compound 1 demonstrates antiaggregant activity in rats when administered per os and its activity was comparable with that of acetylsalicylic acid and orbofiban. Moreover, similarly, tirofiban, a well-known GPIIb-IIIa blocker, compound 1, effectively decreased the expression of P-selectin to the values similar to those of the intact platelets. Collectively, here, we show, for the first time, the potent antiaggregant activity of compound 1 both in vitro and in vivo due to its ability to bind with the GPIIb-IIIa receptor on platelets.

Monoterpene Thiols: Synthesis and Modifications for Obtaining Biologically Active Substances.

Monoterpene thiols are one of the classes of natural flavors that impart the smell of citrus fruits, grape must and wine, black currants, and guava and are used as flavoring agents in the food and perfume industries. Synthetic monoterpene thiols have found an application in asymmetric synthesis as chiral auxiliaries, derivatizing agents, and ligands for metal complex catalysis and organocatalysts. Since monoterpenes and monoterpenoids are a renewable source, there are emerging trends to use monoterpene thiols as monomers for producing new types of green polymers. Monoterpene thioderivatives are also known to possess antioxidant, anticoagulant, antifungal, and antibacterial activity. The current review covers methods for the synthesis of acyclic, mono-, and bicyclic monoterpene thiols, as well as some investigations related to their usage for the preparation of the compounds with antimicrobial properties.

Terpene-Functionalized Fluoroquinolones as Potential Antimicrobials: Synthesis and Properties.

This study was the first to synthesize terpene-containing conjugates of fluoroquinolones, ciprofloxacin and norfloxacin, and to evaluate their antibacterial activity against gram-positive methicillin sensitive (MSSA) and methicillin resistant (MRSA) S. aureus, gram-negative P. aeruginosa as well as antifungal activity against C. albicans. The ability of obtained fluoroquinolones to inhibit S. aureus growth was found to depend upon the presence of a linker separating the bulky terpene and fluoroquinolone fragments, and this activity diminished with increasing its length. The highest activity against MSSA was demonstrated by ciprofloxacin derivatives with campholenic (MIC 1 µg/mL) and 2-(isobornan-2-yl-sulfanyl)acetyl (MIC 0.5 µg/mL) substituents. The compound with the last fragment showed high activity against MRSA (MIC 8 µg/mL). The terpene-functionalized norfloxacin derivatives generally proved to be less active than those containing ciprofloxacin fragment. Camphor-10-sulfonylamide derivative with the ciprofloxacin fragment was the only one of all compounds that showed high antifungal activity against C. albicans (8 µg/mL). The study presents data on docking fluoroquinolones to S. aureus DNA gyrase to explain the reasons for manifestation or disappearance of antibacterial activity. The cytotoxicity of fluoroquinolones that showed any antimicrobial activity was investigated against bovine primary lung cells, and they were found to be not toxic in most cases.

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.

Thioterpenoids as Potential Antithrombotic Drugs: Molecular Docking, Antiaggregant, Anticoagulant and Antioxidant Activities.

Natural monoterpenes and their derivatives are widely considered as effective ingredients for the design and production of new biologically active compounds with high antioxidant, antimicrobial and anti-protozoa properties. In this study, we synthesized two series of thiotherpenoids "sulfide-sulfoxide-sulfone", with different bicyclic monoterpene skeleton (bornane and pinane) structures. The effect of the obtained compounds on platelet aggregation was investigated by using the molecular docking technique. The obtained data revealed that all the synthesized compounds may act as potential inhibitors of platelet aggregation. Moreover, the studied sulfides have shown high antioxidant activity as revealed by lipid peroxidation (LPO) process inhibition in a non-cellular substrate containing animal lipids. The sulfides were able to inhibit erythrocyte oxidative hemolysis, to reduce the accumulation of secondary LPO products in cells and to prevent the oxidation of native oxyhemoglobin. Additionally, the corresponding sulfones and sulfoxides exhibited insignificant antioxidant activity. However, the sulfides were found to exhibit significant antiaggregant and anticoagulant effects. These findings suggest as well that the sulfides could serve as a leader compound for future research and possible practical applications.

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.

Synthesis and Biological Activity of Unsymmetrical Monoterpenylhetaryl Disulfides.

New unsymmetrical monoterpenylhetaryl disulfides based on heterocyclic disulfides and monoterpene thiols were synthesized for the first time in 48-88% yields. Hydrolysis of disulfides with fragments of methyl esters of 2-mercaptonicotinic acid was carried out in 73-95% yields. The obtained compounds were evaluated for antioxidant, antibacterial, antifungal activity, cytotoxicity and mutagenicity.

Design, Spectral Characteristics, Photostability, and Possibilities for Practical Application of BODIPY FL-Labeled Thioterpenoid.

This paper presents the design and a comparative analysis of the structural and solvation factors on the spectral and biological properties of the BODIPY biomarker with a thioterpene fragment. Covalent binding of the thioterpene moiety to the butanoic acid residue of meso-substituted BODIPY was carried out to find out the membranotropic effect of conjugate to erythrocytes, and to assess the possibilities of its practical application in bioimaging. The molecular structure of the conjugate was confirmed via X-ray, UV/vis-, NMR-, and MS-spectra. It was found that dye demonstrates high photostability and high fluorescence quantum yield (to ~100%) at 514-519 nm. In addition, the marker was shown to effectively penetrate the erythrocytes membrane in the absence of erythrotoxicity. The conjugation of BODIPY with thioterpenoid is an excellent way to increase affinity dyes to biostructures, including blood components.

Conjugate of meso-carboxysubstituted-BODIPY with thioterpenoid as an effective fluorescent probe: Synthesis, structure, spectral characteristics, and molecular docking.

This paper is devoted to the design of a fluorescent probe based on meso-carboxysubstituted-BODIPY with a thioterpene fragment. The functional replacement of the methoxy group in the BODIPY molecule on a thioterpene fragment was carried out in order to find out the antiplatelet and anticoagulant action mechanisms of thioterpenoids and to assess the membrane and receptor factors contributions. The molecular structure of the conjugate was confirmed via UV/vis-, NMR- and MS-spectra. It is found that the probe is a high fluorescence quantum yield (to âˆ¼ 100%) in the blue-green region at 509-516 nm. Molecular docking of all studied molecules showed that the BODIPY with terpenoid conjugation is an excellent way to increase their affinity to platelet receptor P2Y12.

Synthesis and Oxidative Transformations of New Chiral Pinane-Type γ-Ketothiols: Stereochemical Features of Reactions.

Chiral γ-ketothiols, thioacetates, thiobenzoate, disulfides, sulfones, thiosulfonates, and sulfonic acids were obtained from ß-pinene for the first time. New compounds open up prospects for the synthesis of other polyfunctional compounds combining a biologically active pinane fragment with various pharmacophore groups. It was shown that the syntheses of sulfanyl and sulfonyl derivatives based on 2-norpinanone are characterized by high stereoselectivity in comparison with similar reactions of pinocarvone. The conditions for the preparation of diastereomerically pure thioacetyl and thiobenzoyl derivatives based on pinocarvone, as well as for the chemoselective oxidation of γ-ketothiols with chlorine dioxide to the corresponding thiolsulfonates and sulfonic acids, were selected. The effect of the VO(acac)2 catalyst on the increase in the yields of thiosulfonates was shown. A new direction of the transformation of thiosulfonates with the formation of sulfones was revealed. In the case of pinocarvone-based sulfones, the configuration is inversed at the C2 atom. An epimerization scheme is proposed.

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.

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.