Exploring the Antimicrobial Properties of 99 Natural Flavour and Fragrance Raw Materials against Pathogenic Bacteria: A Comparative Study with Antibiotics.

Currently, one of the most serious global problems is the increasing incidence of infectious diseases. This is closely related to the increase in antibiotic use, which has resulted in the development of multidrug resistance in microorganisms. Another problem is the numerous microbiological contaminations of cosmetic products, which can lead to dangerous bacterial infections in humans. Natural fragrance raw materials exhibit a wide spectrum of biological properties, including antimicrobial properties. Despite their prevalence and availability on the commercial market, there is little research into their effects on multidrug-resistant microorganisms. This study examines the inhibitory effect of natural substances on Gram-positive and Gram-negative bacteria. For this purpose, screening and appropriate assays were carried out to determine the minimum inhibitory concentration (MIC) value of individual substances, using the alamarBlueTM reagent. The lowest MIC values were observed for Staphylococcus aureus (black seed (Nigella sativa) expressed oil, MIC = 25 µg/mL), Kocuria rhizophila (fir balsam absolute, MIC = 12.5 µg/mL), and Pseudomonas putida (cubeb oil and fir balsam absolute, MIC = 12.5 µg/mL). The most resistant Gram-negative species was Enterobacter gergoviae, while Staphylococcus epidermidis was the most resistant Gram-positive species.

Comparative evaluation of mutagenic, genotoxic, cytotoxic, and antimicrobial effects of flavour and fragrance aldehydes, ketones, oximes, and oxime ethers.

Despite the large number of odoriferous compounds available, new ones with interesting olfactory characteristics are desired due to their potentially high commercial value. Here, we report for the first time mutagenic, genotoxic, and cytotoxic effects, and antimicrobial properties of low-molecular fragrant oxime ethers, and we compare their properties with corresponding oximes and carbonyl compounds. 24 aldehydes, ketones, oximes, and oxime ethers were evaluated for mutagenic and cytotoxic effects in Ames (using Salmonella typhimurium strains TA 98 with genotype hisD3052, rfa, uvrB, pKM101, and TA100 with genotype hisG46, rfa, uvrB, pKM101, concentration range: 0.0781-40 mg/mL) and MTS (using HEK293T cell line concentration of tested substances: 0.025 mM) assays. Antimicrobial evaluation was carried out against Bacillus cereus (ATCC 10876), Staphylococcus aureus (ATCC 6538), Enterococcus hirae (ATCC 10541), Pseudomonas aeruginosa (ATCC 15442), Escherichia coli (ATCC 10536), Legionella pneumophila (ATCC 33152); Candida albicans (ATCC 10231) and Aspergillus brasiliensis (ATCC 16404) with concentration range of tested substances 9.375 - 2.400 mg/mL. Furthermore, 5 representatives of carbonyl compounds, oximes, and an oxime ether (stemone, buccoxime, citral, citral oxime, and propiophenone oxime O-ethyl ether) were evaluated for genotoxic properties in SOS-Chromotest (concentration range: 7.8·10-5 - 5·10-3 mg/mL). All of the tested compounds did not exhibit mutagenic, genotoxic, or cytotoxic effects. Oximes and oxime ethers showed relevant antimicrobial activity against pathogenic species (P. aeruginosa, S. aureus, E.coli, L. pneumophila, A. brasiliensis, C. albicans) in the MIC range 0.075 - 2.400 mg/mL compared to the common preservative methylparaben with the MIC range 0.400-3.600 mg/mL. Our study shows that oxime ethers have the potential to be used as fragrant agents in functional products.

Evaluation of the anti-SARS-CoV-2 properties of essential oils and aromatic extracts.

Essential oils and aromatic extracts (oleoresins, absolutes, concretes, resinoids) are often used as food flavorings and constituents of fragrance compositions. The flavor and fragrance industry observed significant growth in the sales of some natural materials during the COVID-19 outbreak. Some companies worldwide are making false claims regarding the effectiveness of their essential oils or blends (or indirectly point toward this conclusion) against coronaviruses, even though the available data on the activity of plant materials against highly pathogenic human coronaviruses are very scarce. Our exploratory study aimed to develop pioneering knowledge and provide the first experimental results on the inhibitory properties of hundreds of flavor and fragrance materials against SARS-CoV-2 main and papain-like proteases and the antiviral potential of the most active protease inhibitors. As essential oils are volatile products, they could provide an interesting therapeutic strategy for subsidiary inhalation in the long term.

Cytotoxicity, early safety screening, and antimicrobial potential of minor oxime constituents of essential oils and aromatic extracts.

Due to market and legislative expectations, there is a constant need to explore new potential antimicrobial agents for functional perfumery. In this study, we evaluated the antimicrobial activity of 53 low molecular oximes and the corresponding carbonyl compounds against Escherichia coli, Enterococcus hirae, Pseudomonas aeruginosa, Bacillus cereus, Staphylococcus aureus, Aspergillus brasiliensis, Legionella pneumophila and Candida albicans. The most potent compound was α-isomethylionone oxime, which exhibited a minimum inhibitory concentration (MIC) of 18.75 µg/mL against E. hirae. The evaluation of the MICs for bacterial and fungal strains was performed for selected compounds, for example, the MIC of 2-phenylpropionaldehyde, cis-jasmone oxime, and trans-cinnamaldehyde measured against A. brasiliensis was 37.50 µg/mL. ADME-Tox (Absorption, Distribution, Metabolism, Excretion, and Toxicity) and 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) cell viability assays were performed to assess the cytotoxicity of tested compounds. ADME-Tox indicated the safety and promising properties of selected compounds, which enables their usage as nontoxic supporting antibacterial agents. The results of the in vitro MTS assay were consistent with the ADME-Tox results. None of the compounds tested was toxic to Human Embryonic Kidney 293T (HEK293T) cells, with all cell viabilities exceeding 85%.

Biological Activity of Selected Natural and Synthetic Terpenoid Lactones.

Terpenoids with lactone moieties have been indicated to possess high bioactivity. Certain terpenoid lactones exist in nature, in plants and animals, but they can also be obtained by chemical synthesis. Terpenoids possessing lactone moieties are known for their cytotoxic, anti-inflammatory, antimicrobial, anticancer, and antimalarial activities. Moreover, one terpenoid lactone, artemisinin, is used as a drug against malaria. Because of these abilities, there is constant interest in new terpenoid lactones that are both isolated and synthesized, and their biological activities have been verified. In some cases, the activity of the terpenoid lactone is specifically connected to the lactone moiety. Recent works have revealed that new terpenoid lactones can demonstrate such functions and are thus considered to be potential active agents against many diseases.

Minor constituents of essential oils and aromatic extracts. Oximes derived from natural flavor and fragrance raw materials - Sensory evaluation, spectral and gas chromatographic characteristics.

A small library of 57 low molecular weight oximes was prepared from fragrant aldehydes and ketones, and their olfactory profiles were determined. The most substantive and interesting in terms of the sensory impressions were (+)-isomenthone oxime (fresh, musty, green) and cyclocitral oxime (earthy with patchouli, moss and leather notes). The linear retention indices (LRI) were determined for DB-1, DB-5 and DB-WAX columns, and E/Z isomers of 22 out of 57 compounds were resolved on the DB-5 column. Attempts were made to resolve enantiomers of the chosen oximes on chiral GC columns. The best results were obtained by using a Cyclosil B column, on which the enantiomers of camphor, menthone, piperitone and carvone oximes were fully resolved. NMR and MS spectra were acquired to characterize the synthesized library. Gas chromatography-olfactometry was used to assess odoriferous properties of both isomers of oximes. In most cases both isomers possessed similar profile and intensity.

Novel Benzene-Based Carbamates for AChE/BChE Inhibition: Synthesis and Ligand/Structure-Oriented SAR Study.

A series of new benzene-based derivatives was designed, synthesized and comprehensively characterized. All of the tested compounds were evaluated for their in vitro ability to potentially inhibit the acetyl- and butyrylcholinesterase enzymes. The selectivity index of individual molecules to cholinesterases was also determined. Generally, the inhibitory potency was stronger against butyryl- compared to acetylcholinesterase; however, some of the compounds showed a promising inhibition of both enzymes. In fact, two compounds (23, benzyl ethyl(1-oxo-1-phenylpropan-2-yl)carbamate and 28, benzyl (1-(3-chlorophenyl)-1-oxopropan-2-yl) (methyl)carbamate) had a very high selectivity index, while the second one (28) reached the lowest inhibitory concentration IC50 value, which corresponds quite well with galanthamine. Moreover, comparative receptor-independent and receptor-dependent structure⁻activity studies were conducted to explain the observed variations in inhibiting the potential of the investigated carbamate series. The principal objective of the ligand-based study was to comparatively analyze the molecular surface to gain insight into the electronic and/or steric factors that govern the ability to inhibit enzyme activities. The spatial distribution of potentially important steric and electrostatic factors was determined using the probability-guided pharmacophore mapping procedure, which is based on the iterative variable elimination method. Additionally, planar and spatial maps of the host⁻target interactions were created for all of the active compounds and compared with the drug molecules using the docking methodology.

Reductive capabilities of different cyanobacterial strains towards acetophenone as a model substrate - Prospect of applications for chiral building blocks synthesis.

Bioreductive capabilities of four morphologically different strains of cyanobacteria have been assessed in this work. Arthrospira maxima, Leptolyngbya foveolarum, Nodularia sphaerocarpa and Synechococcus bigranulatus were applied as catalysts for the reduction of acetophenone to the corresponding chiral phenylethyl alcohol. The process was modified regarding substrate concentration, duration of pre-cultivation period, duration of biotransformation, light regime and glucose addition to the culture media. Obtained results clearly showed that cyanobacteria were active towards acetophenone what resulted in the substrate reduction to (S)-1-phenylethanol with high enantiomeric excess. The reaction efficiency increased with the biotransformation time, but the higher concentration of substrate limited the process yield. Also, all tested strains performed reaction with the highest efficacy under continuous light regime. The most active strains - N. sphaerocarpa and S. bigranulatus carried out the conversion of 1 mM acetophenone with high efficiency of respectively 97.6% and 96.2% after 13 days of biotransformation. A. maxima reached 45.8% of conversion after 13 days of biotransformation whereas L. foveolarum did not exceed 20%. The enantiomeric excesses were respectively 98.8%- A. maxima, 91.7%- L. foveolarum, 72.6%- S. bigranulatus and N. sphaerocarpa 16.2%.

Burkholderia cepacia lipase immobilization for hydrolytic reactions and the kinetic resolution of the non-equimolar mixtures of isomeric alcohols.

The major drawbacks of native lipase applications in processes occurring in water or in organic solvents include: difficulties in catalyst recycling, low activity and operational instability. The immobilization of Burkholderia cepacia lipase by adsorption or covalent binding onto 5 differently functionalized carriers (silica, acrylic, cellulose-based) was performed to overcome this problem. The optimization of the reaction preparation in water-rich media was based on the hydrolytic reactivity of the preparations, as well as the thermal, operational and storage stabilities. Aminated silica carrier, activated with glutaraldehyde, was determined to be the carrier of choice. Regarding processes in water-restricted media, carrier selection was based on reactivity after drying and five preparations were chosen for the resolution of a non-equimolar isomer mixture (85:15 ratio of R to S isomers), treating the kinetic resolution of ((+)-(S/R)-1-[(1S,5R)-6,6-dimethylbicyclo[3.1.0]hex-2-en-2-yl)]ethanol as a model. The resulting acetate of R configuration exhibits interesting sensory properties. The operational stability of the chosen catalysts was tested over 15 consecutive batch processes; the most beneficial results were obtained with lipase adsorbed on an acrylic carrier. Conversion increased gradually from 10 to 84% over the first five processes, which could be explained by the product sorption onto the carrier. Full kinetic resolution with maximal substrate conversion (approximately 84%) was achieved and remained stable during the next 10 runs, an excellent result, and thus, the proposed system might be regarded as an exceptionally attractive solution for the perfume and cosmetic industries.

The anxiolytic-like activity of a novel N-cycloalkyl-N-benzoylpiperazine derivative.

BACKGROUND: Anxiety-related disorders are among the most common mental illnesses in the world for which benzodiazepines, buspirone and antidepressant drugs remain the first-line treatment. These drugs have good efficacy but they have numerous disadvantages, such as drug abuse potential, delayed onset of action or tolerance. A literature review reveals that a variety of piperazine derivatives may exhibit interesting pharmacological properties, including anxiolytic-like, antidepressant, nootropic and antinociceptive activities demonstrated in animal models, as well as an antioxidant capacity shown in some in vitro tests. Hence, the aim of this study was the synthesis and preliminary pharmacological in vivo evaluation of a novel N-cycloalkyl-N-benzoylpiperazine derivative, compound 9. METHODS: The test compound 9 was synthesized from a cyclic ketone 6,6-dimethylbicyclo[3.1.0]hexan-3-one (compound 7) and N-benzoylpiperazine. The final product was evaluated in vivo for its anxiolytic-like and antinociceptive activity after intraperitoneal (ip) administration. Its impact on animals' locomotor activity and motor performance was also evaluated. RESULTS: At the dose of 50mg/kg the test compound 9 showed statistically significant (p<0.01) anxiolytic-like activity in the four plate test. This effect was completely abolished by pretreatment with naloxone hydrochloride (1mg/kg; ip). Compound 9 did not influence animals' locomotor activity or motor coordination. No antinociceptive effect was demonstrated in the hot plate test. CONCLUSIONS: The anxiolytic-like properties of N-bicyclo-[3.1.0]hexyl derivative (9) in the four plate test are mediated by the opioid system. The results obtained make this compound a promising lead structure for further development of anxiolytic drugs.

Synthesis of the aggregation pheromone of the Colorado potato beetle from its degradation product.

Incubation of the Colorado potato beetle aggregation pheromone, (S)-1,3-dihydroxy-3,7-dimethyl-6-octen-2-one, with antennal or leg extracts from this beetle gave 6-methyl-5-hepten-2-one as the major product. This ketone was used as a substrate in a stereoselective synthesis of the pheromone. It was attached to the butanediacetal of glycolic acid with good stereoselectivity and the desired isomer was further enriched by purification of the product of this reaction on silica gel.

Application of microorganisms towards synthesis of chiral terpenoid derivatives.

Biotransformations are a standard tool of green chemistry and thus are following the rules of sustainable development. In this article, we describe the most common types of reactions conducted by microorganisms applied towards synthesis of chiral terpenoid derivatives. Potential applications of obtained products in various areas of industry and agriculture are shown. We also describe biological activity of presented compounds. Stereoselective hydroxylation, epoxidation, Baeyer-Villiger oxidation, stereo- and enantioselective reduction of ketones, and various kinetic resolutions carried out by bacteria and fungi have been reviewed. Mechanistic considerations regarding chemical and enzymatic reactions are presented. We also briefly describe modern approaches towards enhancing desired enzymatic activity in order to apply modified biocatalysts as an efficient tool and green alternative to chemical catalysts used in industry.

Evaluation of the irritating influence of carane derivatives and their antioxidant properties in a deoxyribose degradation test.

Previous studies of the propranolol monoterpene derivative (-)-4-[2-hydroxy-3-(N-isopropylamino)-propoxyimino]-cis-carane hydrochloride (KP-23) and its diastereoisomers, KP-23R and KP-23S, demonstrated different effects on the cyclic AMP generating system as well as anti-inflammatory, analgesic, antihistaminic and antioxidant activity. The present study examined the influence of KP-23 and its diastereoisomers KP-23R and KP-23S on the skin-irritating activity and the mucous membrane-irritating activity as well as their influence on a late-type contact allergy in the in vivo tests. The hydroxyl radical scavenging potential of the three analogues was evaluated using their ability to inhibit Fe(II)/H2O2-induced oxidative degradation of 2-deoxyribose (2-DR) in the in vitro tests. The results obtained indicated that the hydroxyamine carane derivative did not evoke irritative changes and did not induce a late-type contact allergy in the guinea-pig. Diastereoisomers of KP-23 exhibit antioxidant properties in a dose-dependent manner and protected against OH-radicals generated from the Fenton reaction.

Incidence, management, and outcome of incidental gallbladder carcinoma: analysis of the database of the Swiss association of laparoscopic and thoracoscopic surgery.

BACKGROUND: Little is known about the long-term survival of patients with incidental gallbladder carcinoma (IGBC). The role of radical resection for this disease is discussed controversially in the literature. We present the long-term survival and the results of re-resection versus simple cholecystectomy of the database of the Swiss Association for Laparoscopic and Thoracoscopic Surgery (SALTS) from 1994 to 2004. METHODS: Eighty-nine patients with histologically confirmed carcinoma of the gallbladder were identified out of 30,960 patients undergoing laparoscopic cholecystectomy. Sixty-nine patients were included in our study. Long-term survival by different T-stage and comparison of patients with extended resection versus simple cholecystectomy were calculated using the log-rank test. The time-to-event data are demonstrated by Kaplan-Meier curves. RESULTS: The overall incidence of IGBC in patients who underwent laparoscopic cholecystectomy was 0.28% (89 of 30,960). Fifty patients underwent simple cholecystectomy [n = 2: carcinoma in situ (CIS); n = 2: pT1a; n = 10: pT1b; n = 23: pT2; n = 8: pT3; n = 5: pT4], whereas extended resection was performed in 19 cases (n = 2: pT1b; n = 11: pT2; n = 6: pT3). The comparison of simple cholecystectomy versus extended re-resection of the gallbladder bed and regional lymph node resections showed a significant benefit in overall survival for the pT2 and pT3 group (p < 0.05). The pT1b group showed no significant benefit in overall survival (p = 0.34). CONCLUSION: IGBC has a low incidence (0.28%). We present a large study of patients with IGBC, comparing the overall survival by different histological findings. We observed a significant benefit for the group with pT2 and pT3. Therefore we recommend extended resection of the gallbladder bed and the regional lymph nodes for patient with incidental histologically confirmed pT2 and pT3 carcinoma of the gallbladder after performance of laparoscopic cholecystectomy. For patients with pT1b stage no recommendations can be given based on this study.