ABSTRACT
BACKGROUND: The Mediterranean fruit fly, Ceratitis capitata, is one of the most economically important insect pests attacking fruits and vegetables in tropical and subtropical areas of the world. Semiochemical-based pest management programs are being used to provide environmentally friendly control methods for medflies. The goals of the current study were to discover potential new, attractive, kairomones by designing, synthesizing, and testing simplified ethers of thymol and carvacrol along with their ether derivatives in short-range attraction assays and electroantennogram (EAG) assays with male C. capitata. To the best of our knowledge, this study represents the first investigation of thymol and carvacrol, and their respective ethers for attractancy to C. capitata, a major agricultural pest worldwide. RESULTS: In short-range attraction bioassays, parent compounds, thymol and carvacrol, along with their propyl, butyl, benzyl, and octyl ethers captured the most male C. capitata. The attraction patterns changed over time and captures were only significant if they were greater than the positive control tea tree oil (TTO) at 90 min. In EAG assays, thymol benzyl, octyl ethers, and carvacrol benzyl ether evoked significantly greater antennal responses than their parent compounds. The EAG responses did not correlate with short-range male attraction. The aliphatic side chains of thymol and carvacrol had a small effect on the activity. Future studies will investigate the long-range attraction of the ethers that elicited large EAG responses. CONCLUSION: This report provides new information for discovering potential kairomones through synthesis and structure-activity studies for sterile male medflies. Thymol, carvacrol, and several of their ether derivatives displayed improved longevity of attraction compared with TTO (a strong medfly attractant), with significantly higher captures than TTO observed at 90 min in laboratory bioassays. Further chemical synthesis of thymol and carvacrol ethers within this series may lead to the development of ethers that are more attractive or persistent than their parent compounds, thymol and carvacrol. © 2024 Society of Chemical Industry. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.
ABSTRACT
Responsive and adaptive soft-matter systems represent an advanced category of materials with potential applications in drug delivery. Among these, liquid crystals (LCs) emerge as multifunctional anisotropic scaffolds capable of reacting to temperature, light, electric or magnetic fields. Specifically, the ordering and physical characteristics of thermotropic LCs are primarily contingent on temperature as an external stimulus. This comprehensive review aims to bridge a notable gap in the biomedical application of thermotropic mesogens by exclusively focusing on drug delivery. Anticipated to inspire diverse ideas, the review intends to facilitate the elegant exploitation of controllable and temperature-induced characteristics of LCs to enhance drug permeation. Here, we delineate recent advancements in thermally-driven LCs with a substantial emphasis on LC monomer mixtures, elastomers, polymers, microcapsules and membranes. Moreover, special emphasis is placed on the biocompatibility and toxicity of LCs as the foremost prerequisite for their application in healthcare. Given the promising prospect of thermotropic LC formulations in a clinical context, a special section is devoted to skin drug delivery. The review covers content from multiple disciplines, primarily targeting researchers interested in innovative strategies in drug delivery. It also appeals to those enthusiastic about firsthand exploration of the feasible biomedical applications of thermotropic LCs. To the best of our knowledge, this marks the first review addressing thermotropic LCs as tunable soft-matter systems for drug delivery.
Subject(s)
Delayed-Action Preparations , Drug Carriers , Drug Delivery Systems , Liquid Crystals , Temperature , Liquid Crystals/chemistry , Humans , Drug Delivery Systems/methods , Drug Carriers/chemistry , Animals , Drug Liberation , Polymers/chemistry , Skin/metabolism , Skin/drug effects , Administration, CutaneousABSTRACT
Herein, we report the properties of nanostructured lipid carriers (NLCs) prepared with a gradient concentration of Bergenin (BGN) isolated from Pentaclethra macrophylla stem bark powder. A gradient concentration of BGN (BGN 0, 50, 100, 150, and 200 mg) was prepared in a 5 % lipid matrix consisting of Transcutol HP (75 %), Phospholipon 90H (15 %), and Gelucire 43/01 (10 %) to which a surfactant aqueous phase consisting of Tween 80, sorbitol, and sorbic acid was dissolved. The NLCs were evaluated by size, polydispersity index (PDI), zeta potential, Fourier Transform Infrared Spectroscopy (FTIR), Differential Scanning Calorimetry (DSC), encapsulation efficiency, and in vitro drug release. The result shows polydispersed nanoparticles with high drug encapsulation (94.26-99.50 %). The nanoparticles were mostly spherical, but those from the 50 mg BGN batch were more cuboidal than spherical. The drug release was highest from the latter to the tune of 40 % compared to the pure BGN solution, which released about 15 % BGN. The anti-inflammatory activity of the BGN-NLC and total plant extract was studied on lipopolysaccharide (LPS)-inflamed macrophages. The cell study showed that BGN and plant extract had low cytotoxicity on macrophages and exhibited a dose-dependent anti-inflammatory effect on the LPS-induced inflammatory process in macrophages.
Subject(s)
Anti-Inflammatory Agents , Benzopyrans , Drug Carriers , Lipids , Lipopolysaccharides , Macrophages , Nanoparticles , Lipopolysaccharides/pharmacology , Animals , Mice , Macrophages/drug effects , Macrophages/metabolism , Anti-Inflammatory Agents/pharmacology , Anti-Inflammatory Agents/administration & dosage , Anti-Inflammatory Agents/chemistry , Drug Carriers/chemistry , Benzopyrans/pharmacology , Benzopyrans/administration & dosage , Benzopyrans/chemistry , Nanoparticles/chemistry , Lipids/chemistry , RAW 264.7 Cells , Drug Liberation , Nanostructures/chemistry , Saxifragaceae/chemistry , Particle Size , Inflammation/drug therapy , Inflammation/chemically induced , Plant Extracts/pharmacology , Plant Extracts/administration & dosage , Plant Extracts/chemistryABSTRACT
Stimuli-responsive and tunable soft-matter systems are an advanced class of materials applicable for drug delivery. Liquid crystals (LCs) are promising candidates as multifunctional materials that can respond to temperature, light or magnetic field. Particularly, ordering and physical properties of thermoresponsive LCs depend predominantly on temperature as external trigger. The current work addresses an elegant strategy to implement the anisotropic properties of thermoresponsive LCs with a view to extending their application for drug delivery. We firstly fabricated novel compositions with a thermotropic core based on natural products - cholesteryl esters and mono-/bicyclic terpenoids. The distinctive feature of aforementioned systems is their temperature-induced switchability of drug release by transition to the LC state, depending on the skin temperature. Their mesomorphic and optical behavior was characterized via differential scanning calorimetry and polarizing optical microscopy. Furthermore, we describe the dependence of helical pitch on LC formulation for various ternary cholesteric systems doped with terpenoids, suggesting that these stimuli-responsive chiral dopants are nominally untwisting. Data from fluorescence probe technique indicate that cholesteryl esters and terpenoids as essential components of those LC systems jointly disrupt the tight structure of phospholipid bilayer packing enabling the facilitated penetration of drugs. The potential of LC formulations was explored for several model drugs with diverse physicochemical properties by in vitro and ex vivo penetration tests using artificial membranes and full human skin. Our findings confirm the potential of LC systems for various applications in skin drug delivery.
ABSTRACT
Genotoxicity and mutagenicity of monoterpene carvone along with the related monoterpene alcohols - carvacrol and thymol have been studied using Drosophila melanogaster as model system. The viability, pre-imaginal stage duration, level of dominant lethal mutations, unequal crossover in the Bar mutant of D. melanogaster and the influence of monocyclic terpenoids on the multiplication of the nuclear genome in salivary gland cells were investigated. The compounds tested after oral administration (0.02% in 1,2-propylene glycol) influence the degree of chromosome polyteny in salivary gland cells of D. melanogaster larvae. Among the terpenoids examined, carvacrol exhibited the most significant impact on imago lifespan, frequency of dominant lethal mutations, unequal crossover in the Bar mutant when added to the culture medium. Oral administration of terpenoids increases the average level of chromosome polyteny with the highest value for carvacrol - 1178 C compared to control (776 C). The conceivable mechanism of action for monocyclic terpenoids associated with the impact on juvenile hormone activity is debated.
ABSTRACT
The ketene dithioacetal 3 generated from 2-nitroperchlorobutadiene 1 reacted with various heterocyclic amines and aliphatic, aromatic and heterocyclic thiols to produce functionalized new ketene-N,S,S-acetals and S,S,S-acetals 4a-f, 5a-h as heterocyclic dithiolanes. They were separated/purified by chromatographic methods and their exact structure characterization were made clear by spectroscopic methods. These compounds synthesized could act as effective drugs for versatile activity. Evaluation of the antimicrobial effect of the obtained substances determined derivatives 4e and 5h, which have MIC=15.6â µg/mL for the test culture of Mycobacterium luteum bacteria closing to the control drug Vancomycin. The obtained compounds can be proposed as a promising synthetic objects for future molecular design to enhance the antimicrobial action. Ketene dithioacetals 3, 4a, 4b, 4e, 5g (50â mg/kg) exhibited antiseizure effect comparable with reference drug (valproic acid) on the model of pentylenetetrazole-induced convulsions after single oral administration both at 3â h and 24â h. Furthermore, tested dithioacetals possessed prolonged antidepressant activity in forced swim test (FST) considerable decreasing the duration of immobility time compared to reference drug amitriptyline. This is the first study of the investigation of anticonvulsant and antidepressant activities of ketene dithioacetals.
Subject(s)
Acetals , Antifungal Agents , Acetals/chemistry , Acetals/pharmacology , Anti-Bacterial Agents/pharmacology , Anticonvulsants/pharmacology , Antidepressive Agents/chemistry , Antidepressive Agents/pharmacology , Antifungal Agents/pharmacology , Ethylenes , KetonesABSTRACT
Hydrazones based on mono- and bicyclic terpenoids (verbenone, menthone and carvone) have been investigated in vitro as potential biomembrane penetration enhancers. In this regard, liposomes composed of lecithin or cardiolipin as phospholipid phase components with incorporated fluorescence probes have been prepared using the thin-film ultrasonic dispersion method. The mean particle size of the obtained liposomes, established using laser diffraction, was found to be 583 ± 0.95 nm, allowing us to categorize them as multilamellar vesicles (MLVs) according to their morphology. Pursuant to fluorescence analysis, we may assume a reduction in microviscosity and, consequently, a decrease in the packing density of lecithin and cardiolipin lipids to be the major mechanism of action for terpenoid hydrazones 1-15. In order to determine the molecular organization of the lipid matrix, lipids were isolated from rat strata cornea (SCs) and their interaction with tested compounds was studied by means of Fourier transform infrared spectroscopy. FT-IR examination suggested that these hydrazones fluidized the SC lipids via the disruption of the hydrogen-bonded network formed by polar groups of SC constituents. The relationship between the structure of terpenoid hydrazones and their ability to enhance biomembrane penetration is discussed.
Subject(s)
Hydrazones/analysis , Hydrazones/chemistry , Spectroscopy, Fourier Transform Infrared , Terpenes/chemistry , Fluorescence , Fluorescent Dyes , Hydrogen Bonding , Lipids/chemistry , Liposomes/chemistry , Molecular Structure , Phospholipids/chemistryABSTRACT
Novel hydrazones based on (â)-carvone were synthesized via condensation of terpenoid with 4-R-phenoxyacetic acid hydrazides. The structure of target compounds was established by FT-IR, Raman, 1H-NMR and 13C-NMR spectral analysis, FAB/ESI mass spectrometry. (â)-Carvone hydrazones were proven to exist as Z/E geometrical isomers about C = N bond using ion mobility-tandem mass spectrometry (IM-MS/MS). Single crystal X-ray diffraction study was applied to determine molecular and crystal structure of compound 3e. Hydrazones 3a-3e were evaluated as potential anticonvulsant agents after their oral administration against maximal electroshock (MES) and pentylenetetrazole (PTZ)-induced seizures in mice. Analgesic activity of compounds was investigated by topical application on models of capsaicin and AITC-induced pain. The present findings indicate that (â)-carvone derivatives afforded seizure protection both at short (1 h) and long (24 h) time period by blocking electroshock- and chemical-induced convulsions. Hydrazones binding to TRPA1/TRPV1 ion channels was proposed as possible mechanism explaining significant analgesic effect of compounds.
Subject(s)
Anticonvulsants , Tandem Mass Spectrometry , Analgesics/pharmacology , Animals , Anticonvulsants/pharmacology , Cyclohexane Monoterpenes , Mice , Spectroscopy, Fourier Transform Infrared , Structure-Activity RelationshipABSTRACT
The present study investigated the effect of four carvacrol ethers (propyl-, butyl, octyl- and benzyl) on the viability, level of dominant lethal mutations of Drosophila melanogaster and their influence on the multiplication of the nuclear genome in salivary gland cells. The fertility and viability of fruit flies were assessed after oral administration (0.05 % to culture medium) and inhalation exposure (5 mg per 1 cm2 of polyvinyl alcohol film) of compounds 1â4 and initial carvacrol. The influence of terpenoid and its ethers on the degree of chromosomes polyteny in salivary gland cells of D. melanogaster larvae has been revealed. Among all tested compounds, carvacrol exhibited the most significant impact on frequency of dominant lethal mutations, fecundity and insect survival when inhaled or adding to the culture medium. Oral administration of ethers 1â4 was found to decrease the average level of chromosome polyteny degree (366 C-500 C) while pure carvacrol adding to culture medium had the opposite effect (763 C) compared to control (695 C). The possible mechanism of action for carvacrol and its ethers is discussed.
Subject(s)
Animals, Genetically Modified/growth & development , Chromosome Duplication/drug effects , Chromosomes/drug effects , Cymenes/toxicity , Drosophila melanogaster/drug effects , Ethers/toxicity , Mutation , Animals , Animals, Genetically Modified/genetics , Cell Nucleus , DNA Damage , Drosophila melanogaster/genetics , Drosophila melanogaster/growth & development , Female , Genotype , MaleABSTRACT
Novel heterocyclic dichloronaphthoquinone derivatives have been synthesized by chlorine atom substitution in 2,3-dichloro-1,4-naphthoquinone to pyrazole or pyrimidine fragments. The structures of these compounds have been confirmed by FT-IR, ESI-MS, 1H?NMR, 13C-NMR and elementary analysis. Synthesized compounds were evaluated for their anticonvulsant action in a pentylenetetrazole (PTZ)-convulsion model and antidepressant activity in the forced swimming test (FST). All naphthoquinone derivatives at a dose 100 mg/kg indicated anticonvulsant effect in PTZ-induced test at 3 h and 24 h after oral administration. In addition, these compounds possessed prolonged antidepressant properties significantly reducing the duration of immobility time when compared to the reference drug amitriptyline.
Subject(s)
Anticonvulsants/therapeutic use , Antidepressive Agents/therapeutic use , Depression/drug therapy , Naphthoquinones/therapeutic use , Seizures/drug therapy , Animals , Animals, Outbred Strains , Anticonvulsants/chemical synthesis , Antidepressive Agents/chemical synthesis , Male , Mice , Naphthoquinones/chemical synthesis , Pentylenetetrazole , Pyrazoles/chemical synthesis , Pyrazoles/therapeutic use , Pyrimidines/chemical synthesis , Pyrimidines/therapeutic use , Seizures/chemically inducedABSTRACT
The influence of esters based on gamma-aminobutyric acid (GABA) and mono-/bicyclic terpenoids on membrane structure was investigated. The mechanism of action for terpenoid esters on phospholipids of artificial membranes and lipids isolated from the rat stratum corneum was studied by fluorescence and FT-IR spectroscopy. We report here, that inclusion of monocyclic terpenoid esters in phospholipid liposomes leads to growth of excimer to monomer ratio (IE/IM) indicating a decrease of membrane microviscosity. Another mechanism of influence on biomembranes was proposed for ester of bicyclic borneol - in this case a high ratio of vibronic peak intensities (I1/I3) was revealed. The addition of terpenoid esters appears in the FT-IR spectra as intensity reduction of absorption bands associated with C = O, P = O and P-O-С groups of lecithin phospholipids. Similar results were obtained after esters addition to lipids isolated from stratum corneum indicating a decrease of hydrogen bonds number between polar groups of lipids. Thus, the influence of terpenoid esters on molecular organization of the lipid matrix substantiates the feasibility of their use after transdermal delivery in vivo.
Subject(s)
Esters/chemistry , Liposomes/chemistry , Membranes, Artificial , Phospholipids/chemistry , Terpenes/chemistry , gamma-Aminobutyric Acid/chemistry , Administration, Cutaneous , Animals , Camphanes/chemistry , Hydrogen Bonding , Lecithins/chemistry , Male , Membrane Fluidity , Pyrenes/chemistry , Rats, Wistar , ViscosityABSTRACT
Esters based on mono- and bicyclic terpenoids with glycine have been synthesized via Steglich esterification and characterized by ¹H-NMR, IR, and mass spectral studies. Their analgesic and anti-inflammatory activities were investigated after transdermal delivery on models of formalin, capsaicin, and AITC-induced pain, respectively. Glycine esters of menthol and borneol exhibited higher antinociceptive action, whereas eugenol derivative significantly suppressed the development of the inflammatory process. The mechanism of competitive binding between terpenoid esters and TRPA1/TRPV1 agonists was proposed explaining significant analgesic effect of synthesized derivatives. For an explanation of high anti-inflammatory activity, competitive inhibition between terpenoid esters and AITC for binding sites of the TRPA1 ion channel has been suggested.
ABSTRACT
Novel esters of γ-aminobutyric acid (GABA) with monocyclic terpenes were synthesized via Steglich esterification and characterized by ¹H-NMR, IR and mass spectral studies. Their anticonvulsant, analgesic and anti-inflammatory activities were evaluated by a PTZ-induced convulsion model, AITC-induced hyperalgesia and AITC-induced paw edema, respectively. All studied esters, as well as their parent terpenes, were found to produce antinociceptive effects in the AITC-induced model and attenuate acute pain more than the reference drug benzocaine after their topical application. GABA esters of l-menthol and thymol were also shown to exceed the reference drug ibuprofen in their ability to decrease the inflammatory state induced by intraplantar injection of the TRPA1 activator AITC. The present findings indicate that GABA esters of carvacrol and guaiacol are not a classical prodrug and possess their own pharmacological activity. Prolonged antiseizure action of the ester based on the amino acid and guaiacol (200 mg/kg) was revealed at 24 h after oral administration. Furthermore, orally co-administered gidazepam (1 mg/kg) and GABA esters of l-menthol, thymol and carvacrol produce synergistic seizure prevention effects.
ABSTRACT
Analgesic activity of novel GABA esters with l-menthol (1), thymol (2), carvacrol (3) and guaiacol (4) was investigated by pharmacological models of thermal and chemical stimuli in mice after topical application in an ointment (2% w/w). The initial terpenes - l-menthol (5), thymol (6), carvacrol (7) and guaiacol (8) have also been studied under the same experimental conditions. All studied compounds were found to produce an antinociceptive effect in both thermal- and chemical-induced models of acute pain after their topical application. In the hot plate test, compound 1 demonstrated maximum analgesic activity and attenuated acute pain more than the reference drug BZC. GABA esters with l-menthol (1) and carvacrol (3), as well as l-menthol (5) itself exhibited analgesic activity which is the same or better in comparison with benzocaine in chemical-stimulated models of pain caused by either formalin or capsaicin.