Thymol Derivatives Research Articles

Two thymol derivatives from the flower buds of Lonicera japonica and their antibacterial activity

A new monoterpenoid, 7-acetyl-8,9-dihydroxy thymol (1), together with a known one 7,8-dihydroxy-9-buyryl thymol (2), were isolated from the dried flower buds of Lonicera japonica Thunb. Their structures were elucidated on the basis of extensive 1D and 2D NMR spectroscopic data analyses. The potential antibacterial effects of these compounds on Staphylococcus aureus, Escherichia coli, Micrococcus luteus, and Bacillus cereus were evaluated. Interestingly, both compounds 1 and 2 exhibited significant antibacterial activities with IC50 values range from 27.64 ± 2.26 to 128.58 ± 13.26 μg/mL.

Synthesis, biological activities and molecular docking simulation of hydrazone scaffolds of carvacrol, thymol and eugenol

In present work, we report the synthesis of 12 new hydrazones and sulfonyl hydrazones linkage containing carvacrol, thymol and eugenol derivatives by simple condensation reactions. Synthesized derivatives have been characterized by 1H NMR, 13C NMR, LC–MS, and X-ray single crystallography techniques, and these derivatives were screened for anticancer testing by using sulforhodamine B assay and anti-oxidant testing by using DPPH assay. Docking studies of all the derivatives against the active site of human heme oxygenase-1 indicated that interaction with the maximum site of the amino acid residue of human heme oxygenase-1 was crucial for anti-oxidant activity. The results show that all derivatives possess interesting biological activities.

Total Synthesis of a Dimeric Thymol Derivative Isolated from Arnica sachalinensis

AbstractThe total synthesis of a dimeric thymol derivative (thymarnicol) isolated from Arnica sachalinensis was accomplished in 6 steps. A key biomimetic Diels–Alder dimerization was found to occur at ambient temperature and the final oxidative cyclization occurs when the substrate is exposed to air and visible light. These results indicate that this natural product is likely the result of spontaneous (non‐enzyme‐mediated) reactivity.

Total Synthesis of a Dimeric Thymol Derivative Isolated from Arnica sachalinensis.

The total synthesis of a dimeric thymol derivative (thymarnicol) isolated from Arnica sachalinensis was accomplished in 6 steps. A key biomimetic Diels-Alder dimerization was found to occur at ambient temperature and the final oxidative cyclization occurs when the substrate is exposed to air and visible light. These results indicate that this natural product is likely the result of spontaneous (non-enzyme-mediated) reactivity.

Two New Thymol Derivatives from the Roots of Ageratina adenophora.

Two new thymol derivatives, 7,9-diisobutyryloxy-8-ethoxythymol (1) and 7-acetoxy-8-methoxy-9-isobutyryloxythymol (2), were isolated from fresh roots of Ageratina adenophora, together with four known compounds, 7,9-di-isobutyryloxy-8-methoxythymol (3), 9-oxoageraphorone (4), (−)-isochaminic acid (5) and (1α,6α)-10-hydroxycar-3-ene-2-one (6). Their structures were established on the basis of detailed spectroscopic analysis, and they were all isolated from the roots of A. adenophora for the first time. All the compounds were tested for their in vitro antibacterial activity toward three Gram-positive and two Gram-negative bacterial strains. Thymol derivatives 1–3 only selectively showed slight in vitro bacteriostatic activity toward three Gram-positive bacteria. The two known carene-type monoterpenes 5 and 6 were found to show moderate in vitro antibacterial activity against all five tested bacterial strains, with MIC values from 15.6 to 62.5 μg/mL. In addition, compounds 5 and 6 were further revealed to show in vitro cytotoxicity against human tumor A549, HeLa and HepG2 cell lines, with IC50 values ranging from 18.36 to 41.87 μM. However, their cytotoxic activities were inferior to those of reference compound adriamycin.

Design, synthesis, biological screenings and docking simulations of novel carvacrol and thymol derivatives containing acetohydrazone linkage

Carvacrol and thymol are well-known phenolic monoterpenoids present as functional ingredients in numerous products. Keeping the diverse therapeutic activities of phenolic monoterpenes in mind, we attempted to synthesize a new series of acetohydrazone linkage containing carvacrol and thymol derivatives. All synthesized derivatives were characterized by spectroscopic techniques. Finally, all the derivatives were screened for their anti-oxidant activities by using DPPH assay, and anticancer activities by using SRB assay against pancreatic cancer with the MIAPaCa-2 cell line and colon cancer with the HCT-15 cell line. Themolecular docking studies of all the synthesized derivatives were carried out on the cyclooxygenase-2 (COX-2) protein enzyme. In the anti-oxidant test, EC50 values of all the compounds showed excellent anti-oxidant potency, and similarly the values of GI50 in the anticancer test displayed that most of the compounds possess good anticancer potency. Total docking results suggested that all the synthesized compounds exhibit good binding affinity towards receptors.

Phyto-Fungicides: Structure Activity Relationships of the Thymol Derivatives against <i>Rhizoctonia solani</i>

Thymol, the key component of the thyme oil and its derivatives were evaluated for their structure activity relationship as fungicide against Rhizoctonia solani. Since plant-based chemicals are considered as “Generally Recognized as Safe” (GRAS) chemicals, there is great potential to use those and synthetic derivatives against R. solani and other fungal pathogens, in vitro, and in the greenhouse or field conditions. Among the six thymol derivatives evaluated, thymol acetate was considered as the most suitable commercially viable plant-based fungicide due to its superior efficacy as well as lowest residue.

Synthesis and Antibacterial Study of Thymol Derivatives

Synthesis and Antibacterial Study of Thymol Derivatives

Synthesis, anticholinesterase activity and molecular modeling study of novel carbamate-substituted thymol/carvacrol derivatives

New thymol and carvacrol derivatives with the carbamate moiety were synthesized and their inhibitory effects on acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) were evaluated. 5-isopropyl-2-methylphenyl(3-fluorophenyl)carbamate (29) was found to be the most potent AChE inhibitor with IC50 values of 2.22μM, and 5-isopropyl-2-methylphenyl (4-fluorophenyl)carbamate (30) exhibited the strongest inhibition against BuChE with IC50 value of 0.02μM. Additionally, the result of H4IIE hepatoma cell toxicity assay for compounds 18, 20, 29, 30 and 35 showed negligible cell death at 0.07–10μM. Moreover in order to better understand the inhibitory profiles of these molecules, molecular modeling studies were applied. Binding poses of studied compounds at the binding pockets of AChE and BuChE targets were determined. Predicted binding energies of these compounds as well as structural and dynamical profiles of molecules at the target sites were estimated using induced fit docking (IFD) algorithms and post-processing molecular dynamics (MD) simulations methods (i.e., Molecular mechanics Poisson–Boltzmann surface area (MM-PBSA) approaches).

Further Thymol Derivatives from Ageratina cylindrica.

From the leaves of Ageratina cylindrica, in addition to the described [(2S)-2-{4-formyl-5-hydroxy-2-[(2-methylpropanoyl)oxy]phenyl}oxiran-2-yl]methyl benzoate (cylindrinol A, 8), seven new thymol derivatives were isolated and named cylindrinols B - H (1 - 7). The structures of these compounds were established as (2-{4-(hydroxymethyl)-2-[(2-methylpropanoyl)oxy]phenyl}oxiran-2-yl)methyl benzoate (1), (2-{4-formyl-2-[(2-methylpropanoyl)oxy]phenyl}oxiran-2-yl)methyl benzoate (2), (2-{4-[(acetyloxy)methyl]-2-[(2-methylpropanoyl)oxy]phenyl}oxiran-2-yl)methyl benzoate (3), [2-(2-[(2-methylpropanoyl)oxy]-4-{[(2-methylpropanoyl)oxy]methyl}phenyl)oxiran-2-yl]methyl benzoate (4), [2-(5-hydroxy-2-[(2-methylpropanoyl)oxy]-4-{[(2-methylpropanoyl)oxy]methyl}phenyl)oxiran-2-yl]methyl benzoate (5), 2-{4-(hydroxymethyl)-2-[(2-methylpropanoyl)oxy]phenyl}prop-2-en-1-yl benzoate (6), and 2-hydroxy-2-[2-hydroxy-4-(hydroxymethyl)-phenyl]-3-[(2-methylpropanoyl)oxy]propyl benzoate (7), by spectroscopic means. Compounds 1 showed moderate antiprotozoal activity on both protozoa. Compounds 4 and 5 showed selectivity on Giardia lamblia trophozoites. All isolated compounds were less active than two antiprotozoal drugs, metronidazole and emetine, used as positive controls. Compound 5 exhibited a high inhibitory effect on hyperpropulsive movement of the small intestine in rats; its effect was best than loperamide, antidiarrheal drug used as a positive control.

Antidiarrheal Thymol Derivatives from Ageratina glabrata. Structure and Absolute Configuration of 10-Benzoyloxy-8,9-epoxy-6-hydroxythymol Isobutyrate.

Chemical investigation of the leaves from Ageratina glabrata yielded four new thymol derivatives, namely: 10-benzoyloxy-8,9-dehydro-6-hydroxythymol isobutyrate (4), 10-benzoyloxy-8,9-dehydrothymol (5), 10-benzoyloxythymol (6) and 10-benzoyloxy-6,8-dihydroxy-9-isobutyryl-oxythymol (7). In addition, (8S)-10-benzoyloxy-8,9-epoxy-6-hydroxythymol isobutyrate (1), together with other two already known thymol derivatives identified as 10-benzoyloxy-8,9-epoxy-6-methoxythymol isobutyrate (2) and 10-benzoyloxy-8,9-epoxythymol isobutyrate (3) were also obtained. In this paper, we report the structures and complete assignments of the 1H and 13C-NMR data of compounds 1–7, and the absolute configuration for compound 1, unambiguously established by single crystal X-ray diffraction, and evaluation of the Flack parameter. The in vitro antiprotozoal assay showed that compound 1 and its derivative 1a were the most potent antiamoebic and antigiardial compounds. Both compounds showed selectivity and good antiamoebic activity comparable to emetine and metronidazole, respectively, two antiprotozoal drugs used as positive controls. In relation to anti-propulsive effect, compound 1 and 1a showed inhibitory activity, with activities comparable to quercetin and compound 9, two natural antipropulsive compounds used as positive controls. These data suggest that compound 1 may play an important role in antidiarrheal properties of Ageratina glabrata.

Investigation of antibacterial activity of new classes of essential oils derivatives

Essential oils (EOs) have deserved much attention in the past decades for their antimicrobial activity, since many of them have demonstrated efficacy against food-borne pathogenic and spoilage microorganisms. Moreover, they have potential application in animal nutrition as multifunctional feed supplements, avoiding or diminishing the use of antibiotics in livestock. However, low solubility and bioavailability as well as volatility and marked aromatic note are important limitations in food and feed applications. In this study we present the synthesis, characterization and evaluation of the antibacterial activity of new thymol, carvacrol and menthol derivatives. The new compounds have been designed to overcome the limitations of the precursors, such as poor water solubility and volatility, still maintaining a good antimicrobial profile. We evaluated the activity of the synthetized compounds against pathogens causing important foodborne diseases, i.e. Clostridium perfringens, Salmonella typhimurium, Salmonella enteritidis and Escherichia coli. The low MICs and MBCs values for some of the studied compounds, combined with water solubility and negligible cytotoxicity towards HT-29 human cells, confirmed the potential use for EOs derivatives in the food industry.

Bioactive Secondary Metabolites from Schizogynesericea (Asteraceae) Endemic to Canary Islands.

Schizogynesericea (Asteraceae) is a halophytic shrub endemic to the Canary Islands and traditionally employed as analgesic, astringent, anti-inflammatory, and vulnerary. A comprehensive phytochemical investigation was conducted on the flowering aerial parts by analyzing both essential oil constituents and polar compounds. The essential oil was dominated by p-cymene, with the noteworthy occurrence of β-pinene and thymol esters. From the EtOH extract, eight compounds were isolated and structurally elucidated. Essential oil, polar fractions, and isolates (2), (4), and (5) were separately invitro assayed for antiproliferative activity on human tumor cell lines (A375, MDA-MB 231, and HCT116) by MTT assay, for antioxidant potential by DPPH, ABTS, and FRAP assays, and for antimicrobial activity by the agar disk diffusion method. Results revealed that essential oil and compounds 1 and 2 exert a strong inhibition on tumor cells, and in some cases, higher than that of cisplatin. Fractions containing thymol derivatives (1 and 2) and caffeoylquinic acid derivatives 4 and 5 displayed antioxidant activity comparable to that of Trolox, making S.sericea extract an interesting natural product with potential applications as preservative or in the treatment of diseases in which oxidative stress plays an important role.

In vitro and in vivo mechanism of immunomodulatory and antiviral activity of Edible Bird's Nest (EBN) against influenza A virus (IAV) infection

Ethnopharmacological relevanceFor centuries, Edible Bird Nest (EBN) has been used in treatment of variety of respiratory diseases such as flu and cough as a Chinese natural medicine. Aim of the studyThis natural remedy showed the potential to inhibit influenza A virus (IAV). However, little is known about the mechanism of this process and also the evaluation of this product in an animal model. Hence, the current study was designed to elucidate the antiviral and immunomodulatory effects of EBN against IAV strain A/Puerto Rico/8/1934 (H1N1). Materials and methodsFirst, influenza infected MDCK cells treated with EBNs from two locations of Malaysia (Teluk Intan and Gua Madai) that prepared with different enzymatic preparations were analyzed by RT-qPCR and ELISA for detection of viral and cytokines genes. The sialic acid composition of these EBNs was evaluated by H-NMR. Subsequently, after toxicity evaluation of EBN from Teluk Intan, antiviral and immunomodulatory effects of this natural product was evaluated in BALB/c mice by analysis of the viral NA gene and cytokine expressions in the first week of the infection. ResultsEBN showed high neuraminidase inhibitory properties in both in vitro and in vivo, which was as effective as Oseltamivir phosphate. In addition, EBN decreased NS1 copy number (p<0.05) of the virus along with high immunomodulatory effects against IAV. Some of the immune changes during treatment of IAV with EBN included significant increase in IFNγ, TNFα, NFκB, IL2, some proinflammatory cytokines like IL1β, IL6, and cytokines with regulatory properties like IL10, IL27, IL12, CCL2 and IL4 depends on the stage of the infection. EBNs from two locations contained different composition of sialic acid and thymol derivatives, which gave them different antiviral properties. EBN from Gua Madai that contained more acetylated sialic acid (Neu2,4,7,8,9 Ac6) showed higher antiviral activity. ConclusionThe findings of this study support the antiviral activity of EBN against influenza virus and validate the traditional usage of this natural remedy by elucidation of toxicity and the molecular mechanism of action.

Chemical analysis of the essential oils from Schizogyne sericea growing in different areas of Tenerife (Spain)

Schizogyne sericea, also known as ‘salado’, is a halophytic species widespread throughout all the Canary Islands (Spain), being more common in Tenerife and Gran Canaria. The plant has been traditionally used as analgesic, astringent, anti-inflammatory and vulnerary. The aim of this work was to investigate the chemical variability in the volatile profiles obtained from the flowering aerial parts of S. sericea harvested in different localities (Palm Mar, Los Roques and La Barranquera) of Tenerife characterized by different microclimates. For the purpose, the essential oils were hydrodistilled from the dried aerial parts by a Clevenger-type apparatus and analysed by GC–MS. A similar chemical composition for the essential oil samples from the different geographic areas was obtained. The aromatic monoterpene hydrocarbon p-cymene (43.0–57.0%) was by far the main component of the essential oils, with minor amounts of isobornyl acetate (4.5–11.0%), limonene (4.7–5.6%), β-pinene (0.7–5.3%), α-phellandrene (2.2–4.8%) and camphene (1.8–4.5%). Interesting to note was the occurrence of thymol derivatives. That may be considered important chemotaxonomic markers of the genus Schizogyne, and, more in general, of the tribe Inulae. The volatile chemical profile obtained for S. sericea was similar to that of Schizogyne glaberrima previously studied.

Structural revision of aristol: a fresh look at the oxidative coupling of thymol under iodination conditions

Aristol represents a complex mixture of products of oxidative coupling of iodothymols and monomeric iodinated thymol derivatives.

THYMOL ESTER OF GAMMA-AMINOBUTYRIC ACID: SYNTHESIS AND ANTICONVULSANT ACTIVITY

Thymol ester of gamma-aminobutyric acid (GABA) − 2-isopropyl-5-methylphenyl 4-aminobutyrate hydrochloride − was synthesized via Steglich esterification and characterized by 1H NMR, IR and mass spectral studies. The anticonvulsant activity of obtained compound was estimated over a wide range of doses 5-80 mg/kg by determining the minimum effective doses of pentylenetetrazole inducing clonic-tonic convulsions and tonic extension. Present findings indicate that thymol ester of GABA is not a classical prodrug and possesses its own pharmacological activity. Prolonged antiseizure action of thymol derivative (20 mg/kg) was revealed at 24 hours after oral administration. Furthermore, orally co-administered gidazepam (1 mg/kg) and thymol ester of GABA (20 mg/kg) produce synergistic effect in seizures prevention.

Systematic evaluation of thymol derivatives possessing stereogenic or prostereogenic centers

Thymol (2-isopropyl-5-methylphenol) is an aromatic molecule typically distributed in the genera Thymus and Origanum, which possesses both pharmacological and industrial relevance. This review highlights thymol derivatives with a stereogenic or prostereogenic center, which are distributed in 42 genera of the Asteraceae family whose chemotaxonomy is also outlined. In order to achieve a systematic analysis, which includes a structural examination and accounts for the vegetal sources, the reviewed thymol derivatives were grouped into mono-, di-, and multisubstituted compounds. According to the substitution on the aromatic ring, as well as on the isopropyl residue, and considering the functional groups, an evaluation of the 1H NMR signals, including multiplicities, was carried out. Optical activity data compilation of thymol derivatives revealed that 21 molecules show no optical activity in spite of having a stereogenic center, while two groups of 16 and 15 compounds exhibit, respectively, levorotatory and dextrorotatory optical activity. In addition, two thymol derivatives showed different optical behavior depending on the vegetal source, and only in a single case, the absolute configuration of a thymol derivative is known. Some 10 % of the known functionalized thymol derivatives have been evaluated biologically as antibacterial, anti-inflammatory, antiprotozoal, antioxidant, cytotoxic, piscicidal or allelopathic agents, being the last biological activity the most assayed one.

ChemInform Abstract: New Thymol Derivatives and Cytotoxic Constituents from the Root of Eupatorium cannabinum ssp. asiaticum.

Abstractisolation, structure elucidation and cytotoxic activities of two new thymol derivatives, (I) and (II), along with six known compounds

Quantitative analysis of sesquiterpene lactones and thymol derivatives in extracts from Telekia speciosa

A high-performance liquid chromatographic method based on a gradient elution and the application of core–shell type stationary phase was developed to estimate contents of sesquiterpene lactones and monoterpenoid thymol derivatives in the tissues of Telekia speciosa. The detection and quantification limits of the analytes were 0.05–0.29μgml−1 and 0.15–0.89μgml−1, respectively. Calibration curves showed good linearities (R2>0.9996) within the test ranges. Intra-day and inter-day precisions were satisfactory with RSD<2.6%. The recoveries of the standards tested ranged from 96 to 107%. The overall time of analysis was less than 35min. Using the method, seven major sesquiterpene lactones and one thymol derivative were quantified in different organs of the plant and plants of different origin. Aerial parts of T. speciosa accumulated miscellaneous sesquiterpene lactones, mainly of guaiane, pseudoguaiane, xanthane and eudesmane type, whereas roots of the plant contained almost exclusively isoalantolactone – an eudesmanolide of antiproliferative and anti-inflammatory activity (up to 1.2% dry weight). Flowers of T. speciosa proved to be an excellent source of xanthanolide – 8-epi-tomentosin (0.16–0.94%). Provenience of the plant material strongly influenced its biosynthetic potential.