Given the importance of quinazolines and quinazolinethiones in therapeutic and Food and Drug Administration (FDA)-approved molecules, we thought interesting to consider their synthesis in green solvents. We have shown that obtain 4-(arylamino)quinazoline-2-(1H)-thiones and 4-(arylamino)pteridine-2-(1H)-thiones analogues was efficient in green solvents derived from biomass, especially eucalyptol. Although reaction times are somewhat long to achieve good yields, the products were obtained by simple filtration. This considerably limited the loss of atoms due to the use of large quantities of solvents for purification on silica gel columns, and makes our route a sustainable one.

The mechanism through which gravity influences the biosynthesis of essential oils in herbs is an important issue for plant and space biology. Sweet basil (Ocimum basilicum L.) seedlings were cultivated under centrifugal hypergravity conditions at 100 g in the light, and the growth of cotyledons, development of glandular hairs, and biosynthesis of essential oils were analyzed. The area and fresh weight of the cotyledons increased by similar amounts irrespective of the gravitational conditions. On the abaxial surface of the cotyledons, glandular hairs, where essential oils are synthesized and stored, developed from those with single-cell heads to those with four-cell heads; however, hypergravity did not affect this development. The main components, methyl eugenol and 1,8-cineole, in the essential oils of cotyledons were lower in cotyledons grown under hypergravity conditions. The gene expression of enzymes in the phenylpropanoid pathway involved in the synthesis of methyl eugenol, such as phenylalanine ammonia lyase (PAL) and eugenol O-methyltransferase (EOMT), was downregulated by hypergravity. Hypergravity also decreased the gene expression of enzymes in the 2C-methyl-d-erythritol 4-phosphate (MEP) pathway involved in the synthesis of 1,8-cineole, such as 1-deoxy-d-xylulose-5-phosphate synthase (DXS) and 1,8-cineole synthase (CINS). These results indicate that hypergravity without affecting the development of glandular hairs, decreases the expression of genes related to the biosynthesis of methyl eugenol and 1,8-cineole, which may cause a decrease in the amounts of both essential oils in sweet basil cotyledons.

Loss of the inner blood-retinal barrier (BRB) integrity is a main feature of ocular diseases such as diabetic macular edema. However, there is a lack of clarity on how inner BRB function is modulated within the diabetic retina. The current study examined whether eucalyptol inhibited inner BRB destruction and aberrant retinal angiogenesis in 33 mM glucose-exposed human retinal microvascular endothelial (RVE) cells and db/db mice. This study further examined the molecular mechanisms underlying endothelial dysfunction including retinal endoplasmic reticulum (ER) stress and angiopoietin (Ang)/Tie axis in conjunction with vascular endothelial growth factor (VEGF). Eucalyptol is a naturally occurring monoterpenoid and an achiral aromatic component of many plants including eucalyptus leaves. Nontoxic eucalyptol reduced the production of amyloid-β (Aβ) protein in glucose-loaded RVE cells and in diabetic mice. This natural compound blocked apoptosis of Aβ-exposed RVE cells in diabetic mouse eyes by targeting ER stress via the inhibition of PERK-eIF2α-ATF4-CHOP signaling. Eucalyptol promoted activation of the Ang-1/Tie-2 pathway and dual inhibition of Ang-2/VEGF in Aβ-exposed RVE cells and in diabetic eyes. Supply of eucalyptol reversed the induction of junction proteins in glucose/Aβ-exposed RVE cells within the retina and reduced permeability. In addition, oral administration of eucalyptol reduced vascular leaks in diabetic retinal vessels. Taken together, these findings clearly show that eucalyptol inhibits glucose-induced Aβ-mediated ER stress and manipulates Ang signaling in diabetic retinal vessels, which ultimately blocks abnormal angiogenesis and loss of inner BRB integrity. Therefore, eucalyptol provides new treatment strategies for diabetes-associated RVE defects through modulating diverse therapeutic targets including ER stress, Ang-1/Tie-2 signaling, and Ang-2/VEGF.

Peach brown rot, attributed to Monilinia fructicola, presents a significant threat to postharvest peach cultivation, causing losses of up to 80%. With an increasing number of countries, spearheaded by the European Union, imposing bans on chemical agents in fruit production, there is a growing interest in mining highly active antibacterial compounds from biological control strains for postharvest disease management. In this study, we highlight the unique ability of Streptomyces lincolnensis strain JCP1-7 to inhibit M. fructicola sporulation, despite its limited antimicrobial efficacy. Through GC-MS analysis, eucalyptol was identified as the key compound. Fumigation of diseased fruits with eucalyptol at a concentration of 0.0335 μg cm-3 demonstrated an in vivo inhibition rate against M. fructicola of 93.13%, completely suppressing spore formation. Transcriptome analysis revealed the impact of eucalyptol on multiple pathogenesis-related pathways, particularly through the inhibition of catalase 2 (Cat2) expression. Experiments with a MfCat2 knockout strain (ΔMfCat2) showed reduced pathogenicity and sensitivity to JCP1-7 and eucalyptol, suggesting MfCat2 as a potential target of JCP1-7 and eucalyptol against M. fructicola. Our findings elucidate that eucalyptol produced by S. lincolnensis JCP1-7 inhibits M. fructicola sporulation by regulating MfCat2, thereby effectively reducing postharvest peach brown rot occurrence. The use of fumigation of eucalyptol offers insights into peach brown rot management on a large scale, thus making a significant contribution to agricultural research.

Accumulating evidence strongly support the key role of NLRP3-mediated pyroptosis in the pathogenesis and progression of vascular endothelial dysfunction associated with diabetes mellitus. Various studies have demonstrated that the activation or upregulation of Silent Information Regulation 2 homolog 2 (SIRT2) exerts inhibitory effect on the expression of NLRP3. Although 1,8-cineole has been found to protect against endothelial dysfunction and cardiovascular diseases, its role and mechanism in diabetic angiopathy remain unknown. Therefore, the aim of this study was to investigate the ameliorative effect of 1,8-cineole through SIRT2 on pyroptosis associated with diabetic angiopathy in human umbilical vein endothelial cells (HUVECs) and to elucidate the underlying mechanism. The findings revealed that 1,8-cineole exhibited a protective effect against vascular injury and ameliorated pathological alterations in the thoracic aorta of diabetic mice. Moreover, it effectively mitigated pyroptosis induced by palmitic acid-high glucose (PA-HG) in HUVECs. Treatment with 1,8-cineole effectively restored the reduced levels of SIRT2 and suppressed the elevated expression of pyroptosis-associated proteins. Additionally, our findings demonstrated the occurrence of NLRP3 deacetylation and the physical interaction between NLRP3 and SIRT2. The SIRT2 inhibitor AGK2 and siRNA-SIRT2 effectively attenuated the effect of 1,8-cineole on NLRP3 deacetylation in HUVECs and compromised its inhibitory effect against pyroptosis in HUVECs. However, overexpression of SIRT2 inhibited PA-HG-induced pyroptosis in HUVECs. 1,8-Cineole inhibited the deacetylation of NLRP3 by regulating SIRT2, thereby reducing pyroptosis in HUVECs. In conclusion, our findings suggest that PA-HG-induced pyroptosis in HUVECs plays a crucial role in the development of diabetic angiopathy, which can be mitigated by 1,8-cineole.

Naturally occurring substances and their derivatives function as vital resources for pesticides that can be used in fields, such as insecticide production and fungicide development. As a botanical entity displaying multifaceted biological functions, wormwood has received thorough scrutiny across multiple sectors. The insect repellency potency combined with antibacterial and antifungal activities of wormwood position it as a potential candidate for prospective development into eco-friendly chemical pesticides. In this research, Wormwood essential oil was procured via ethanol water under ultrasonic scenarios and subsequently diluted with PEG 400 to formulate green chemical pesticides. The defensive efficacy of this green pesticide on plants was validated through 2 weeks of clustered plant growth experiments. Active constituents that exerted their effects were scrutinized by GC-MS. Furthermore, this green pesticide also displays efficacious effects on the prevention and management of aphids, exhibiting a dose-dependent relationship. 4-terpenol, eucalyptol, carvacrol, and L-borneol were identified by GC-MS as the predominant active constituents in this green chemical pesticide. Wormwood can be leveraged to develop green chemical pesticides, which can protect plants without contaminating the environment.

The excessive and indiscriminate use of synthetic insecticides has led to environmental pollution, wildlife destruction, and adverse effects on human health, while simultaneously giving rise to resistance in insect pest populations. This adaptive trait is expressed through various mechanisms, such as changes in the cuticle, heightened activities of detoxifying enzymes, and alterations in the sites of action that reduce their affinity for insecticides. In this context, we associate variation in toxicological response with genomic variation, to identify genetic polymorphisms underlying the different steps of the insect (genotype)-response (phenotype)-insecticide (environment) interaction. Under this framework, our objective was to investigate the genetic factors involved in the toxicological response of D. melanogaster lines when exposed to citronellal and eucalyptol vapors (monoterpenes of plant origin). We quantified KT50 in adult males, representing the time necessary for half of the exposed individuals to be turned upside down (unable to walk or fly). Since the genomes of all lines used are completely sequenced, we perform a Genome Wide Association Study to analyze the genetic underpinnings of the toxicological response. Our investigation enabled the identification of 656 genetic polymorphisms and 316 candidate genes responsible for the overall phenotypic variation. Among these, 162 candidate genes (77.1%) exhibited specificity to citronellal, 45 (21.4%) were specific to eucalyptol, and 3 candidate genes (1.5%) namely CG34345, robo2, and Ac13E, were implicated in the variation for both monoterpenes. These suggest a widespread adaptability in the response to insecticides, encompassing genes influenced by monoterpenes and those orchestrating resistance to the toxicity of these compounds.

This research aimed to evaluate the antidiabetic, dermatoprotective, and antibacterial activities of Mentha viridis L. essential oil (MVEO) collected in the province of Ouezzane (Northwest Morocco). Gas chromatography-mass spectrometry (GC-MS) analysis revealed that the main constituents of MVEO were carvone (37.26 %), 1,8-cineole (11.82 %), limonene (5.27 %), α-terpineol (4.16 %), and β-caryophyllene (4.04 %). MVEO showed strong inhibitory effects on α-amylase and α-glucosidase activities, exceeding those of acarbose, but weak anti-elastase activity. The main compounds, β-caryophyllene (IC50=79.91±2.24 and 62.08±2.78 μg/mL) and limonene (IC50=90.73±3.47 and 68.98±1, 60 μg/mL), demonstrated the strongest inhibitory effects on both digestive enzymes (α-glucosidase and α-amylase, respectively). In silico investigations, using molecular docking, also showed the inhibitory potential of these bioactive compounds against the enzymes tested. In conclusion, MVEO, due to its main components such as limonene, 1,8-cineole, β-caryophyllene, carvone, and α-terpineol, shows promising prospects for drug discovery and natural therapeutic applications.

OBJECTIVE: Dysregulated platelet aggregation is a fatal condition in many bacterial- and virus-induced diseases. However, classical antithrombotics cannot completely prevent immunothrombosis, due to the unaddressed mechanisms towards inflammation. Thus, targeting platelet hyperactivation together with inflammation might provide new treatment options in diseases, characterized by immunothrombosis, such as COVID-19 and sepsis. The aim of this study was to investigate the antiaggregatory effect and mode of action of 1.8-cineole, a monoterpene derived from the essential oil of eucalyptus leaves, known for its anti-inflammatory proprieties.
METHODS: Platelet activity was monitored by measuring the expression and release of platelet activation markers, i.e., P-selectin, CD63 and CCL5, as well as platelet aggregation, upon treatment with 1.8-cineole and stimulation with several classical stimuli and bacteria. A kinase activity assay was used to elucidate the mode of action, followed by a detailed analysis of the involvement of the adenylyl-cyclase (AC)-cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA) pathway by Western blot and ELISA.
RESULTS: 1.8-cineole prevented the expression and release of platelet activation markers, as well as platelet aggregation, upon induction of aggregation with classical stimuli and immunological agonists. Mechanistically, 1.8- cineole influences the activation of the AC-cAMP-PKA pathway, leading to higher cAMP levels and vasodilator-stimulated phosphoprotein (VASP) phosphorylation. Finally, blocking the adenosine A2A receptor reversed the antithrombotic effect of 1.8-cineole.
CONCLUSIONS: Given the recognized anti-inflammatory attributes of 1.8-cineole, coupled with our findings, 1.8-cineole might emerge as a promising candidate for treating conditions marked by platelet activation and abnormal inflammation.

1,8-Cineole is a bicyclic monoterpene widely distributed in the essential oils of various medicinal plants, and it exhibits significant anti-inflammatory and antioxidant activities. We aimed to investigate the therapeutic effect of 1,8-cineole on anti-Alzheimer\'s disease by using transgenic Caenorhabditis elegans models. Our studies demonstrated that 1,8-cineole significantly relieved Aβ1-42-induced paralysis and exhibited remarkable antioxidant and anti-Aβ1-42 aggregation activities in transgenic nematodes CL4176, CL2006 and CL2355. We developed a 1,8-cineole/cyclodextrin inclusion complex, displaying enhanced anti-paralysis, anti-Aβ aggregation and antioxidant activities compared to 1,8-cineole. In addition, we found 1,8-cineole treatment activated the SKN-1/Nrf-2 pathway and induced autophagy in nematodes. Our results demonstrated the antioxidant and anti-Alzheimer\'s disease activities of 1,8-cineole, which provide a potential therapeutic approach for Alzheimer\'s disease.