Profiles, exposure assessment and expanded screening of PAHs and their derivatives in one petroleum refinery facility of China.

This study investigated environmental distribution and human exposure of polycyclic aromatic hydrocarbons (PAHs) and their derivatives in one Chinese petroleum refinery facility. It was found that, following with high concentrations of 16 EPA PAHs (∑Parent-PAHs) in smelting subarea of studied petroleum refinery facility, total derivatives of PAHs [named as XPAHs, including nitro PAHs (NPAHs), chlorinated PAHs (Cl-PAHs), and brominated PAHs (Br-PAHs)] in gas (mean= 1.57 × 104 ng/m3), total suspended particulate (TSP) (mean= 4.33 × 103 ng/m3) and soil (mean= 4.37 × 103 ng/g) in this subarea had 1.76-6.19 times higher levels than those from other subareas of this facility, surrounding residential areas and reference areas, indicating that petroleum refining processes would lead apparent derivation of PAHs. Especially, compared with those in residential and reference areas, gas samples in the petrochemical areas had higher ∑NPAH/∑PAHs (mean=2.18), but lower ∑Cl-PAH/∑PAHs (mean=1.43 × 10-1) and ∑Br-PAH/∑PAHs ratios (mean=7.49 × 10-2), indicating the richer nitrification of PAHs than chlorination during petrochemical process. The occupational exposure to PAHs and XPAHs in this petroleum refinery facility were 24-343 times higher than non-occupational exposure, and the ILCR (1.04 × 10-4) for petrochemical workers was considered to be potential high risk. Furthermore, one expanded high-resolution screening through GC Orbitrap/MS was performed for soils from petrochemical area, and another 35 PAHs were found, including alkyl-PAHs, phenyl-PAHs and other species, indicating that profiles and risks of PAHs analogs in petrochemical areas deserve further expanded investigation.

A near-infrared ratiometric fluorescent probe for the sensing and imaging of sulfur dioxide derivatives in living systems.

As a reactive sulfur species, sulfur dioxide (SO2) and its derivatives play crucial role in various physiological processes, which can maintain redox homeostasis at normal levels and lead to the occurrence of many diseases at abnormal levels. So, the development of a suitable fluorescent probe is a crucial step in advancing our understanding of the role of SO2 derivatives in living organisms. Herein, we developed a near-infrared fluorescent probe (SP) based on the ICT mechanism to monitor SO2 derivatives in living organisms in a ratiometric manner. The probe SP exhibited excellent selectivity, good sensitivity, fast response rate (within 50 s), and low detection limit (1.79 µM). In addition, the cell experiment results suggested that the SP has been successfully employed for the real-time monitoring of endogenous and exogenous SO2 derivatives with negligible cytotoxicity. Moreover, SP was effective in detecting SO2 derivatives in mice.

Evaluation of perioperative pachymetry of thin corneas during corneal crosslinking using hypo-osmolar riboflavin and hydroxypropyl methylcellulose

ABSTRACT Purpose: This study aimed to analyze variations in intraoperative corneal thickness during corneal cross-linking in patients with keratoconus and to investigate its possible correlation with presurgical maximal keratometry (Kmax) and pachymetry. Methods: This was a prospective case series. We used a method similar to the Dresden protocol, with the application of hydroxypropyl methylcellulose 0.1% hypo-osmolar riboflavin in corneas between 330 and 400 µm after epithelium removal. Corneal thickness was measured using portable calipers before and immediately after epithelium removal, and 30 and 60 min after the procedure. Results: The 30 patients in this study were followed up for one year. A statistically significant difference was observed in pachymetry values during the intraoperative period (p<0.0001) and an increase of 3.05 µm (95%C1: 0.56-5.54) for each diopter was seen after epithelium removal (p0.019). We found an average Kmax difference of —2.12 D between men and women (p0.013). One year after treatment, there was a statistically significant reduction in pachymetry (p<0.0001) and Kmax (p0.0170) values. Conclusions: A significant increase in pachymetry measurements was seen during the procedure, and most patients showed a regression in Kmax and pachymetry values one year after surgery.

Novel quinoline-4-carboxamide derivatives potentiates apoptosis by targeting PDK1 to overcome chemo-resistance in colorectal cancer: Theoretical and experimental results.

A series of novel N,2-diphenyl-6-(aryl/heteroaryl)quinoline-4-carboxamide derivatives were designed and synthesized using the Suzuki coupling reaction and evaluated them for their anticancer activity. These compounds were screened for anti-colon cancer activity through in-silico studies by molecular docking and molecular dynamics studies. Furthermore, the density functional theory was used to determine the molecule's electrical properties. The molecular electrostatic potential map is used to evaluate the charge distribution on the molecule surface. Unveiling that the compound 7a (binding energy of -10.2 kcal/mol) has good inhibition activity compared to other synthesized compounds (7b-7j) as well as the standard drug Gefitinib. The stability of the compound 7a with the 1OKY protein was confirmed through molecular dynamics simulation studies, indicating potential anti-colon cancer activity against phosphoinositide dependent protein kinase-1 (PDK1). The in-silico ADMET pharmacokinetic properties indicate adherence to Lipinski's rule of five for favorable safety profiles and the compound falls within the optimal range for physicochemical and pharmacokinetic properties, which is comparable to that of the standard medication drug Gefitinib. The synthesized library of compounds was further evaluated for their in-vitro anticancer potency against colon, pancreatic and breast cancer cells. The results demonstrated that the compounds effectively suppressed the proliferative potential of the screened cells in a concentration-dependent manner, as revealed by MTT assay. The anticancer potential of these molecules was further evaluated by acridine orange/PI, and Hoechst/PI which demonstrates the potential of molecules to induce apoptosis in cancer cells. Further investigations and optimization of these derivatives could lead to the development of effective anticancer strategies.

Discovery of anti-infective compounds against Mycobacterium marinum after biotransformation of simple natural stilbenes by a fungal secretome.

Introduction: Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis, remains a serious threat to human health worldwide and the quest for new anti-tubercular drugs is an enduring and demanding journey. Natural products (NPs) have played a significant role in advancing drug therapy of infectious diseases. Methods: This study evaluated the suitability of a high-throughput infection system composed of the host amoeba Dictyostelium discoideum (Dd) and Mycobacterium marinum (Mm), a close relative of Mtb, to identify anti-infective compounds. Growth of Dd and intracellular Mm were quantified by using luminescence and fluorescence readouts in phenotypic assays. The system was first benchmarked with a set of therapeutic anti-Mtb antibiotics and then used to screen a library of biotransformed stilbenes. Results: The study confirmed both efficacy of established antibiotics such as rifampicin and bedaquiline, with activities below defined anti-mycobacterium susceptibility breakpoints, and the lack of activity of pyrazinamide against Mm. The screening revealed the promising anti-infective activities of trans-δ-viniferins and in particular of two compounds 17 and 19 with an IC50 of 18.1 µM, 9 µM, respectively. Both compounds had no activity on Mm in broth. Subsequent exploration via halogenation and structure-activity relationship studies led to the identification of derivatives with improved selectivity and potency. The modes of action of the anti-infective compounds may involve inhibition of mycobacterial virulence factors or boosting of host defense. Discussion: The study highlights the potential of biotransformation and NP-inspired derivatization approaches for drug discovery and underscores the utility of the Dd-Mm infection system in identifying novel anti-infective compounds.

Identification of nitrile-containing isoquinoline-related natural product derivatives as coronavirus entry inhibitors in silico and in vitro.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused millions of infections and deaths worldwide since its emergence in Wuhan, China, in late 2019. Natural product inhibitors targeting the interaction between the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein and human angiotensin-converting enzyme 2 (ACE2), crucial for viral attachment and cellular entry, are of significant interest as potential antiviral agents. In this study a library of nitrile- and sulfur-containing natural product derived compounds were used for virtual drug screening against the RBD of the SARS-CoV-2 spike protein. The top 18 compounds from docking were tested for their efficacy to inhibit virus entry. In vitro experiments revealed that compounds 9, 14, and 15 inhibited SARS-CoV-2 pseudovirus and live virus entry in HEK-ACE2 and Vero E6 host cells at low micromolar IC50 values. Cell viability assays showed these compounds exerted low cytotoxicity towards MRC5, Vero E6, and HEK-ACE2 cell lines. Microscale thermophoresis revealed all three compounds strongly bound to the RBDs of SARS-CoV-2, SARS-CoV-2 XBB, SARS-CoV-1, MERS-CoV, and HCoV-HKU1, with their Kd values increasing as RBD sequence similarity decreased. Molecular docking studies indicated compounds 9, 14, and 15 bound to the SARS-CoV-2 spike protein RBD and interacted with hotspot amino acid residues required for the RBD-ACE2 interaction and cellular infection. These three nitrile-containing candidates, particularly compound 15, should be considered for further development as potential pan-coronavirus entry inhibitors.

Sm(â ¢), Gd(â ¢), and Eu(â ¢) complexes with 8-hydroxyquinoline derivatives as potential anticancer agents via inhibiting cell proliferation, blocking cell cycle, and inducing apoptosis in NCI-H460 cells.

Four lanthanide complexes with 8-hydroxyquinoline-2-aldehyde-2-hydrazinopyridine (H-L1), 8-hydroxyquinoline-2-aldehyde-2-hydrazimidazole (H-L2): [Sm(L1)2][Sm(L1)(NO3)3]·CHCl3·2CH3OH (1), [Gd(L1)2][Gd(L1)(NO3)3]·CHCl3·2CH3OH (2), [Sm(L2)(NO3)2]2·CH3OH (3), and [Eu(L2)(NO3)2]2·CH3OH (4) were synthesized and characterized. In vitro cytotoxicity evaluation showed that the ligands and four lanthanide complexes exhibited cytotoxicity to the five tested tumor cell lines. Among them, complex 1 showed the best antiproliferative activity against NCI-H460 tumor cells. Mechanistic studies demonstrated that complex 1 arrested the cell cycle of NCI-H460 cells in G1 phase and induced mitochondria-mediated apoptosis, which resulted in the loss of mitochondrial membrane potential, enhanced intracellular Ca2+ levels and reactive oxygen species generation. In addition, complex 1 affected the expression levels of intracellular apoptosis-related proteins and activated the caspase-3/9 in NCI-H460 cells. Therefore, complex 1 is a potential anticancer agent.

Design, synthesis and biological evaluation of indazole derivatives as VEGFR-2 kinase inhibitors with anti-angiogenic properties.

The strategy of inhibiting angiogenesis, specifically by targeting vascular endothelial growth factor receptor 2 (VEGFR-2), has been proven effective in tumor treatment. In this study, we designed several VEGFR-2 kinase inhibitors based on an indazole scaffold. Among them, the most potent compound, 30, inhibits VEGFR-2 (IC50 = 1.24 nM) with subtle selectivity over other kinases. It demonstrates significant inhibitory activity against HUVEC angiogenesis and inhibits cell migration in a dose-dependent manner. Additionally, it exhibits low acute toxicity in mice. In vivo studies, compound 30 demonstrates favorable pharmacokinetic profiles. It suppresses tumor angiogenesis in the zebrafish subintestinal vessel model, indicating that it may be a potential angiogenesis inhibitor for further development.

A novel fluorescent probe based on coumarin derivatives-grafted cellulose for specific detection of Fe3+ and its application.

Fe3+ is one of the most important ions for maintaining the normal growth of plants and animals. However, imbalance and accumulation of Fe3+ can lead to serious damage to the environmental system. Hence, it is considerably crucial to monitor the concentration of Fe3+. In this paper, a high-performance fluorescent probe CA-NCC for specifically detecting Fe3+ was obtained by grafting cellulose acetate (CA) with coumarin derivative (NCC). The resulted probe displayed a bright blue fluorescence in THF solution and showed a distinct "turn-off" fluorescence response to Fe3+, while the small molecule compound NCC could not realize the detection of Fe3+. CA-NCC displayed excellent response performance to Fe3+ including excellent selectivity and sensitivity, rapid reaction time (2.5 min), wide pH detection range (6-11), and low detection limit (0.178 µM). More importantly, CA-NCC was successfully fabricated into fluorescent film based on the good processability of cellulose acetate, and achieved highly selective recognition of Fe3+ from various metal ions.

A Carbazole-based Fluorescent Probe with AIE Performance and a Large Stokes Shift for Peroxynitrite Detection and Imaging in Live Cells.

A carbazole-based fluorescent probe YCN with AIE performance and a large Stokes shift (242 nm) shift was synthesized by attaching 4-acetonitrile pyridine to the 3-phenylaldehyde butylcarbazole. Its structure was characterized by 1H NMR, 13C NMR and MS. Probe YCN has high selectivity and sensitivity toward ONOO-. The addition of ONOO- to the probe YCN solution results in a noticeable color change from pale yellow to colorless under natural light, and a fluorescent color change from bright orange-yellow to bright yellow-green under a 365 nm UV lamp, which can be distinguished by the naked eye. The research results on the reaction mechanism showed that when YCN reacted with ONOO-, -C = C- was oxidized and broken into -CHO, and the ICT effect was significantly inhibited, resulting in changes in UV absorption and fluorescence emission phenomenon. The recognition mechanism was verified by 1H NMR, mass spectrometry (MS) and density function theory (DFT) calculations. The experiments of live cells imaging suggested that compound YCN can be used as a fluorescent probe for the detection of ONOO- in HeLa cells. This result indicates that YCN has potential application prospects in the biological aspects.

Exploring the Role of Excited States' Degeneracy on Vibronic Coupling with Atomic-Scale Optics.

Interactions between molecular electronic and vibrational states manifest themselves in a variety of forms and have a strong impact on molecular physics and chemistry. For example, the efficiency of energy transfer between organic molecules, ubiquitous in biological systems and in organic optoelectronics, is strongly influenced by vibronic coupling. Using an approach based on scanning tunneling microscope-induced luminescence (STML), we reveal vibronic interactions in optical spectra of a series of single phthalocyanine derivative molecules featuring degenerate or near-degenerate excited states. Based on detailed theoretical simulations, we disentangle spectroscopic signatures belonging to Franck-Condon and Herzberg-Teller vibronic progressions in tip-position-resolved STML spectra, and we directly map out the vibronic coupling between the close-lying excited states of the molecules.

Biomimetic Multi-Interface Design of Raspberry-like Absorbent: Gd-doped FeNi3@Covalent Organic Framework Derivatives for Efficient Electromagnetic Attenuation.

Structural design and interface regulation are useful strategies for achieving strong electromagnetic wave absorption (EMWA) and broad effective absorption bandwidth (EAB). Herein, a monomer-mediated strategy is employed to control the growth of covalent organic framework (COF) wrapping flower-shaped Gd-doped FeNi3 (GFN), and a novel raspberry-like absorbent based on biomimetic design is fabricated by thermal catalysis. Further, a unique dielectric-magnetic synergistic system is constructed by utilizing the COF-derived nitrogen-doped porous carbon (NPC) as the shell and anisotropic GFN as the core. The electromagnetic parameters of the GFN@NPC composites can be tuned by adjusting the proportions of GFN and NPC. Off-axis electron holography results further clarify the interface polarization and microscale magnetic interactions affecting the EMW loss mechanism. As a result, the GFN@NPC samples exhibit broad EMWA performance. The EAB values of all GFN@NPC composites reach up to 6.0 GHz, with the GFN@NPC-2 sample showing a minimum reflection loss (RLmin) of -69.6 dB at 1.68 mm. In addition, GFN@NPC-2 achieves a maximum radar cross-section (RCS) reduction of 29.75 dB·m2. A multi-layer gradient structure is also constructed using metamaterial simulation to achieve an ultra-wide EAB of 12.24 GHz. Overall, this work provides a novel bio-inspired design strategy to develop high-performance EMWA materials.

Downregulation of chemokine (C­C motif) ligand 5 induced by a novel 8­hydroxyquinoline derivative (91b1) suppresses tumor invasiveness in esophageal carcinoma.

Esophageal squamous cell carcinoma (ESCC) is a particularly aggressive form of cancer with high mortality. In the present study, a novel 8­hydroxyquinoline derivative (91b1) was investigated for its anticancer activities in ESCC along with its associated mechanisms. The in vitro cytotoxic effect of 91b1 were evaluated across five ESCC cell lines using MTS assay, with cisplatin serving as a comparative standard. Changes in gene expression profile were identified by cDNA microarray and further validated by qualitative PCR and immunostaining. Additionally, protein levels of the most notably downregulated target in archival ESCC samples were also studied. 91b1 demonstrated comparable anticancer effect with cisplatin. Notably, chemokine ligand 5 (Ccl5) was identified as the most substantially downregulated gene, with its suppression at both mRNA and protein expression in ESCC cells, exhibiting a dose­dependent manner. The recombinant human protein of CCL5 enhanced the invasion of ESCC cells using the Transwell assay. The upregulation of CCL5 protein was also detected in 50% of ESCC cell lines. CCL5 was also overexpressed in 76.9% of ESCC specimens. The overall results indicated that 91b1 could effectively induce anticancer effect on ESCC cells through downregulating CCL5 expression with suppression of tumor invasion. Overall, these findings suggested that 91b1 effectively inhibited ESCC cell proliferation and tumor invasion by downregulating CCL5 expression, highlighting its potential as a therapeutic agent for ESCC treatment.

A Novel Lactam and Two Rare Mycophenolic Acid Derivatives from the Fungus Penicillium sclerotiorum JBHL321.

A novel lactam penicillactam (1), two rare mycophenolic acid (MPA) derivatives penimycophens A and B (2 and 3), together with two known biogenetically related MPA derivatives (4 and 5) and a known alkaloid (6) were isolated from the Penicillium sclerotiorum JBHL321. The structures of these compounds were determined by comprehensive spectroscopic analyses. The absolute configuration of 1 was confirmed by electronic circular dichroism (ECD) calculations. Compound 1 represent the rare example of a oxygen bridge-linked lactam from natural products. Structurally, compounds 2 and 3 were rare MPA derivatives featuring a methoxy group at C-3. The inhibitory activity of compounds 1-6 against two phytopathogenic fungi, three phytopathogenic bacteria and four cancer cell lines were evaluated. Compounds 2-5 exhibited significant cytotoxic activity against HeLa, MCF-7, A549 and MGC-803 cells with IC50 values in the low micromolar to nanomolar. Compound 3 exhibited especially cytotoxic activity against four different cell lines with IC50 values ranging from 0.06 to 0.14 µM, compared to IC50 values ranging from 0.62 to 2.51 µM for epirubicin.

[Cytotoxicity Studies of 5-Arylaminouracil Derivatives].

We have previously shown that 5-arylaminouracil derivatives can inhibit HIV-1, herpesviruses, mycobacteria, and other pathogens through various mechanisms. The purpose of this study was to evaluate the potential of 5-arylaminouracils and their derivatives against leukemia, neuroblastoma, and glial brain tumors. 5-Aminouracils with various substituents and their 5'-norcabocyclic and ribo derivatives were screened for cytotoxicity against two neuroblastoma cell lines (SH-SY5Y and IMR-32), K-562 lymphoblastic cells, HL-60 promyeoloblastic cells, and low-passage variants of well-differentiated glioblastoma multiforme (GBM5522 and GBM6138). Cytotoxicity assessment by the standard MTT test showed that most of the compounds lack significant toxicity towards the above cells. However, 5-(4-isopropylphenylamine)uracil and 5-(4-tert-butylphenylamine)uracil exhibited a dose-dependent toxic effect towards the GBM6138 cell line with half-maximal inhibitory concentrations (IC50) of 9 and 2.3 µÐœ, respectively. Antitumor activity was for the first time demonstrated for compounds of this type and can serve as a starting point for further research.

Engineering Plant Metabolism for Synthesizing Amino Acid Derivatives of Animal Origin Using a Synthetic Modular Approach.

The biosynthesis of amino acid derivatives of animal origin in plants represents a promising frontier in synthetic biology, offering a sustainable and eco-friendly approach to enhancing the nutritional value of plant-based diets. This study leverages the versatile capabilities of Nicotiana benthamiana as a transient expression system to test a synthetic modular framework for the production of creatine, carnosine, and taurine-compounds typically absent in plants but essential for human health. By designing and stacking specialized synthetic modules, we successfully redirected the plant metabolic flux toward the synthesis of these amino acid derivatives of animal origin. Our results revealed the expression of a standalone creatine module resulted in the production of 2.3 µg/g fresh weight of creatine in N. benthamiana leaves. Integrating two modules significantly carnosine yield increased by 3.8-fold and minimized the impact on plant amino acid metabolism compared to individual module application. Unexpectedly, introducing the taurine module caused a feedback-like inhibition of plant cysteine biosynthesis, revealing complex metabolic adjustments that can occur when introducing foreign pathways. Our findings underline the potential for employing plants as biofactories for the sustainable production of essential nutrients of animal origin.

Molecular Docking, Pharmacophore Modeling, and ADMET Prediction of Novel Heterocyclic Leads as Glucokinase Activators.

BACKGROUND: A pivotal impetus has driven the development of numerous small molecules aiming to improve therapeutic strategies for type 2 diabetes. Glucokinase (GK) activation has been offered a new realm of therapeutic antidiabetic activity with novel heter-ocyclic derivatives. In the context of antidiabetic drug design, GK is an interesting and newly validated target. A key enzyme needed for blood glucose homeostasis is Glucokinase, which is dysfunctional in individuals with type 2 diabetes. Heterocyclic derivatives are utilized in this innovative approach to activate GK enzymes as medicinal agents that will significantly improve type 2 diabetes management. OBJECTIVE: To address type 2 diabetes, as well as minimize unwanted side effects, this research endeavor aimed to develop activators of glucokinase. METHODS: A rigorous scrutiny was conducted of the Maybridge online repository, which houses a formidable collection of 53,000 lead compounds. A collection of 125 compounds that contain the thiazolidinedione core was selected from this extensive collection. The struc-tures were generated using ChemDraw 2D, stabilized conformation with ChemBioDraw Ul-tra, and docked using Auto Dock Vina 1.5.6 in this methodology. In addition, log P was pre-dicted online using the Swiss ADME algorithm. The PKCSM software was used to predict the toxicity of the leading compounds. RESULTS: The highest binding affinity was found for AS72 and AS108 to GK receptors. GI absorption and excretion of these compounds were efficient due to Lipinski's Rule of Five compliance. When compared with the standard drugs Dorzagliatin (GKA) and MRK (co-crys-tallized ligand), these substances demonstrated a notable lack of AMES toxicity, skin sensiti-zation, and hepatotoxicity. CONCLUSION: In recent studies, lead molecules that possess enhanced pharmacokinetic profiles, increased binding affinity, and lower toxicity were developed to act as glucokinase activators.

Preconcentration of Cinnamic Acid Derivatives in Traditional Chinese Medicines by an Effective Dispersive Liquid-Liquid Microextraction Based on a Hydrophobic Deep Eutectic Solvent.

A dispersive liquid-liquid microextraction based on hydrophobic deep eutectic solvent (hDES) was developed for the extraction and quantification of four cinnamic acid derivatives in traditional Chinese medicines coupled with high-performance liquid chromatography-ultraviolet detection. In this method, a hDES (tetrabutylammonium chloride-hexanoic acid, molar ratio of 1:2) was prepared as the extractant. It only took 15 s to handle multiple samples simultaneously by hand-assisted dispersion. The use of a narrow-bore tube reduced the amount of the hydrophobic extractant with easier recovery. The approach was influenced by several key parameters, including the composition and consumption of the DES, sample phase pH, salt amount, extraction time, and centrifugation time, all of which had been investigated and optimized. Moreover, the formation of the DES was characterized by Fourier-transform infrared spectroscopy and differential scanning calorimetry. Under the optimal conditions, enrichment factors of the target analytes ranged from 135 to 220. Satisfactory linearities (r ≥ 0.9977), detection limits (0.2-0.4 ng/mL), precision (<8.5%), and accuracy (recoveries: 90.0%-104.6%) were obtained. The method has been successfully applied to the simultaneous extraction and preconcentration of four cinnamic acid derivatives in Chinese medicinal samples with rapidness, high efficiency, and convenience.

Anxiolytic and Anticonvulsant Potential of Biosynthetic Limonene Derivatives in Adult Zebrafish.

This study investigated the anxiolytic and anticonvulsant effects and safety profile of limonene enantiomers and their oxidized derivatives. The toxicity test was performed by monitoring the animals for 96 hours, with no deaths or significant toxicity observed up to the highest dose, which allowed the determination of the LD50. Doses of 4, 20 and 40 mg/kg were tested, with no toxicity observed up to 96h (LD50 > 40 mg/kg). Anxiolytic activity was measured in a preference test for light and dark areas, and the effect of the compounds was evaluated in the presence of serotonergic antagonists. The (S)-(-)-LIM and (R)-(+)-LIM enantiomers showed anxiolytic effects, with (S)-(-)-LIM being effective at all doses. In the anticonvulsant test, the oxidized derivatives, such as perilyl acid (PAC), significantly delayed PTZ-induced seizures, an effect blocked by flumazenil (FMZ). The oxidized derivatives, especially perilyl acid (PAC), showed anxiolytic effects at all doses and significantly delayed the three PTZ-induced seizure events. This effect was blocked by FMZ, suggesting a relationship between PAC and the GABAergic pathway. PAC, being the most oxidized derivative, was the most effective for both anxiety and delaying seizure progression, suggesting that oxidation of limonene compounds may increase their therapeutic efficacy.

Safety assessment of novel oxadiazole derivatives in acute and sub-acute toxicity studies.

1,3,4-Oxadiazole is a fascinating heterocyclic compound with a unique five-membered ring structure containing nitrogen and oxygen atoms. It has garnered significant attention for its interactions and activities within biological systems. This versatility has led to the production of several ligands using this compound as a pharmacophore. This study evaluates the acute toxicity of three oxadiazole derivatives (1,3,4-Bromo, Chloro, and Iodo) followed by a 28 days sub-acute study involving four different doses of each derivative. The study followed the guideline, the Organization for Economic Cooperation and Development (OECD) outlined, specifically OECD Guidelines 425 for the acute toxicity study and OECD Guidelines 407 for the sub-acute study. In the acute toxicity study, a high dose of 2000 mg/kg was administered to male and female rats to establish lethal dose 50 (LD50) values, and the rats were closely monitored for 14 days. The subsequent sub-acute study involved the administration of four different doses (1.25, 2.5, 5, and 10 mg/kg) of each derivative to male and female rats for 28 days. Throughout both studies, careful monitoring for signs of toxicity and comprehensive hematological, biochemical, and histological analysis were carried out thoroughly. The results of the acute toxicity study indicated that all three derivatives had LD50 values exceeding 2000 mg/kg, and the rats did not display significant signs of toxicity. Similarly, no organ or systemic toxicity was observed in the repeated dose sub-acute study for any of the three derivatives. In conclusion, based on the findings of these studies, it was determined that the derivatives are safe for further investigation of their pharmacological activity.