Search Results (468)

Background/Objectives: Indoles and benzimidazoles are important nitrogen-containing heterocyclic scaffolds and are a cornerstone of synthetic drugs. In this study, benzamides of 2-aminophenylindoles and 2-aminophenylbenzimidazoles were synthesized and evaluated for their potential. Further, they were also subjected to computational studies for their ADMET profiling and binding with target proteins. Methods: The synthesized compounds were characterized by ATR-FTIR, 1H NMR, 13C NMR and electrospray ionization mass spectroscopy (ESI-MS). They were screened for their in vitro antibacterial activity by the Microplate Alamar Blue Assay (MABA) and for their anticancer potential by the MTT assay against the HeLa, PC3 and 3T3 cell lines. Further, the compounds were assessed for their ADMET profiles by the Deep-PK platform, and binding with selected kinases was assessed by AutoDock Vina v1.2.7, followed by MD simulations in GROMACS. Density functional theory (DFT) calculations were also performed to investigate the electronic properties of the synthesized compounds. Results: All synthesized compounds were inactive in antibacterial assays and mildly active against cancer cells. N-[4-(1H-benzimidazol-2-yl-phenyl]benzamide (4-APB-B) exhibited good activity against the HeLa cell line (IC50: 5.48 ± 0.01 µM) while showing very low cytotoxicity against the 3T3 cell line (selectivity index: 10.7), against which doxorubicin was highly active, indicating selectivity towards specific cancer cells. Docking studies indicated favorable binding affinities towards the selected kinase targets. Further, ligands with the best binding affinities in docking studies were subjected to MD simulations of 100 ns, and DFT studies were also performed to assess the electronic properties of the synthesized compounds. Conclusion: Our study provides a pathway for the synthesis of 2-phenylbenzimidazoles and 2-phenylindoles and demonstrates that the synthetic compound 4-APB-B possesses remarkable selective cytotoxic activity and can serve as a lead molecule for further development into a successful anticancer agent. Full article

Osteoporosis is a prevalent skeletal disorder characterized by excessive bone resorption and an increased risk of fragility fracture. Cathepsin K (CatK), a lysosomal cysteine protease predominantly expressed in osteoclasts, is an established target for anti-resorptive drug development. Here, an integrated computational workflow comprising virtual screening, molecular docking, 300 ns molecular dynamics (MD) simulations, molecular mechanics/Poisson–Boltzmann surface area (MM/PBSA) calculations, and drug-likeness/ADMET prediction was used to prioritize natural product-derived CatK ligands from the MEGxM database. Among approximately 6500 screened compounds, TOP1 (PubChem ID: 97043052) and TOP2 (PubChem ID: 135765825) showed docking scores of −8.2 and −7.8 kcal/mol, respectively, compared with −6.6 kcal/mol for the comparative reference ligand (STD). Both compounds satisfied Lipinski’s rule of five; however, their predicted ADMET profiles were mixed, including negative predictions for human intestinal absorption for both compounds and compound-specific metabolic and toxicity liabilities. The 300 ns MD trajectories indicated broadly stable CatK ligand complexes. TOP1 showed slightly lower mean RMSD)/RMSF values than TOP2. In contrast, TOP2 exhibited more favorable MM/PBSA binding free energies than TOP1 at both analyzed intervals (−83.45 ± 10.06 and −80.74 ± 10.18 kJ/mol for TOP2 versus −74.28 ± 10.08 and −57.21 ± 15.04 kJ/mol for TOP1), while STD showed the most favorable MM/PBSA binding free energies overall. Collectively, TOP1 and TOP2 exhibited complementary computational profiles and should therefore be regarded as candidates for biochemical and cellular validation rather than confirmed CatK inhibitors or orally suitable drug leads. Full article

Ensitrelvir and nirmatrelvir are the two most widely used oral SARS-CoV-2 main protease inhibitors, yet their toxicological profiles have never been compared under a single computational panel. An identical panel of 105 toxicity endpoints per compound was generated with ADMETlab 3.0, ProTox 3.0, Deep-PK, admetSAR 3.0 and Pred-hERG 5.0, yielding 210 endpoint-level predictions across 17 toxicological domains. Each endpoint formed a matched pair classified as shared positive, shared negative, discriminant or crossed, and predictions were compared against primary clinical and nonclinical literature under a three-level admissibility hierarchy that excluded prescribing information, regulatory review documents and commercial databases. Of 93 class-assignable pairs, 73 assigned both to the same class, 62 negative, and 20 differed. Four domains were shared positive: genotoxicity, with broad genotoxicity and micronucleus probabilities of 1.000 for both molecules, respiratory toxicity, nephrotoxicity and neurotoxicity; ototoxicity was high for both in a single tool. The largest separation was hepatic: ensitrelvir returned drug-induced liver injury 1.000 and human hepatotoxicity 0.994, against 0.314 and 0.456 for nirmatrelvir. Target class therefore does not determine predicted toxicological profile. Genotoxicity, respiratory, renal and neural endpoints are class-level validation priorities, whereas hepatic and hERG endpoints require compound-specific testing. These findings are hypothesis-generating prioritization markers, not confirmed toxicity. Full article

Aim of the Study: The aim of this study was to characterize the volatile phytochemical composition of Cannabis sativa L. essential oil (CSEO) and evaluate its in vitro inhibitory activity against selected digestive enzymes and its antiglycation activity. Molecular docking and ADMET analyses were additionally performed to explore the possible interactions and predicted pharmacokinetic properties of the major identified constituents. Materials and Methods: The chemical composition of CSEO was characterized by Gas Chromatography–Mass Spectrometry (GC-MS). Its in vitro inhibitory activity was evaluated against α-amylase, α-glucosidase, and pancreatic lipase, while its antiglycation activity was assessed by monitoring the formation of glycation products at different stages of the glycation process. Molecular docking simulations were performed to investigate the potential interactions of major identified terpenes with the active sites of the investigated enzymes. In addition, ADME analysis was conducted to predict selected pharmacokinetic and drug-likeness properties of the major constituents. Results: gc-ms analysis revealed a complex terpenoid profile, with β-caryophyllene as the major constituent, followed by selina-3,7(11)-diene (8.00%), cubenol (6.62%), γ-eudesmol (6.57%), epiglobulol (6.04%), and valencene (5.80%). CSEO showed significant in vitro inhibitory activity against α-amylase, α-glucosidase, and pancreatic lipase. The essential oil also exhibited antiglycation activity, with inhibition observed at different stages of glycation-product formation. Molecular docking analysis indicated that several major sesquiterpenes could interact with the investigated enzyme targets through different binding interactions. ADME analysis provided predicted pharmacokinetic and drug-likeness profiles for the major constituents. Conclusions: The findings demonstrate that Cannabis sativa L. essential oil possesses in vitro digestive-enzyme inhibitory and antiglycation activities. The docking results provide molecular-level insights into possible interactions between major essential-oil constituents and the investigated enzyme targets. These findings support further investigation of CSEO and its major constituents using appropriate in vivo and mechanistic studies to determine their biological relevance and potential applications. Full article

Objectives: Candidate estrogen receptor alpha (ERα) antagonists should combine strong inhibitory activity with favorable absorption, distribution, metabolism, excretion, and toxicity (ADMET)-related properties. This study developed an integrated framework for multi-endpoint prediction, multi-objective optimization in molecular descriptor space, and prioritization of feasible solutions. Methods: A dataset of 1974 compounds with 729 molecular descriptors, pIC₅₀ values, and five binary ADMET-related endpoints was analyzed. Key descriptors were identified through two-stage cross-method and cross-endpoint screening. One regression model for pIC₅₀ and five independent classification models for the ADMET-related endpoints were developed and evaluated separately. The final selected models were incorporated into a two-phase hybrid adaptive multi-objective evolutionary algorithm (2P-HAMOEA). Feasible Pareto solutions were ranked using objective weighting, multi-criteria decision-making, reliability-based fusion, and a performance uncertainty index-based adjustment. Results: The final dataset comprised 1875 compounds and 24 key molecular descriptors. The three-model stacking ensemble for pIC₅₀ achieved an R² of 0.650 in the internal holdout set, and the AUC values of the five ADMET models ranged from 0.878 to 0.979. Under the prespecified criteria, 2P-HAMOEA generated 155 feasible Pareto solutions. Its generational distance was significantly lower than that of four comparator algorithms, whereas its inverted generational distance and hypervolume were not superior to those of most comparators. pIC₅₀ received the highest fused weight (0.328), and pairwise rank correlations among TOPSIS, VIKOR, and WASPAS exceeded 0.90. The top 20% of RWS-ranked solutions (n = 31) were used for descriptor-interval analysis. Conclusions: The framework offers an early-stage, descriptor-level way to examine endpoint-specific predictions before alternative multi-endpoint profiles are compared. The Pareto solutions are numerical descriptor profiles rather than explicit or experimentally validated ERα antagonist structures; independent validation and molecular structure generation remain necessary. Full article

Ficus carica L., a widely cultivated member of the Moraceae family, is recognized for its rich phytochemical composition and diverse biological activities; however, the influence of harvest season and extraction solvent on its bioactive profile remains insufficiently explored. In this context, leaves collected from Dalaman (Muğla, Türkiye) in April and November were comparatively evaluated in terms of phenolic profiles, antioxidant capacity, enzyme inhibitory potential, molecular docking interactions, and preliminary ADMET properties. Eight extracts were prepared using ethyl acetate, methanol, aqueous ethanol, and water, and phenolic composition was characterized by HPLC-DAD using 42 reference standards. Major contributors to bioactivity included hesperidin, rutin, chlorogenic acid, cynarin, naringenin, and 4-hydroxyresorcinol. Antioxidant activity was assessed via DPPH˙, ABTS˙⁺, CUPRAC, and β-carotene–linoleic acid assays, while enzyme inhibitory activities against acetylcholinesterase, butyrylcholinesterase, and tyrosinase were determined. Hesperidin reached its highest concentration in the water extract FC14 (80.06 mg/g). FC14 showed the strongest DPPH˙ (IC₅₀: 54.46 ± 0.94 μg/mL), ABTS˙⁺ (IC₅₀: 10.75 ± 0.17 μg/mL), and CUPRAC (A_0.5: 95.38 ± 1.69 μg/mL) activities, whereas the ethyl acetate extract FC11 showed the strongest β-carotene–linoleic acid activity (IC₅₀: 37.77 ± 2.11 μg/mL). The water extract FC24 showed the strongest AChE (IC₅₀: 135.52 ± 0.77 μg/mL) and tyrosinase (IC₅₀: 34.46 ± 1.05 μg/mL) inhibition. The results demonstrated that both harvesting season and extraction solvent significantly influenced the phytochemical composition and biological activities. Principal component analysis revealed clear discrimination among extracts, and molecular docking supported these findings by highlighting strong interactions of hesperidin and rutin with target enzymes. PCA explained 50.30% of the total variance. Molecular docking analysis revealed the strongest binding affinities for hesperidin toward AChE (−9.3 kcal/mol), hesperidin and rutin toward BChE (both −10.8 kcal/mol), and rutin toward tyrosinase (−10.3 kcal/mol). ADMET predictions suggested favorable oral drug-likeness for selected compounds, whereas others may require further optimization. Overall, these findings indicate that F. carica leaves represent a promising source of natural phenolics with multifunctional bioactivity. Full article

Background: Angiostrongylus cantonensis is a neurotropic nematode recognized as the leading cause of eosinophilic meningitis worldwide. Despite its growing medical importance, therapeutic options for angiostrongyliasis remain limited, highlighting the need for new anthelmintic agents. Methods: The anthelmintic activity of andrographolide, a diterpene lactone isolated from Cymbopogon schoenanthus, was evaluated against first-stage (L1) larvae, infective third-stage (L3) larvae, and adult worms of A. cantonensis using motility-based phenotypic assays. Toxicity was assessed in mammalian cell models and Caenorhabditis elegans, and drug-likeness and ADMET properties were evaluated using in silico approaches. Results: Andrographolide exhibited concentration-dependent activity across all developmental stages, with EC₅₀ values of 12.5, 11.2, and 7.3 µM for L1, L3, and adult worms, respectively. These EC₅₀ values were similar to those of albendazole, with no statistically significant differences detected for any developmental stage. No toxicity was detected at the highest concentrations tested in mammalian cell models (CC₅₀ > 500 µM) or C. elegans (LD₅₀ > 1000 µM), supporting a preliminary selectivity profile. The in silico analyses predicted compliance with major drug-likeness rules, absence of PAINS alerts, high gastrointestinal absorption, and low probabilities of hepatotoxicity, nephrotoxicity, and neurotoxicity. Conclusions: Andrographolide represents a promising in vitro anthelmintic hit against A. cantonensis and warrants further preclinical investigation. Full article

Background: Pregnancy involves coordinated immunological adaptations that maintain maternal–fetal tolerance while preserving protection against infections. There is growing evidence that vaginal microbiota-associated metabolites contribute to immune balance, yet their molecular mechanisms remain incompletely understood. Methods: This study used an in silico approach combining absorption, distribution, metabolism, excretion, and toxicity (ADMET) profiling, molecular docking, and structural interaction analysis. Eight compounds—five organic acids, two bacteriocins, and hydrogen peroxide—were evaluated against eight immune and inflammatory protein targets relevant to pregnancy. Results: The ADMET predictions revealed favorable pharmacokinetic and safety profiles for small organic acids, particularly butyric and propionic acids. Enterocin-HF yielded the most favorable predicted binding energies across the evaluated targets, particularly TNF-α and NF-κB. Redocking of the COX-2 co-crystallized ligand reproduced the experimental binding pose with an RMSD of 1.21 Å, supporting the ability of the protocol to recover the crystallographic binding mode. Conclusions: Overall, these findings prioritize Enterocin-HF and selected organic acids for subsequent experimental evaluation. However, the predicted interactions should not be interpreted as evidence of functional immunomodulation or therapeutic efficacy. Full article

Leukemia progression is increasingly shaped by reciprocal interactions between leukemic cells and the bone marrow microenvironment, yet the extracellular regulatory networks associated with these interactions remain incompletely understood. Here, we investigated the biological context associated with the antileukemic activity of LCC-10 (NSC765599), a synthetic biphenyl benzamide derivative, using an integrated pharmacogenomic and structure-guided computational framework. Antiproliferative activity was first characterized using the NCI-60 screen and subsequently integrated with pharmacogenomic response similarity analysis, baseline transcriptomic profiling, similarity-based target prediction, systems-level network analysis, molecular docking, coarse-grained molecular dynamics simulations, comparative in silico ADMET evaluation, and zebrafish embryo developmental toxicity assessment. LCC-10 exhibited potent antiproliferative activity across leukemia cell lines, with submicromolar GI₅₀ values in five of six models. Computational analyses converged on a matrix metalloproteinase (MMP)-associated extracellular matrix (ECM) regulatory network, with MMP2 and MMP9 among the recurrently implicated candidates. Structure-guided analyses suggested structural compatibility of LCC-10 with representative MMP catalytic domains but did not establish direct biochemical inhibition or target engagement. Comparative in silico ADMET analyses supported the predicted developability profile of LCC-10, whereas zebrafish embryo assays indicated concentration-dependent developmental tolerability within the tested range. Collectively, these findings associate LCC-10 with an MMP-associated ECM regulatory network in leukemia while defining this relationship as a hypothesis requiring direct experimental validation. This integrated framework provides a rationale for subsequent biochemical, target-engagement, and functional studies to clarify the molecular basis of LCC-10 activity. Full article

Modern scientific and technological developments are driving major advances in drug research and development. This narrative review, based on a structured search of PubMed, Scopus, and Web of Science (2018–2026), examines how artificial intelligence (AI) and machine learning (ML) are accelerating a historically prolonged and expensive process, alongside pharmacogenomics, organ-on-a-chip systems, three-dimensional (3D) bioprinting, and nanotechnology. In benchmark studies, deep learning techniques have achieved an area under the receiver operating characteristic curve (AUROC) of over 0.85 for a subset of absorption, distribution, metabolism, excretion, and toxicity (ADMET) endpoints. AI-powered models show promising, albeit platform-dependent, accuracy in predicting candidate drug properties. Pharmacogenomics enables personalized medicine by tailoring therapies according to patients’ genetic profiles, whereas organ-on-a-chip systems and 3D bioprinting provide physiologically relevant human tissue models for preclinical evaluation. In a blinded benchmark study, the Emulate Liver-Chip showed 87% sensitivity and 100% specificity for drug-induced liver injury, outperforming animal models in that specific comparison. Nanotechnology is advancing drug delivery through the use of nanoparticle systems, such as Doxil^® and Onpattro^®. Obstacles remain, including regulatory constraints, ethical considerations, data quality limitations, and the need for stronger validation, although ongoing funding, interdisciplinary collaboration, and evolving regulatory frameworks may support further development. Overall, these technologies show meaningful potential to shorten development time and improve treatment safety, although further prospective validation is required before realizing this potential at scale. Full article

This study investigated the neuroprotective potential of Xanthoceras sorbifolium Bunge (XSB) seed oil through fatty acid profiling, antioxidant assays, and in silico targeting of FABP7. Among the solvent-to-solid ratios tested, 1:20 (w/v) gave the highest oil yield (72.91%) and the strongest ABTS, DPPH, and FRAP activities. GC-MS identified 17 fatty acids from the 1:20 (w/v) oil extract, with linoleic acid (38.93%) and oleic acid (31.3%) as the major constituents. Following GC-MS fatty acid profiling, lipid structural characterization was performed using ¹H NMR and FT-IR. ADME/T prediction and BOILED-EGG analysis suggested favorable pharmacokinetic properties and BBB permeability for the selected fatty acids. Molecular docking and simulation revealed strong and stable interactions of five compounds with FABP7: nervonic acid (−6.1 kcal/mol), erucic acid (−6.002 kcal/mol), eicosadienoic acid (−6.08 kcal/mol), oleic acid (−6.03 kcal/mol), and linoleic acid (−6.00 kcal/mol), outperforming the native ligand, oleic acid (−5.8 kcal/mol). These findings indicate that XSB seed oil contains bioactive lipids with promising FABP7-targeted neuroprotective potential and warrant further investigation as therapeutic leads for neurodegenerative diseases. Full article

Background/Objectives: In the search for potent non-sugar α-glucosidase inhibitors with improved safety profiles, a novel flavonoid glycoside was isolated for the first time from the stem bark of Albizia saponaria (Fabaceae). The objective of this study was to elucidate its chemical structure and evaluate its therapeutic potential as an anti-hyperglycemic agent compared to known related flavonoids and a standard clinical drug. Methods: Comprehensive structural elucidation was performed using high-resolution mass spectrometry and multidimensional 1D/2D NMR (¹H, ¹³C, HSQC-DEPT, COSY, and CIGAR). To assess its inhibitory efficacy and pharmacokinetic profiles, an in silico comparative study was conducted against a database of related flavonoids (Quercitrin, Hyperoside, and Isoquercitrin) and the clinical drug Acarbose. This involved molecular docking simulations against human intestinal maltase-glucoamylase (PDB ID: 3TOP) alongside integrated ADMET modeling and toxicological screening. Results: The compound was successfully identified as 4′,7-dihydroxyflavan-3′-O-β-D-glucoside (1). Molecular docking revealed that Compound 1 exhibited a superior predicted binding affinity of −9.5 kcal/mol, outperforming Quercitrin (−9.3 kcal/mol), Hyperoside (−8.3 kcal/mol), Isoquercitrin (−7.9 kcal/mol), and Acarbose (−7.2 kcal/mol). This strong thermodynamic stability is driven by a robust conventional hydrogen-bonding network with key active site residues (Arg1377, Gln1372, and Gly1365), successfully overriding a localized electrostatic strain at Asp1279. Furthermore, ADMET modeling demonstrated a highly desirable local pharmacokinetic framework; its low Caco-2 permeability (−6.432) and low human intestinal absorption (HIA = 0.120) favor targeted luminal retention in the gastrointestinal tract, mirroring Acarbose while minimizing systemic exposure. Crucially, toxicological screening unveiled a significant safety advantage for Compound 1, marked by negligible CYP3A4 interaction (0.004) and a remarkably low risk of Drug-Induced Liver Injury (DILI = 0.213) compared to the high-risk hepatotoxic profile of Acarbose (DILI = 0.882) and the reference flavonoids (DILI > 0.69). Conclusions: These predictive findings establish Compound 1 as a highly promising, low-toxicity natural scaffold for anti-hyperglycemic drug development. Its superior binding affinity and minimized hepatotoxicity risk warrant subsequent in vitro and in vivo functional validation. Full article

Background: Building on earlier work with methoxy-, dimethoxy-, bromo-, and nitro-substituted salicylaldehyde benzoylhydrazones, we synthesized and evaluated new 4-chloro- and 5-chloro derivatives bearing an additional chlorine substituent on the hydrazide-derived phenyl ring to further explore the impact of halogenation on cytotoxic activity. Methods: Chloro-hydrazones were obtained through a one-step condensation of 4- or 5-chlorosalicylaldehyde with benzhydrazide or 2-, 3-, and 4-chlorobenzhydrazides. Their physicochemical, pharmacokinetic, ADME, lead-likeness, and drug-likeness profiles were evaluated in silico using SwissADME, ACD/Labs v9.10, and MDL QSAR v2.2.0.0.446. The synthesized compounds were structurally characterized by IR, ¹H NMR, ¹³C NMR, and HR ESI–MS, and their cytotoxic activity was subsequently assessed by the MTT assay in selected cancer cell lines. Molecular docking was performed against ABL1 tyrosine kinase (ABL1 TK), a potential molecular target relevant to two of the investigated leukemia cell lines, using GOLD v.5.2.2 (CCDC Ltd., Cambridge, UK). Results: The chloro-substituted salicylaldehyde benzoylhydrazones exhibited pronounced, cell-type-dependent cytotoxicity, with leukemia cells being substantially more sensitive than breast carcinoma cells. Most derivatives showed low- to sub-micromolar IC₅₀ values against SKW-3 human T-cell prolymphocytic leukemia, K-562 human chronic myeloid (myelogenous) leukemia, and BV-173 human BCR::ABL1-positive leukemia cells, with K3 and K4 exhibiting the highest activity in SKW-3 cells (IC₅₀ = 0.5 ± 0.1 µM). K5 showed particularly strong activity against K-562 and BV-173 cells (IC₅₀ = 0.7 ± 0.1 and 0.9 ± 0.1 µM, respectively), compared with 26.9 ± 2.4 and 21.5 ± 3.3 µM for imatinib. HL-60 human acute promyelocytic leukemia cells showed intermediate sensitivity (IC₅₀ = 1.3–13.9 µM), whereas the activity against MCF-7 estrogen receptor-positive and MDA-MB-231 triple-negative breast carcinoma cells was more variable (1.5–32.1 and 4.1–62.5 µM, respectively). The derivatives showed high selectivity toward malignant cells relative to non-malignant CCL-1 non-malignant mouse fibroblasts, with lower-bound SI values frequently exceeding 50 and reaching >200 in SKW-3 cells. Conclusions: The chloro-substituted salicylaldehyde benzoylhydrazones exhibited pronounced and selective cytotoxicity, particularly toward leukemia cell lines, identifying this scaffold as a promising starting point for further anticancer drug-discovery studies. Full article

Background/Objectives: Chronic inflammation sustained by cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) underlies many human diseases, while the cardiovascular liabilities of coxibs have renewed interest in plant-derived alternatives. This study characterised the volatile composition of Corymbia citriodora essential oil under two distillation regimes and identified constituents able to inhibit human COX-2 and iNOS. Methods: Oils obtained by steam distillation (SD) and microwave-assisted steam distillation (MSD) were profiled by GC–MS/MS. All identified constituents were screened with SASA Vina against human COX-2 (PDB: 5KIR, 3LN1), ovine COX-1 (4COX) and human iNOS (3E7G), with native-ligand re-docking validating each protocol (RMSD 0.39–0.84 Å). The lead compound underwent density functional theory (B3LYP/3-21G/CPCM), 100 ns all-atom molecular dynamics, MM/GBSA and MM/PBSA decomposition, and pkCSM ADMET prediction. Results: Sixty-three constituents were identified (99.85% SD; 99.97% MSD). MSD enriched oxygenated monoterpenes (93.23% versus 88.27%), citronellal rose from 38.24% to 48.41%. (Z,Z,Z)-1,5,9,9-Tetramethyl-1,4,7-cycloundecatriene ranked highest at COX-2 (−8.0 to −8.2 kcal/mol) and also bound COX-1 (−8.8 kcal/mol) and iNOS (−6.8 kcal/mol). DFT indicated high kinetic stability (ΔE = 6.12 eV; η = 3.06 eV) and purely non-covalent hydrophobic binding. The COX-2 complex remained stable over 100 ns (Cα RMSD 0.17 ± 0.02 nm), with MM/GBSA and MM/PBSA binding energies of −23.98 and −21.95 kcal/mol and Val523 as the principal hotspot. ADMET prediction returned 96.61% human intestinal absorption and no mutagenicity, hepatotoxicity or hERG I blockade. Conclusions: MSD offers a faster route to a citronellal-enriched oil, and C. citriodora hydrocarbon sesquiterpenes emerge as chemically stable, multi-target COX-2/iNOS scaffolds. Comparable binding at COX-1 indicates that isoform selectivity remains to be established; in vitro enzymatic and cell-based validation is therefore required. Full article

Background: The current study uses a computational technique to investigate synthesized thiazine compounds that exhibit potential interactions with the GABA_A receptor. A series of novel thiazine derivatives was synthesized via the cyclization reaction of chalcone with thiourea. Methods: For the synthesized compounds, spectroscopic characterization, namely FT-IR, ¹H NMR, ¹³C NMR, and mass spectrometry, was carried out. In addition, the AutoDock Vina 4.2 software was applied to carry out an in silico docking study. Results: The synthesized compounds C3 and C6 exhibited comparable predicted docking scores (−9.0 and −9.1 kcal/mol, respectively), with favorable predicted interactions at the GABAA receptor binding site. Furthermore, in silico ADMET analysis provided insights into the drug-likeness and pharmacokinetic profiles of the synthesized compounds; however, potential safety liabilities, including Ames positivity, hERG II liability, and hepatotoxicity, were predicted for some derivatives. Conclusions: It was determined that the synthesized compounds’ various physiologically significant and physiologically relevant parameters fell within the range of Lipinski’s rule of five. The synthesized compounds (C1–C10) were tested for anxiolytic activity by the elevated plus maze test, and compound C6 was found to be the most potent. Additionally, the in vitro GABA-AT enzyme activity assay showed that compound C6 had the highest inhibitory potential, with an IC50 of 13.29 ± 1.622 µM. Full article