Chemical Methodologies

Abstract The development of novel ionic liquids (ILs) with dual functions as catalysts and green reaction media continues to attract considerable attention in sustainable organic synthesis. In this study, the synthesis of 2-oxopyrrolidinium bisulfate, a new, efficient, and environmentally benign acidic IL was reported. Its catalytic performance was evaluated in the one-pot, three-component synthesis of imidazole derivatives through the condensation of benzil, aldehydes, and ammonium acetate under solvent-free conditions. The protocol afforded the desired imidazoles in high to excellent yields within short reaction times, highlighting the efficiency of the system. Beyond its catalytic activity, the IL exhibited excellent recyclability and could be reused for at least four consecutive cycles with minimal loss of performance, confirming both its stability and practical applicability. The superior performance of 2-oxopyrrolidinium bisulfate compared to conventional acid catalysts can be attributed to its strong Brønsted acidity, hydrogen-bonding ability, and homogeneous nature, which collectively facilitate efficient activation of substrates under mild, solvent-free conditions. Due to its ease of preparation, operational simplicity, non-chromatographic product purification, and low environmental footprint, this IL represents a promising addition to the library of task-specific catalysts. Moreover, the methodology aligns with the principles of green chemistry by eliminating volatile organic solvents, minimizing waste, and enabling catalyst recovery. These findings not only establish 2-oxopyrrolidinium bisulfate as a powerful medium for imidazole synthesis, but also suggest its potential applicability in a broader range of heterocyclic and multicomponent transformations.

Abstract Calicotome villosa (Fabaceae), commonly known as thorny broom, is a Mediterranean shrub traditionally used in Lebanon and neighboring regions to treat abscesses, cardiovascular, and nervous system disorders. This review presents an integrated analysis of the chemical and pharmacological assessment of Calicotome villosa based on the current literature, linking analytical chemistry with bioactivity profiling. Phytochemical analyses identified over forty secondary metabolites, including quinolizidine alkaloids (lupinine, lupanine, and cytisine), flavonoids (chrysin, luteolin, apigenin, and kaempferol), flavonoid glycosides (orientin and genistein derivatives), anthraquinones, and volatile constituents (cineole, camphor, eugenol, and furfural). These compounds were characterized using Soxhlet extraction, hydrodistillation, chromatographic methods (HPLC and GC–MS), and spectroscopic techniques (FTIR and UV–Vis). The methanolic leaf extract exhibited strong antioxidant activity (IC₅₀ ≈ 14.5 µg/mL) along with antibacterial, antifungal, cytotoxic, vasodilatory, and hypotensive effects. Mechanistic insights suggest involvement of reactive oxygen species scavenging, metal chelation, enzyme modulation, microbial membrane disruption, mitochondrial apoptosis, calcium-channel interference, and nitric oxide release. Comparative evaluation with related Fabaceae species (Genista tinctoria, Spartium junceum, Retama raetam, and Calicotome villosa subsp. intermedia) revealed superior metabolite diversity and multi-target pharmacological potential. Despite its promising chemical profile, mechanistic and in vivo studies remain limited. Future work integrating structure–activity relationship modeling, semisynthetic derivatization, and nanocarrier-based delivery systems may enhance therapeutic performance. This work represents the first integrated analytical–pharmacological synthesis of Calicotome villosa, establishing a framework for future drug discovery from Mediterranean Fabaceae.

Abstract An established target for anticoagulant treatment, factor Xa (FXa) is an essential serine protease in the coagulation cascade.  The search for natural alternatives with safer profiles is prompted by the fact that, despite their clinical efficacy, synthetic inhibitors like rivaroxaban are still burdened by bleeding risks, metabolic interactions, and costs. This study investigated the potential of bioactive compounds from licorice root (Glycyrrhiza glabra L.) as inhibitors of coagulation factor Xa (FXa), a key therapeutic target. Initial in vitro screening of isoliquiritigenin, glycyrrhizic acid, and glabridin identified isoliquiritigenin as the sole compound exhibiting inhibitory activity. Therefore, an integrated in vitro and in silico evaluation of isoliquiritigenin was conducted, utilizing rivaroxaban as a reference inhibitor. In conclusion, the findings identify isoliquiritigenin as a promising natural scaffold for FXa inhibition, warranting further investigation. Frontier molecular orbital (FMO) analysis, molecular electrostatic potential (MEP), non-covalent interaction (NCI) mapping, molecular docking, molecular dynamics (MD) simulations, and ADMET/toxicity predictions were among the computational techniques used. The results indicated that isoliquiritigenin inhibited the activity of FXa dose-dependent manner. Although rivaroxaban demonstrated higher electronic stability and complementarity, the FMO and MEP results showed that isoliquiritigenin has reactive sites for hydrogen bonding. Both ligands interact with the catalytic residues of FXa, according to docking, but rivaroxaban has a higher binding affinity. While isoliquiritigenin exhibited more flexibility while maintaining compactness, MD simulations verified that rivaroxaban maintained higher structural stability. According to toxicity predictions, isoliquiritigenin had a lower carcinogenic potential than rivaroxaban, but it was more likely to be ecotoxic and mutagenic. In conclusion, isoliquiritigenin was identified as a weak inhibitor of FXa and represents a potential natural scaffold for the design of more potent derivatives. However, its low intrinsic potency (IC₅₀ ~700 µM) represents a major limitation, necessitating significant structural optimization to achieve therapeutic relevance. Isoliquiritigenin may have a pharmacological significance and could be utilized as a lead compound for more potent FXa inhibitors, although its stability and safety need to be improved through structural optimization and experimental validation.

Abstract Cancer is caused by genetic changes in the body's cells that lead to the uncontrolled and rapid proliferation of these mutated cells. The side effects of chemotherapy drugs are severe and also affect healthy cells. As a result, there is a need for a new method, such as targeted drug delivery, that can reduce side effects, deliver appropriate dose of drug to cancer cells, and increase efficiency. In this research, SWCNT was used as nanocarriers. This study investigates effect of various variables on interaction potential of anticancer drugs on walls of SWCNT. Interaction energy was estimated at B3LYP/6-311+G* theoretical level and optimized using BSSE method. Evaluation of interaction between SWCNT and doxorubicin drug indicates that this adsorption is spontaneous. Also, the type of chemical environment and the increase in electric constant of solvent lead to a reduction in bond energy and an increase in the stability of the complex nanotechnology system. According to results, NBO analysis revealed significant electron donation from the nitrogen lone pair of doxorubicin to the σ*-antibonding orbital of the SWCNT's carbon framework. Complementary AIM analysis unequivocally identified the N32···C111 contact as a non-covalent interaction, with topological parameters (low ρ and positive ∇²ρ) consistent with closed-shell characteristics. Monte Carlo simulations demonstrated a progressively negative solvation free energy in aqueous medium upon complex formation. The total energy of the resulting complex was more negative than that of the isolated SWCNT, showing consistent correlation between all analytical methods.

Abstract Three 7-methoxyquinazoline derivatives were successfully synthesized 6-8. Among them, compound 7 is a new deuterated analog, while compound 8 is the deuterated version of a previously reported non-deuterated compound. The three compounds 6-8 were evaluated for their inhibitory activity against eight tyrosine kinase receptors (EGFR, HER2, HER4, IGF1R, InsR, VEGFR2, PDGFRα, and PDGFRβ). The results showed that compound 7 exhibited strong inhibition (>80% inhibition) against EGFR, HER2, and VEGFR2, while compound 8 showed strong inhibition against EGFR and moderate inhibition (40-60% inhibition) against HER2 and VEGFR2. The results of molecular docking using AutoDock showed that the deuterated methoxy of compound 7 provided a better inhibition constant value than the other compounds. Meanwhile, the results of visualization of the interaction of compounds 6-8 in the receptor showed that the quinazoline ring was positioned the active site like native ligand. Molecular dynamics simulations indicated that the molecular complexations between compounds 7 and receptors are likely to be stable in an aqueous environment. The ADMET prediction indicates that the deuterated compound is promising as a lead compound for further development as tyrosine kinase inhibitors.

Abstract The development of efficient and recyclable catalytic systems for benzopyran synthesis remains a major challenge in sustainable chemistry. This study reports the design and characterization of a novel magnetic nanocatalyst (Fe₃O₄@SiO₂@Cl) prepared by functionalizing silica-coated magnetite nanoparticles with thionyl chloride. Comprehensive characterization using TG-DTA, FT-IR, XRD, and SEM confirmed the successful synthesis of the catalyst. The nanocatalyst showed exceptional performance in multicomponent benzopyran synthesis, achieving high yields (up to 98%) in short reaction times (15 min) under mild conditions. Notably, the system exhibited broad functional group tolerance, as verified by melting point analysis and NMR spectroscopy (¹H and ¹³C). Key advantages include outstanding selectivity, and easy magnetic separation for recycling. The synergistic combination of a superparamagnetic Fe₃O₄ core, silica interlayer, and active chlorine species enhances the catalyst's activity. This work offers an eco-friendly, high-performance catalytic solution for benzopyran synthesis with significant industrial potential.

Abstract Medicinal plants have been recognized for centuries for their therapeutic potential, and in modern times, they continue to attract great research interest due to their pharmacological significance. Nigella sativa (black cumin seeds) is an herbaceous plant whose seeds contain bioactive compounds with well-documented medicinal properties. Similarly, Olea europaea (olive) has played an important role in food, trade, and medicine since ancient times. This study focuses on the extraction, phytochemical screening, and practical applications of these plants. Black cumin seed extracts were prepared using hexane and ethanol, while olive leaf extracts were obtained using water as a solvent. Extracts were analyzed for yield, moisture content, ash proportion, and metabolite composition through qualitative and quantitative tests. Total phenolic content (TPC) and antioxidant activity were also evaluated, using gallic acid and ascorbic acid as reference standards, respectively. For practical applications, bread was fortified with black cumin seeds at concentrations of 4%, 6%, and 8%. The fortified bread showed significant increases in moisture content and nutritional value, with sensory evaluation by 40 panelists identifying the 4% formulation as the most preferred. Additionally, three types of creams were formulated: one with black cumin seed oil, one with olive oil, and one combining both oils. Each type was prepared at three concentrations (2%, 5%, and 12%). All creams exhibited acidic pH values (3.97–4.15) and appeared homogeneous under light microscopy, although sensory evaluations varied. Furthermore, two types of soaps were prepared with olive oil, one with and one without rosemary essential oil, exhibiting pH values of 10 and 9, respectively.

Abstract Silver nanoparticles were synthesized, followed by 50 mL of Ficus hispida ethyl acetate extract was mixed with 100 mL of 4 mM silver nitrate solution, and stirring at room temperature, with a color change from yellow to brown indicating silver ion reduction. Characterization included UV‒Vis spectroscopy for surface plasmon resonance, FT-IR for functional groups, XRD for crystallinity, FE-SEM and HR-TEM for morphology, and zeta potential and DLS for particle size and stability. The anticancer activity against MCF-7 cells was assessed via the MTT assay, and ROS were detected via fluorescence microscopy. The synthesized FH-Ag-NPs presented a distinct UV‒Vis absorption peak at 191.69 nm, confirming nanoparticle formation. FT-IR analysis revealed characteristic peaks at 3,423 cm⁻¹ (O-H stretching), 2,924 cm⁻¹ (C-H stretching), and 1,636 cm⁻¹ (C=O stretching), indicating the involvement of biomolecules in nanoparticle stabilization. The zeta potential value of -31.0 mV suggested good colloidal stability. The DLS results revealed an average particle size of 122.3 nm with a polydispersity index of 0.368, reflecting moderate size uniformity. The XRD patterns confirmed the crystalline nature, with peaks at 10.67°, 27.65°, and 28.18°. Electron microscopy revealed that the spherical nanoparticles were 64–100 nm in size with minimal aggregation. EDAX confirmed that elemental silver was the main component. The FH-Ag-NPs exhibited dose-dependent cytotoxicity to MCF-7 cells, reducing viability from 85.73% (5 µg/mL) to 42.95% (25 µg/mL). Fluorescence microscopy revealed increased reactive oxygen species generation at higher concentrations, indicating oxidative stress-induced cytotoxicity. These results confirm the successful green synthesis and the FH-Ag-NPs promising anticancer potential.