A series of 21 novel coumarin–triazole–isatin hybrids was synthesized and evaluated for their potential as multitarget agents in Alzheimer’s disease (AD). The compounds featured variations in alkyl linker length that connects coumarin and triazole and substitution at the 5-position of the isatin ring. Several derivatives showed potent butyrylcholinesterase (BChE) inhibition with selectivity over acetylcholinesterase (AChE). The lead compound, 6c1, exhibited strong BChE inhibition (IC₅₀ = 1.74 μM), surpassing donepezil. Enzyme kinetics revealed a mixed-type mechanism, while molecular docking studies confirmed dual binding at catalytic and peripheral sites. Structure–activity relationship (SAR) analysis highlighted the influence of linker flexibility and steric/electronic effects of substituents. The observed BChE selectivity, combined with favorable in vitro profiles, identifies these hybrids as promising leads for AD drug development.

Antioxidants are promising compounds with antimicrobial activity against drug-resistant pathogens, especially when combined with conventional antimicrobials. Our study aimed to characterize the structure of nicotinamides synthesized from nicotinic acid and thiocarbohydrazones and to evaluate their antibacterial and antifungal activity. Seven nicotinic acid hydrazides (NC 1–7) were synthesized using mono-thiocarbohydrazones with hydroxyl group substituents, along with quinolone, phenolic, and pyridine rings known for their antimicrobial activity. The in vitro antimicrobial activity of NC 1–7, at concentrations ranging from 0.001 to 1 mM, was tested against Staphylococcus aureus (ATCC 6538), Enterococcus faecalis (ATCC 29212), Pseudomonas aeruginosa (ATCC 27853), Klebsiella pneumoniae (NCIMB 9111), and Candida albicans (ATCC 24433) using the broth microdilution method per EUCAST 2024 guidelines. Microorganism survival percentages were calculated based on optical density, and target fishing using the PharmMapper database identified potential molecular targets. The results showed that P. aeruginosa was most susceptible to the compounds, while C. albicans was the least susceptible. NC 3 significantly inhibited P. aeruginosa and K. pneumoniae growth at 0.016 mM, while higher concentrations were required for S. aureus, E. faecalis, and C. albicans. NC 5 was most effective against gram-positive bacteria at 0.03 mM. Only NC 4 completely inhibited C. albicans below 1 mM. NC 3, with the lowest concentration for 50% growth inhibition (0.016–0.064 mM), showed promising antibacterial potential against specific AMR-related proteins (bleomycin resistance protein, HTH-type transcriptional regulator QacR, and streptogramin A acetyltransferase), suggesting that this class of compounds could enhance or restore the activity of established antibiotics.

Unsaturated polyester resins (UPRs) were synthesized from camphoric acid and diluted with styrene, partially replaced (up to 30%) by trimethylolpropane triacrylate (TMPTA). Rheological tests showed increased but sustainable viscosity due to TMPTA’s higher polarity. These UPRs served as matrices for composites reinforced with non-woven bamboo and flax mats from recycled waste. Mechanical testing revealed that C_f-UPR/TMPTA30 exhibited the highest tensile strength (25.2 MPa) and modulus (0.96 GPa), compared to 18.7 MPa and 0.74 GPa for the styrene-based resin, respectively, attributed to greater cross-link density. Bamboo composites showed lower tensile properties (13.6 MPa) due to random fiber orientation and porosity, while flax-reinforced systems, especially C_f-UPR/TMPTA30–FLAX, reached 42.7 MPa tensile and 95.5 MPa flexural strength, indicating synergy between TMPTA-modified resin and flax fibers. Dynamic-mechanical analysis confirmed stable thermo-mechanical behavior, and water uptake tests showed reduced absorption (by ~10%), suggesting improved fiber/matrix adhesion. SEM images revealed brittle fracture and fiber pull-out in styrene systems, but fiber breakage and ductile textures in TMPTA-based ones, proving better stress transfer. Thermal analysis indicated slightly earlier degradation onset for TMPTA-modified resins but higher char yield in fiber composites. Overall, TMPTA substitution and flax reinforcement enhance the mechanical, interfacial, and thermal properties of bio-based UPRs, supporting sustainable high-performance composites.

Background/Objectives: Oxidative metabolism can influence the development of bioactive compounds by affecting metabolic stability and cytochrome P450 (CYP) interactions. This study aimed to assess the CYP-related properties and oxidative susceptibility of 21 coumarin–1,2,3-triazole–isatin hybrids by integrating in silico prediction with online electrochemistry–mass spectrometry (EC–MS). Methods: All 21 derivatives were evaluated in silico for CYP substrate and inhibitor profiles and CYP-mediated transformations. Four structurally representative derivatives (6a1, 6b1, 6c1, and 6c2) were selected for analysis by directly coupled online electrochemistry–mass spectrometry (EC–MS). Compounds 6a1, 6b1, and 6c1 formed a C2–C4 homologous series, whereas 6c2 was the 5-fluoro analogue of 6c1. Results: CYP3A4 was the isoform most consistently associated with substrate classification, while CYP3A4 inhibition probabilities remained close to the classification threshold. GLORY identified aromatic hydroxylation as the predominant top-ranked transformation across the series. Linker length had little influence on the principal predicted oxidation sites. EC–MS revealed a conserved principal oxidation pattern across the C2–C4 homologues, including +16 Da ions and two lower-mass ion series showing systematic 14 Da shifts with each additional methylene group, compatible with monooxygenation, oxidative ether cleavage, and N-dealkylation. In the 6c1/6c2 pair, 5-fluoro substitution removed the second-ranked isatin 5-position hydroxylation predicted for 6c1, leaving the three highest-ranked predictions for 6c2 on the coumarin ring, and was accompanied by a selective 18 Da shift in an isatin-containing electrochemical oxidation product. Conclusions: The combined in silico and EC–MS approach identified structurally dependent predicted CYP-related properties and electrochemical oxidative susceptibility within this series. The findings support further evaluation of 6c1 and related analogues using biological metabolism models to establish their metabolic stability and CYP-mediated transformation pathways.