Novel 2-Thiouracil-5-Sulfonamide Derivatives: Design, Synthesis, Molecular Docking, and Biological Evaluation as Antioxidants with 15-LOX Inhibition.

New antioxidant agents are urgently required to combat oxidative stress, which is linked to the emergence of serious diseases. In an effort to discover potent antioxidant agents, a novel series of 2-thiouracil-5-sulfonamides (4-9) were designed and synthesized. In line with this approach, our target new compounds were prepared from methyl ketone derivative 3, which was used as a blocking unit for further synthesis of a novel series of chalcone derivatives 4a-d, thiosemicarbazone derivatives 5a-d, pyridine derivatives 6a-d and 7a-d, bromo acetyl derivative 8, and thiazole derivatives 9a-d. All compounds were evaluated as antioxidants against 2,2-diphenyl-1-picrylhydrazyl (DPPH), hydrogen peroxide (H2O2), lipid peroxidation, and 15-lipoxygenase (15-LOX) inhibition activity. Compounds 5c, 6d, 7d, 9b, 9c, and 9d demonstrated significant RSA in all three techniques in comparison with ascorbic acid and 15-LOX inhibitory effectiveness using quercetin as a standard. Molecular docking of compound 9b endorsed its proper binding at the active site pocket of the human 15-LOX which explains its potent antioxidant activity in comparison with standard ascorbic acid.

Synthesis of second-generation self-assembling Gemini Amphiphilic Pseudopeptides.

HYPOTHESIS: The structural modularity of Gemini Amphiphilic Pseudopeptides (GAPs) allows the tuning of the self-assembling properties by slight modifications in the chemical structures. We hypothesized that the introduction of a flexible linker containing a central nitrogen atom in bipodal and tripodal GAPs would improve their self-assembly properties in aqueous media. EXPERIMENTS: After preparation of the corresponding GAPs, a combination of SEM, TEM and AFM techniques were used to study the morphology of the self-assembled structures in different media. The solution structures in non-aggregated states were also analyzed by combining NMR, UV and CD studies. The transition from the non-aggregated species to the hierarchical self-assembly was monitored by ATR FT-IR spectroscopy, while the critical aggregation concentration in water was determined by fluorescence spectroscopy. FINDINGS: The formation of different morphologies (vesicles or fibers) highly depends on the polarity and the pH of the medium. A reasonable mechanism for the self-assembly has been established in agreement with the experimental techniques used, where the protonation of the nitrogen in the linker must play a key role. In general, the obtained GAPs showed an improved formation of vesicles in aqueous media (different pH or ionic strength) with potential applications in biomedicine and drug delivery.

Structure - membrane activity relationship in a family of peptide-based gemini amphiphiles: An insight from experimental and theoretical model systems.

A study of the interaction between five gemini amphiphilic valine-based pseudopeptides (GAPs) differing by the length of the central aliphatic spacer linking two amino acid subunits, and a model bacterial membrane lipid, 1,2-dimyristoyl-sn-glycero-3-phospho-rac-(1-glycerol) (DMPG), is here presented. Pure DMPG, pure GAPs and mixed GAPs/DMPG monolayers were formed at the air-water interface using Langmuir technique. The properties of the Langmuir films were investigated using surface pressure measurements, polarization modulation-infrared reflection-absorption spectroscopy, and Brewster angle microscopy. The atomic level information concerning the orientation of molecules in the monolayer and hydration of the polar headgroups was obtained from molecular dynamics simulations. It was demonstrated that the length of the central spacer in the GAPs structure is important for the properties of the mixed films; the disorganization of the membrane increases with the length of the spacer. The latter point is important for developing possible antimicrobial agents based on GAPs.