Novel Uracil-Based Inhibitors of Acetylcholinesterase with Potency for Treating Memory Impairment in an Animal Model of Alzheimer’s Disease

Novel derivatives based on 6-methyluracil and condensed uracil, 2,4-quinazoline-2,4-dione, were synthesized with terminal meta- and para-benzoate moieties in polymethylene chains at the N atoms of the pyrimidine ring. In the synthesized compounds, the polymethylene chains were varied from having tris- to hexamethylene chains and quaternary ammonium groups; varying substituents (ester, salt, acid) at benzene ring were introduced into the chains and benzoate moieties. In vivo biological experiments demonstrated the potency of these compounds in decreasing the number of β-amyloid plaques and their suitability for the treatment of memory impairment in a transgenic model of Alzheimer’s disease.     

Deuteron Quadrupolar Chemical Exchange Saturation Transfer (Q-CEST) Solid-State NMR for Static Powder Samples: Approach and Applications to Amyloid-β Fibrils

We provide an experimental and computational framework for ²H quadrupolar chemical exchange saturation transfer NMR experiments (Q-CEST) under static solid-state conditions for the quantification of dynamics on μs-ms timescales. Simulations using simple 2-site exchange models provide insights into the relation between spin dynamics and motions. Biological applications focus on two sites of amyloid-β fibrils in the 3-fold symmetric polymorph. The first site, the methyl group of A2 of the disordered N-terminal domain, undergoes diffusive motions and conformational exchange due to transient interactions. Earlier ²H rotating frame relaxation and quadrupolar CPMG measurements are combined with the Q-CEST approach to characterize the multiple conformational states of the domain. The second site, the methyl group of M35, spans the water-accessible cavity inside the fibrils’ core and undergoes extensive rotameric exchange. Q-CEST permits us to refine the rotameric exchange model for this site and allows the more precise determination of populations and rotameric exchange rate constants than line shape analysis.     

Deuteron Solid-State NMR Relaxation Measurements Reveal Two Distinct Conformational Exchange Processes in the Disordered N-Terminal Domain of Amyloid-β Fibrils

We employed deuterium solid-state NMR techniques under static conditions to discern the details of the μs–ms timescale motions in the flexible N-terminal subdomain of Aβ_1–40 amyloid fibrils, which spans residues 1–16. In particular, we utilized a rotating frame (R_1ρ) and the newly developed time domain quadrupolar Carr-Purcell-Meiboom-Gill (QCPMG) relaxation measurements at the selectively deuterated side chains of A2, H6, and G9. The two experiments are complementary in terms of probing somewhat different timescales of motions, governed by the tensor parameters and the sampling window of the magnetization decay curves. The results indicated two mobile “free” states of the N-terminal domain undergoing global diffusive motions, with isotropic diffusion coefficients of 0.7−1 ⋅ 10⁸ and 0.3−3 ⋅ 10⁶ad² s⁻¹. The free states are also involved in the conformational exchange with a single bound state, in which the diffusive motions are quenched, likely due to transient interactions with the structured hydrophobic core. The conformational exchange rate constants are 2−3 ⋅ 10⁵ s⁻¹ and 2−3 ⋅ 10⁴ s⁻¹ for the fast and slow diffusion free states, respectively.     

Aldol-type transformations of levoglucosenone-derived medium-sized keto lactones

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Thermal analysis and EPR study of copper species in mordenites prepared by conventional and microwave-assisted methods

The main work of this thesis is to study and discuss flame-retardant properties of the flexible polyurethane foam (FPUF) added with borax, expanded graphite (EG), and EG/Borax as flame retardant, respectively. The thermal behavior of samples has been using thermogravimetry (TG) and differential thermogravimetry in air. The activation energies for different stages of thermal degradation are obtained following the equation of Kissinger. The flammability parameters, including limiting oxygen index, rate of heat release, total heat release, yield of CO, yield of CO₂, and smoke production rate, were recorded simultaneously. The char structure was studied by SEM, and their thermal stability and evolved gaseous products were examined by TG analysis–Fourier transform infrared spectroscopy. By analyzing these data, it was concluded that most combustion parameters of FPUF were decreased by the treatment, especially for EG/Borax treatment, which indicated a synergistic effect of flame retardancy. Meanwhile, the probable flame retardation mechanism was proposed.     

Synthesis and Antimycotic Properties of Hydroxy Sulfides Derived from exo- and endo-4-phenyl-3,5,8-trioxabicyclo[5.1.0]octanes

Both exo- and endo-isomers of 4-phenyl-3,5,8-trioxabicyclo[5.1.0]octane were reacted with thiophenol to afford individual diastereomers of hydroxy sulfides which were further processed in search for new antimycotic substances.