New cholinesterase inhibitors for Alzheimer's disease: Structure Activity Studies (SARs) and molecular docking of isoquinolone and azepanone derivatives

A library of isoquinolinone and azepanone derivatives were screened for both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) activity. The strategy adopted included (a) in vitro biological assays, against eel AChE (EeAChE) and equine serum BuChE (EqBuChE) in order to determine the compounds IC50 and their dose-response activity, consolidated by (b) molecular docking studies to evaluate the docking poses and interatomic interactions in the case of the hit compounds, validated by STD-NMR studies. Compound (1f) was identified as one of these hits with an IC50 of 89.5 mu M for EeAChE and 153.8 mu M for EqBuChE, (2a) was identified as a second hit with an IC50 of 108.4 mu M (EeAChE) and 277.8 mu M (EqBuChE). In order to gain insights into the binding mode and principle active site interactions of these molecules, (R)-(1f) along with 3 other analogues (also as the R-enantiomer) were docked into both RhAChE and hBuChE models. Galantamine was used as the benchmark. The docking study was validated by performing an STD-NMR study of (1f) with EeAChE using galantamine as the benchmark.

Systems of coupled clamped beams equations with full nonlinear terms: Existence and location results

This work gives sufficient conditions for the solvability of the fourth order coupled system┊ u⁽⁴⁾(t)=f(t,u(t),u′(t),u′′(t),u′′′(t),v(t),v′(t),v′′(t),v′′′(t)) v⁽⁴⁾(t)=h(t,u(t),u′(t),u′′(t),u′′′(t),v(t),v′(t),v′′(t),v′′′(t)) with f,h: [0,1]×ℝ⁸→ℝ some L¹- Carathéodory functions, and the boundary conditions {┊ u(0)=u′(0)=u′′(0)=u′′(1)=0 v(0)=v′(0)=v′′(0)=v′′(1)=0. To the best of our knowledge, it is the first time in the literature where two beam equations are considered with full nonlinearities, that is, with dependence on all derivatives of u and v. An application to the study of the bending of two elastic coupled campled beams is considered.