Multifunctional Cholinesterase and Amyloid Beta Fibrillization Modulators. Synthesis and Biological Investigation

Abstract

In order to identify novel Alzheimer's modifying pharmacological tools, we developed bis-tacrines bearing a peptide moiety for specific interference with surface sites of human acetylcholinesterase (hAChE) binding amyloid-beta (Aβ). Accordingly, compounds 2a−c proved to be inhibitors of hAChE catalytic and noncatalytic functions, binding the catalytic and peripheral sites, interfering with Aβ aggregation and with the Aβ self-oligomerization process (2a). Compounds 2a−c in complex with TcAChE span the gorge with the bis-tacrine system, and the peptide moieties bulge outside the gorge in proximity of the peripheral site. These moieties are likely responsible for the observed reduction of hAChE-induced Aβ aggregation since they physically hamper Aβ binding to the enzyme surface. Moreover, 2a was able to significantly interfere with Aβ self-oligomerization, while 2b,c showed improved inhibition of hAChE-induced Aβ aggregation.

Synthesis and Multitarget Biological Profiling of a Novel Family of Rhein Derivatives As Disease-Modifying Anti-Alzheimer Agents

“…[6][7][8][9][10] In the past years, many research groups have pursued the development of multi-target antiAlzheimer drugs as an advantageous approach over multi-target multi-drug strategies (drug cocktails and fixed-dose combinations). [11][12][13][14][15] Multi-target compounds have been usually designed to hit at least Aβ formation and aggregation and AChE activity, 16 especially prompted by the finding that AChE can bind Aβ, thereby promoting its aggregation and increasing its neurotoxicity. [17][18][19] The recognition site of Aβ within AChE is the so-called peripheral anionic site (PAS) and it is located at the entrance of a 20 Å deep narrow gorge that leads to the catalytic anionic site (CAS).…”

Structural characterization of Giardia duodenalis thioredoxin reductase ( g TrxR) and computational analysis of its interaction with NBDHEX

“…the Schrödinger suite 2015 by applying the IFD protocol[38][39][40][41] (Induced Fit Docking protocol 2015; Glide version 6.4, Prime version 3.7, Schrödinger, Release 2015). This procedure induces conformational changes in the binding site to accommodate the ligand and exhaustively identify possible binding modes and associated conformational changes by side-chain sampling and 290) with default setting.…”

Development of Potent Inhibitors of Fatty Acid Amide Hydrolase Useful for the Treatment of Neuropathic Pain

“…To better understand the structure-activity relationships (SARs) of the developed compounds, we performed molecular docking studies to assess the interactions of the inhibitors with FAAH at the atomicl evel. We performed an induced-fit docking (IFD) calculation as reported [33][34][35] to identify the main contacts governingt he behavior of our compounds with the enzyme.T he data were compared with those obtained by applying the same protocolt oo ur previously described lead 3 (see the Supporting Information (SI) and Figure S1). In particular, 5h,one of the mostpotent compounds of this series, interacts with the FAAH actives ite by polar and hydrophobic contacts (Figure 2A,B).…”