Acetylcholinesterase Inhibitors:  SAR and Kinetic Studies on ω-[N-Methyl-N-(3-alkylcarbamoyloxyphenyl)methyl]aminoalkoxyaryl Derivatives

Abstract

In this work, we further investigated a class of carbamic cholinesterase inhibitors introduced in a previous paper (Rampa et al. J. Med. Chem. 1998, 41, 3976). Some new omega-[N-methyl-N-(3-alkylcarbamoyloxyphenyl)methyl]aminoalkoxyaryl analogues were designed, synthesized, and evaluated for their inhibitory activity against both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). The structure of the lead compound (xanthostigmine) was systematically varied with the aim to optimize the different parts of the molecule. Moreover, such a structure-activity relationships (SAR) study was integrated with a kinetic analysis of the mechanism of AChE inhibition for two representative compounds. The structural modifications lead to a compound (12b) showing an IC(50) value for the AChE inhibition of 0.32 +/- 0.09 nM and to a group of BuChE inhibitors also active at the nanomolar level, the most potent of which (15d) was characterized by an IC(50) value of 3.3 +/- 0.4 nM. The kinetic analysis allowed for clarification of the role played by different molecular moieties with regard to the rate of AChE carbamoylation and the duration of inhibition. On the basis of the results presented here, it was concluded that the cholinesterase inhibitors of this class possess promising characteristics in view of a potential development as drugs for the treatment of Alzheimer's disease.

Screening of acetylcholinesterase inhibitors by CE after enzymatic reaction at capillary inlet

“…As can be observed, the IC 50 values obtained using inline chromatographic and EMMA methodologies were larger than those obtained with the static Ellman method considered in bibliography as reference method. From the IC 50 value for tacrine obtained with the Ellman method 0.25 lM [3,10,22] and the IC 50 calculated from the inhibition curves using the at-inlet EMMA method a dilution factor, f, of 0. estimated. Obviously the calculated dilution factor correction assumes that the reported literature value is a true value.…”

A Simple One‐pot Synthesis of Indeno[2,1‐f]quinolin‐3‐one Derivatives under Microwave Irradiation

“…1 H NMR spectra were measured on a Bruker DPX 400 MHz spectrometer in DMSO-d 6 with TMS as an internal standard. 13 C NMR spectra were measured on a Bruker DPX 100 MHz spectrometer in DMSO-d 6 . High-resolution mass spectra (HRMS) were obtained on a Varian IonSpec QFT-MS spectrometer with the technique of electrospray ionization.…”

“…In this study, all the products were characterized by IR, 1 H NMR, 13 C NMR and HRMS techniques. Regarding the structure of 4, the IR spectra of compound 4c showed strong absorptions at 1678 cm -1 due to C＝ O.…”

Design of novel carbamate acetylcholinesterase inhibitors based on the multiple binding sites of acetylcholinesterase

“…At the same time, the carbamic group of compound C and D located at the catalytic sites of AChE, and the protonated amine group also interacted with several amino acid residues. 7,8) Dual or multiple-site inhibitors of AChE all focused on new drug discovery, but there have been no relevant reports in the pesticide field. In order to obtain inhibitors able to bind at the catalytic sites and the peripheral sites or at other sites on half of AChE, we designed molecules composed of two moieties (phthalimide and methylcarbamate) to bind at each site, linked by different carbon numbers of alkylene, and synthesized a series of novel phthalimide alkyloxyphenyl methylcarbamates.…”