Dimethyl-Carbamic Acid 2,3-Bis-Dimethylcarbamoyloxy-6-(4-Ethyl-Piperazine- 1-Carbonyl)-Phenyl Ester: A Novel Multi-Target Therapeutic Approach to Neuroprotection

Abstract

We report herein the synthesis and biological evaluation of dimethyl-carbamic acid 2,3-bis-dimethylcarbamoyloxy-6-(4-ethyl-piperazine-1-carbonyl)-phenyl ester (SP-04), a new drug candidate that is designed to offer a multi-target therapeutic neuroprotective approach as a treatment for Alzheimer's disease (AD). SP-04 inhibits acetylcholinesterase (AchE) activity both in vitro and in vivo, and induces a dose-dependent increase in Ach levels. SP-04 releases the metabolite 4-(4-ethyl-piperazin-1-yl)-1-(2,3,4-trihydroxy-phenyl)-butan-1-one (SP-04m). Both SP-04 and SP-04m are s1-receptor antagonists supporting their interest in relieving symptoms related to psychosis, a non-cognitive condition often associated with AD. SP-04m displays important antioxidant properties and both SP-04 and SP-04m offers neuroprotection against Ab42 toxicity in various neuronal cell lines. In addition, both SP-04 and SP-04m protect neuronal cells and rat brain mitochondria exposed to various mitochondrial respiratory chain complex toxins. Taken together these data suggest that the SP-04 multi-targeting approach might offer a novel therapeutic strategy for the treatment of AD.

Multi-Target Directed Ligands (MTDLs) Binding the σ1 Receptor as Promising Therapeutics: State of the Art and Perspectives

“…Among the studied ligands, two compounds (i.e., 2,3,4-trihydroxy-phenyl)butan-1-one 1 and the corresponding N,N-dimethylcarbamoyloxy prodrug 2; Figure 1) showed the best compromise in terms of activity on the different targets. Compound 2 was able to (i) inhibit AChE with a potency comparable to reference compounds; (ii) bind σ 1 receptors (high selectivity, sub-micromolar affinity, and antagonist activity); and (iii) prevent mitochondrial toxicity by inhibiting mitochondrial complex IV and V. On the other hand, compound 1, even if much less active than its bio-precursor toward σ 1 receptors, was also able to attenuate reactive oxygen species (ROS), Aβ 1-42 -induced neurotoxicity, and mitochondrial toxicity by inhibiting complexes I, II, IV, and V. 1) and (2) and their K i and IC 50 values for σ 1 receptor (σ 1 R) and human acetylcholinesterase (hAChE) [77].…”

“…Behavioral studies on animal models are needed, but preliminary data suggest that this multi-target profile can represent a novel therapeutic strategy to treat AD [77].…”

“…Figure 1. Compound (1) and (2) and their K i and IC 50 values for σ 1 receptor (σ 1 R) and human acetylcholinesterase (hAChE)[77].…”