Abstract
Series of twenty-five benzyl (2S)-2-(arylcarbamoyl)pyrrolidine-1-carboxylates was prepared and completely characterized. All the compounds were tested for their in vitro ability to inhibit acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), and the selectivity of compounds to individual cholinesterases was determined. Screening of the cytotoxicity of all the compounds was performed using a human monocytic leukaemia THP-1 cell line, and the compounds demonstrated insignificant toxicity. All the compounds showed rather moderate inhibitory effect against AChE; benzyl (2S)-2-[(2-chlorophenyl)carbamoyl]pyrrolidine-1-carboxylate (IC50 = 46.35 μM) was the most potent agent. On the other hand, benzyl (2S)-2-[(4-bromophenyl)-] and benzyl (2S)-2-[(2-bromophenyl)carbamoyl]pyrrolidine-1-carboxylates expressed anti-BChE activity (IC50 = 28.21 and 27.38 μM, respectively) comparable with that of rivastigmine. The ortho-brominated compound as well as benzyl (2S)-2-[(2-hydroxyphenyl)carbamoyl]pyrrolidine-1-carboxylate demonstrated greater selectivity to BChE. The in silico characterization of the structure–inhibitory potency for the set of proline-based carbamates considering electronic, steric and lipophilic properties was provided using comparative molecular surface analysis (CoMSA) and principal component analysis (PCA). Moreover, the systematic space inspection with splitting data into the training/test subset was performed to monitor the statistical estimators performance in the effort to map the probability-guided pharmacophore pattern. The comprehensive screening of the AChE/BChE profile revealed potentially relevant structural and physicochemical features that might be essential for mapping of the carbamates inhibition efficiency indicating qualitative variations exerted on the reaction site by the substituent in the 3′-/4′-position of the phenyl ring. In addition, the investigation was completed by a molecular docking study of recombinant human AChE.
Highlights
An amide (–CONH–) and/or carbamate (–OCONH–) group is present in a number of clinically used drugs [1] and pesticides [2]
[8,41,42,43], we have selected the methods which have been previously used in our laboratories [8,41,42,43], we have selected the procedure the procedure where propylphosphonic hasa been usedagent as a coupling
(2S)-1-[(benzyloxy)carbonyl]-pyrrolidine-2-carboxylic acid pyrrolidine-2-carboxylic acid and a wide variety of substituted anilines led to the formation of and a wide variety of substituted anilines led to the formation of corresponding substituted anilides 1–8c corresponding substituted anilides
Summary
An amide (–CONH–) and/or carbamate (–OCONH–) group is present in a number of clinically used drugs [1] and pesticides [2] Both terminations can be variously substituted, which results in a privileged structural fragment [3,4]. The major role of AChE is to catalyse the hydrolysis of acetylcholine (ACh) in cholinergic synapses, while BChE can hydrolyse ACh as well as other esters; it seems its concentration in brain is especially important at Alzheimer’s disease (AD) [20,21] The inhibition of both enzymes causes an increase in the ACh concentration in cholinergic synapses and can subsequently affect a number of pathogenic processes.
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