Design, synthesis, in silico and biological evaluations of novel polysubstituted pyrroles as selective acetylcholinesterase inhibitors against Alzheimer’s disease

Abstract

The objective of this study was to design new polysubstituted pyrrole derivatives as selective acetylcholinesterase (AChE) inhibitors to target Alzheimer's disease. In this context, a highly efficient, one-pot, sequential, multi-component synthesis of a diverse range of polysubstituted pyrroles was developed through a sequential domino strategy by the condensation of amines with 1,1-bis(methylthio)-2-nitroethene (BMTNE), Knovenagle reaction of arylglyoxals with malono derivatives and subsequent Michael addition and intramolecular cyclization reaction in EtOH at reflux. Thirty-nine synthesized compounds were evaluated as AChE and butyrylcholinesterase (BChE) inhibitors. Among the synthesized compounds, compound 4ad (IC50 = 2.95 ± 1.31 µM) was the most potent and selective AChE inhibitor with no significant inhibition against butyrylcholinesterase BChE. A kinetic study of 4ad revealed that this compound inhibited AChE in an uncompetitive mode. Based on a molecular modeling study, compound 4ad due to its small size properly fitted into the active site of AChE compared to BChE and stabilized by H-bond and hydrophobic interactions with the critical residues of the AChE binding pocket. Consequently, it was proposed that the 4ad derivative can be an ideal lead candidate against AD with a simple and practical operation of synthetic procedures.

A Review on Recent Approaches on Molecular Docking Studies of Novel Compounds Targeting Acetylcholinesterase in Alzheimer Disease

“…The Thr75 and para chlorophenyl moiety participated in shydrophobic interactions ( Figure 14 ). These interactions supported the biological assessment findings and attested to the high potency of this derivative [ 40 ].…”

“…For this reason, Pourtaher, H. and collaborators [ 40 ] designed and synthesized a series of pyrrole derivatives that were further evaluated for AChE inhibition. They used computational docking studies to simulate 2-(2-(4-(chlorophenyl))-[1-(4-hydroxyphenyl)]-[5-(methylthio)-[4-nitro]-[1H]-pyrrol-3yl]]-[2-cyanoacetamide] (compound 16 , Figure 13 ) on AChE’s binding site.…”

“… ( A ) 3D Binding pattern of compound 16 within the active site of AChE, ( B ) 2D binding interactions of compound 16 in AChE active site [ 40 ]. …”

“…The following supporting information can be downloaded at: , Table S1: Compounds, reference compounds, inhibitory values and docking results [ 21 , 25 , 30 , 31 , 32 , 35 , 36 , 37 , 38 , 40 , 42 , 46 , 48 , 50 , 62 , 68 , 70 , 71 , 76 , 77 , 78 , 82 , 83 , 87 , 92 ].…”

Highly efficient, catalyst-free, one-pot sequential four-component synthesis of novel spiroindolinone-pyrazole scaffolds as anti-Alzheimer agents: in silico study and biological screening

“…The experimental inhibitor constant ( K i ) value was constructed by secondary plots of the 5f concentration versus K m . 60…”