Design and Friedlander Reaction Based Synthesis of New Cycloalkyl Ring Fused Quinolines as Multifunctional Agents for Alzheimer's Treatment: In Silico Studies

Abstract

AbstractA new series of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitors were designed based on the structure of tacrine and synthesized in multicomponent Friedlander reaction between 2‐aminobenzonitrile and cycloalkanones. The synthesized tacrine analogs were characterized by spectral data and evaluated for acetylcholinesterase and butyryl cholinesterase inhibitory activity by following Ellman method. Compound 11 a and 11 g with piperazine containing acetamide and butyrylamide chains have shown equal potency to that of tacrine with IC50 values 0.71±0.04 and 1.01±0.03 μM, and 0.52±0.03 and 0.73±0.04 μM, against AChE and BuChE respectively when compared to standard tacrine with IC50 of 0.23±0.4 μM and 0.31±0.03, whereas rivastigmine showed 0.47±0.2 and 0.65±0.02 μM against AChE and BuChE, respectively. Also, some of the potent compounds were tested for liver toxicity and were found to be much safer than tacrine. Thus, these new tacrine analogs with five, six and seven membered ‘C’ rings have emerged as new cholinesterase inhibitors for further exploitation as anti‐Alzheimer's agents. Docking studies of all the molecules disclosed close hydrogen bond interactions within the binding site.