Synthesis, Solid State Self-Assembly Driven by Antiparallel Π•••π Stacking and {/H-c-c-f}2 Dimer Synthons, and in Vitro Acetyl Cholinesterase Inhibition Activity of Phenoxy Pendant Isatins

Abstract

A series of novel phenoxy pendant isatins PI1-12 have been synthesized in excellent yields by a simple nucleophilic substitution reaction involving isatins and 1-(2-bromoethoxy)-4-substituted benzenes, and characterized by their FT-IR, H-1 NMR, C-13 NMR and GC-MS data, and in the case of PI4 by its single crystal X-ray analysis. The solid-state structure of PI4 showed an intriguing and unique 1D-supramolecular chain-based self-assembled structure, the driving force of which is mainly the strong antiparallel pi center dot center dot center dot pi stacking and {center dot center dot center dot-C-C-F}(2) dimer synthons. This compound not only highlights the potential of the isatin moiety in forming strong antiparallel pi center dot center dot center dot pi stacking interactions but also provides a platform to have considerable insight into the nature, strength and directionality of much debated pi center dot center dot center dot pi and C-H center dot center dot center dot F=C interactions. The in vitro biological studies revealed that three phenoxy pendant isatins PI1, PI2 and PI4 are highly potent inhibitors of acetylcholinesterase enzyme with IC50 values of 0.52 +/- 0.073 mu g ml(-1), 0.72 +/- 0.012 mu g ml(-1) and 0.68 +/- 0.011 mu g ml(-1), respectively, showing comparable activity to the standard drug, donepezil (IC50 = 0.73 +/- 0.015 mu g ml(-1)). A simple and efficient synthesis of phenoxy pendant isatins PI1-12 from inexpensive and commercially available starting materials, and their high potential of acetyl cholinesterase inhibition provide an attractive opportunity to find more effective medication for Alzheimer's disease (AD).