Starting from the chemical structures of the potent brain-permeable AChE inhibitors tacrine, 6-chlorotacrine, and huprine Y, which are of interest in the context of Alzheimer’s disease treatment, we have designed and synthesized two series of derivatives of increased polarity with the aim of precluding their penetration into the central nervous system, thus confining their anticholinesterase action to the peripheral level for potential therapeutic use against myasthenia gravis. Here, ACHE is linked to early-onset autosomal dominant Alzheimer disease.