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Targeted covalent modification is assuming consolidated importance in drug discovery. In this context, the electrophilic tuning of redox-dependent cell signaling is attracting major interest, as it opens prospect for treating numerous pathologic conditions. Herein, we discuss the rationale and the issues of electrophile-based approaches, focusing on the transcriptional Nrf2-Keap1 pathway as a test case. We also highlight relevant medicinal chemistry strategies researchers have devised to meet the ambitious goal, dwelling on the investigational and therapeutic potential of modulating redox-signaling networks through regulatory cysteine switches.

Aim: Alzheimer pathogenesis has been associated with a network of processes working simultaneously and synergistically. Over time, much interest has been focused on cholinergic transmission and its mutual interconnections with other active players of the disease. Besides the cholinesterase mainstay, the multifaceted interplay between nicotinic receptors and amyloid is actually considered to have a central role in neuroprotection. Thus, the multitarget drug-design strategy has emerged as a chance to face the disease network., Methods: By exploiting the multitarget approach, hybrid compounds have been synthesized and studied in vitro and in silico toward selected targets of the cholinergic and amyloidogenic pathways., Results: The new molecules were able to target the cholinergic system, by joining direct nicotinic receptor stimulation to acetylcholinesterase inhibition, and to inhibit amyloid-β aggregation., Conclusion: The compounds emerged as a suitable starting point for a further optimization process.

Alzheimer's disease is a multifactorial syndrome, for which effective cures are urgently needed. Seeking for enhanced therapeutic efficacy, multitarget drugs have been increasingly sought after over the last decades. They offer the attractive prospect of tackling intricate network effects, but with the benefits of a single-molecule therapy. Herein, we highlight relevant progress in the field, focusing on acetylcholinesterase inhibition and amyloid pathways as two pivotal features in multitarget design strategies. We also discuss the intertwined relationship between selected molecular targets and give a brief glimpse into the power of multitarget agents as pharmacological probes of Alzheimer's disease molecular mechanisms.