Phenothiazine-Tacrine Heterodimers: Pursuing Multitarget Directed Approach in Alzheimer's Disease.

Since 2002, no clinical candidate against Alzheimer's disease has reached the market; hence, an effective therapy is urgently needed. We followed the so-called "multitarget directed ligand" approach and designed 36 novel tacrine-phenothiazine heterodimers which were evaluated for their anticholinesterase properties. The assessment of the structure-activity relationships of such derivatives highlighted compound as a potent and selective acetylcholinesterase inhibitor with IC = 8 nM and as a potent butyrylcholinesterase inhibitor with IC = 15 nM. Selected hybrids, namely, , , , , and , showed a significant inhibitory activity toward τ peptide aggregation with percent inhibition ranging from 50.5 to 62.1%. Likewise, and exerted a remarkable ability to inhibit self-induced Aβ aggregation. Notwithstanding, studies displayed cytotoxicity toward HepG2 cells and cerebellar granule neurons; no pathophysiological abnormality was observed when was administered to mice at 14 mg/kg (i.p.). was also able to permeate to the CNS as shown by and models. The maximum brain concentration was close to the IC value for acetylcholinesterase inhibition with a relatively slow elimination half-time. showed an acceptable safety and good pharmacokinetic properties and a multifunctional biological profile.