50971-79-4Relevant academic research and scientific papers
Phenothiazine-Tacrine Heterodimers: Pursuing Multitarget Directed Approach in Alzheimer's Disease
Gorecki, Lukas,Uliassi, Elisa,Bartolini, Manuela,Janockova, Jana,Hrabinova, Martina,Hepnarova, Vendula,Prchal, Lukas,Muckova, Lubica,Pejchal, Jaroslav,Karasova, Jana Z.,Mezeiova, Eva,Benkova, Marketa,Kobrlova, Tereza,Soukup, Ondrej,Petralla, Sabrina,Monti, Barbara,Korabecny, Jan,Bolognesi, Maria Laura
, p. 1698 - 1715 (2021/05/10)
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 in vitro evaluated for their anticholinesterase properties. The assessment of the structure-activity relationships of such derivatives highlighted compound 1dC as a potent and selective acetylcholinesterase inhibitor with IC50 = 8 nM and 1aA as a potent butyrylcholinesterase inhibitor with IC50 = 15 nM. Selected hybrids, namely, 1aC, 1bC, 1cC, 1dC, and 2dC, showed a significant inhibitory activity toward τ(306-336) peptide aggregation with percent inhibition ranging from 50.5 to 62.1%. Likewise, 1dC and 2dC exerted a remarkable ability to inhibit self-induced Aβ1-42 aggregation. Notwithstanding, in vitro studies displayed cytotoxicity toward HepG2 cells and cerebellar granule neurons; no pathophysiological abnormality was observed when 1dC was administered to mice at 14 mg/kg (i.p.). 1dC was also able to permeate to the CNS as shown by in vitro and in vivo models. The maximum brain concentration was close to the IC50 value for acetylcholinesterase inhibition with a relatively slow elimination half-time. 1dC showed an acceptable safety and good pharmacokinetic properties and a multifunctional biological profile.
A Focused Library of Psychotropic Analogues with Neuroprotective and Neuroregenerative Potential
Uliassi, Elisa,Pena-Altamira, Luis Emiliano,Morales, Aixa V.,Massenzio, Francesca,Petralla, Sabrina,Rossi, Michele,Roberti, Marinella,Martinez Gonzalez, Loreto,Martinez, Ana,Monti, Barbara,Bolognesi, Maria Laura
, p. 279 - 294 (2018/10/20)
Overcoming the lack of effective treatments and the continuous clinical trial failures in neurodegenerative drug discovery might require a shift from the prevailing paradigm targeting pathogenesis to the one targeting simultaneously neuroprotection and neuroregeneration. In the studies reported herein, we sought to identify small molecules that might exert neuroprotective and neuroregenerative potential as tools against neurodegenerative diseases. In doing so, we started from the reported neuroprotective/neuroregenerative mechanisms of psychotropic drugs featuring a tricyclic alkylamine scaffold. Thus, we designed a focused-chemical library of 36 entries aimed at exploring the structural requirements for efficient neuroprotective/neuroregenerative cellular activity, without the manifestation of toxicity. To this aim, we developed a synthetic protocol, which overcame the limited applicability of previously reported procedures. Next, we evaluated the synthesized compounds through a phenotypic screening pipeline, based on primary neuronal systems. Phenothiazine 2Bc showed improved neuroregenerative and neuroprotective properties with respect to reference drug desipramine (2Aa). Importantly, we have also shown that 2Bc outperformed currently available drugs in cell models of Alzheimer's and Parkinson's diseases and attenuates microglial activation by reducing iNOS expression.
