However, there is still uncertainty about the clinical benefits of aducanumab, and further post-approval trials are under way in the USA. This antibody, directed against amyloid-beta oligomers, is the first known therapeutic agent to actually alter disease progression and not merely delay it, and it will be administered in the USA to patients with severe AD. Recently, FDA (Food and Drug Administration, US) granted “accelerated approval” to the clinical use of monoclonal antibody aducanumab. Only four drugs are available, including three cholinesterase inhibitors (donepezil, rivastigmine and galantamine) and an NMDA receptor blocker (memantine). These results, paired with the low or absent cytotoxicity of these compounds at tested concentrations, allow us to aim our future research at the study of novel and effective drugs and pro-drugs with similar structural characteristics.Ĭurrently, established therapies are essentially aimed at delaying the progression of symptoms related to the disease, mainly the slow and unstoppable memory loss. Compound 13, on the other hand, while inactive in the DPPH assay, showed the best results in the in vitro antioxidant cell assays conducted on both HepG2 and SHSY-5Y cell lines. In silico docking calculations supported the obtained results. Compounds 11d and 12d showed the most interesting multi-target profiles, with all the assayed activities in the low micromolar range. Furthermore, the drug-likeness properties of these compounds were assessed using cheminformatic tools. The investigation of the resulting hybrids showed, in addition to their antioxidant properties, their activity against some AD-related targets, such as the inhibition of cholinesterases (both AChE and BChE) and in vitro Aβ 1-40 aggregation, as well as the inhibition of the innovative target fatty acid amide hydrolase (FAAH). Herein, we propose a new series of hybrid molecules obtained by linking a phenothiazine moiety, known for its antioxidant properties, with N-benzylpiperidine or N-benzylpiperazine fragments, mimicking the core substructure of DPZ. Among other pathological factors, oxidative stress has emerged as an important factor in AD that could affect several pathways involved in the onset and progression of the pathology. Alzheimer’s disease (AD) is a complex multi-factorial neurodegenerative disorder for which only few drugs (including donepezil, DPZ) are available as symptomatic treatments thus, researchers are focusing on the development of innovative multi-target directed ligands (MTDLs), which could also alter the course of the disease.
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