Studies on novel Tacrine-Donepezil hybrids with potent MTDL profile

Bayraktar G. , Parlar Çoşkun S. , Bagetta D., Ortuso F., Alcaro S., Alptüzün V.

MuTaLig COST ACTION CA15135 3rd WG meeting 2019, Paris, Fransa, 23 - 24 Şubat 2019, ss.12

  • Basıldığı Şehir: Paris
  • Basıldığı Ülke: Fransa
  • Sayfa Sayıları: ss.12


Alzheimer’s disease (AD), is a neurodegenerative disease characterized by various pathologic pathways. The oldest theory regarding AD pathophysiology is the cholinergic hypothesis, relies on decreased Ach levels at the synaptic cleft. Apart from this, there are several other pathways in the pathology of AD including formation and accumulation of toxic amyloid-β (Aβ) plaques, neurofibrillary tangles (NFT), oxidative stress, metal ion dyshomeostasis, inflammation, etc 1,2 . Tacrine, donepezil, rivastigmine, and galantamine are AChE inhibitors approved by FDA for the symptomatic treatment of AD. Considering the complex pathology of the disease, it is essential to target more than one pathological pathway with one molecule to obtain disease modifying effect 2,3 . In our previous study, benzylpiperidine moiety of donepezil and tacrine were selected as core structures and merged with hydrazone functional group to aim dual inhibition of AChE as well as inhibition of Aβ aggregation and metal complex formation properties. Considering all these data, newly synthesized hybrids showed a promising MTDL profile against AD. As lead-like structures should possess drugability properties in order to attain a certain degree of therapeutic efficacy and avoid poor pharmacokinetics, low bioavailability, high toxicity, etc., ADME properties of the title compounds were investigated theoretically to obtain bioavailability and BBB permeability profiles of the compounds. Docking studies were performed on the selected compounds with both AChE and BuChE.