title: Design, synthesis and neuroprotective evaluation of novel tacrine-benzothiazole hybrids as multi-targeted compounds against Alzheimer's disease.
abstract: Alzheimer's disease (AD) is a multifactorial disorder with several target proteins contributing to its etiology. In search for multifunctional anti-AD drug candidates, taking into account that the acetylcholinesterase (AChE) and beta-amyloid (Aβ) aggregation are particularly important targets for inhibition, the tacrine and benzothiazole (BTA) moieties were conjugated with suitable linkers in a novel series of hybrids. The designed compounds (7a-7e) were synthesized and in vitro as well as in ex vivo evaluated for their capacity for the inhibition of acetylcholinesterase (AChE) and Aβ self-induced aggregation, and also for the protection of neuronal cells death (SHSY-5Y cells, AD and MCI cybrids). All the tacrine-BTA hybrids displayed high in vitro activities, namely with IC₅₀ values in the low micromolar to sub-micromolar concentration range towards the inhibition of AChE, and high percentages of inhibition of the self-induced Aβ aggregation. Among them, compound 7a, with the shortest linker, presented the best inhibitory activity of AChE (IC₅₀=0.34 μM), while the highest activity as anti-Aβ₄₂ self-aggregation, was evidenced for compound 7b (61.3%, at 50μM. The docking studies demonstrated that all compounds are able to interact with both catalytic active site (CAS) and peripheral anionic site (PAS) of AChE. Our results show that compounds 7d and 7e improved cell viability in cells treated with Aβ₄₂ peptide. Overall, these multi-targeted hybrid compounds appear as promising lead compounds for the treatment of Alzheimer's disease.
authors.affiliation: Centro de Quimica Estrutural, Instituto Superior Técnico, Universidade Técnica de Lisboa, Av. Rovisco Pais 1, 1049-001 Lisboa, Portugal.
authors.forename: Rangappa S
authors.initials: RS
authors.lastname: Keri
authors.forename: Catarina
authors.initials: C
authors.lastname: Quintanova
authors.forename: Sérgio M
authors.initials: SM
authors.lastname: Marques
authors.forename: A Raquel
authors.initials: AR
authors.lastname: Esteves
authors.forename: Sandra M
authors.initials: SM
authors.lastname: Cardoso
authors.forename: M Amélia
authors.initials: MA
authors.lastname: Santos
mesh_terms: D000368:Aged; D000544:Alzheimer Disease / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D052160:Benzothiazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D002460:Cell Line; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D006801:Humans; D008958:Models, Molecular; D018696:Neuroprotective Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013619:Tacrine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D052160:Benzothiazoles; D002800:Cholinesterase Inhibitors; D018696:Neuroprotective Agents; D013619:Tacrine; C005465:benzothiazole