New Multitarget Hybrids Bearing Tacrine and Phenylbenzothiazole Motifs as Potential Drug Candidates for Alzheimer's Disease

• Autor(a) principal: Rajeshwari, Rajeshwari
• Data de Publicação: 2019
• Outros Autores: Chand, Karam, Candeias, Emanuel, Cardoso, Sandra M., Chaves, Sílvia, Santos, M. Amélia
• Tipo de documento: Artigo
• Idioma: eng
• Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
• Texto Completo: http://hdl.handle.net/10316/107173; https://doi.org/10.3390/molecules24030587
• topic: Alzheimer’s disease; Aβ aggregation; acetylcholinesterase inhibitors; benzothiazole; multitarget; tacrine hybrids; Alzheimer Disease; Amyloid beta-Peptides; Cell Line, Tumor; Cell Survival; Cholinesterase Inhibitors; Drug Design; Humans; Models, Molecular; Molecular Conformation; Molecular Structure; Protein Aggregates; Protein Aggregation, Pathological; Structure-Activity Relationship; Tacrine; Thiazoles

Research on neurodegenerative brain disorders, namely the age-dependent Alzheimer's disease (AD), has been intensified in the last decade due to the absence of a cure and the recognized increasing of life expectancy for populations. To address the multifactorial nature and complexity of AD, a multi-target-directed ligand approach was herein employed, by designing a set of six selected hybrids (14⁻19) that combine in the same entity two pharmacophores: tacrine (TAC) and 2-phenylbenzothiazole (PhBTA). The compounds contain a methoxy substituent at the PhBTA moiety and have a variable length linker between that and the TAC moiety. The docking studies showed that all the compounds assure a dual-binding mode of acetylcholinesterase (AChE) inhibition, establishing π-stacking and H-bond interactions with aminoacid residues at both active binding sites of the enzyme (CAS and PAS). The bioassays revealed that the designed compounds display excellent AChE inhibitory activity in the sub-micromolar range (0.06⁻0.27 μM) and moderate inhibition values for amyloid-β (Aβ) self-aggregation (27⁻44.6%), compounds 14 and 15 being the lead compounds. Regarding neuroprotective effects in neuroblastoma cells, compounds 15, 16 and 19 revealed the capacity to prevent Aβ-induced toxicity, but compound 16 showed the highest neuroprotective effect. Overall these hybrid compounds, in particular 15 and 16, with promising multitarget anti-AD ability, encourage further pursuing studies on this type of TAC-PhBTA derivatives for potential AD therapy.