title: New Tacrine Hybrids with Natural-Based Cysteine Derivatives as Multitargeted Drugs for Potential Treatment of Alzheimer's Disease.
abstract: Alzheimer's disease (AD) is a devastating age-dependent neurodegenerative disorder. The main hallmarks are impairment of cholinergic system and accumulation in brain of beta-amyloid (Aβ) aggregates, which have been associated with oxidative damage and dyshomeostasis of redox-active biometals. The absence of an efficient treatment that could delay or cure AD has been attributed to the complexity and multifactorial nature of this disease. With this in mind and the recent interest on natural-based drugs, we have explored a set of natural-based hybrid compounds by conjugation of a tacrine moiety with an S-allylcysteine (garlic constituent) or S-propargylcysteine moiety aimed at improving the cholinergic system and neuroprotective capacity. The docking modeling studies allowed the selection of linkers to optimize the bimodal drug interaction with acetylcholinesterase enzyme (AChE) active site. The compounds were evaluated for some representative biological properties, including AChE activity and Aβ aggregation inhibition, as well as for their neuroprotective activity to Aβ- and ROS-induced cellular toxicity. The most promising results were achieved by compounds 9d for the AChE inhibition and 9l for the remarkable prevention of superoxide production and Aβ-induced cellular toxicity.
authors.affiliation: Centro de Química Estrutural, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais 1, 1049-001, Lisboa, Portugal.|Centre for Nano and Material Sciences, Jain University, Jain Global Campus, Bangalore, Karnataka, 562112, India.
authors.forename: Rangappa S
authors.initials: RS
authors.lastname: Keri
authors.affiliation: Centro de Química Estrutural, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais 1, 1049-001, Lisboa, Portugal.
authors.forename: Catarina
authors.initials: C
authors.lastname: Quintanova
authors.affiliation: Centro de Química Estrutural, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais 1, 1049-001, Lisboa, Portugal.
authors.forename: Sílvia
authors.initials: S
authors.lastname: Chaves
authors.affiliation: CNBC - Centro de Neurociências e Biologia Celular, Universidade de Coimbra, 3030, Coimbra, Portugal.
authors.forename: Diana F
authors.initials: DF
authors.lastname: Silva
authors.affiliation: CNBC - Centro de Neurociências e Biologia Celular, Universidade de Coimbra, 3030, Coimbra, Portugal.|Faculdade de Medicina, Universidade de Coimbra, 3030, Coimbra, Portugal.
authors.forename: Sandra M
authors.initials: SM
authors.lastname: Cardoso
authors.affiliation: Centro de Química Estrutural, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais 1, 1049-001, Lisboa, Portugal.
authors.forename: M Amélia
authors.initials: MA
authors.lastname: Santos
mesh_terms: D000110:Acetylcholinesterase / Q000187:drug effects; D000544:Alzheimer Disease / Q000188:drug therapy*; D001812:Blood-Brain Barrier; D045744:Cell Line, Tumor; D002800:Cholinesterase Inhibitors / Q000494:pharmacology; D003545:Cysteine / Q000737:chemistry*; D006801:Humans; D013619:Tacrine / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D002800:Cholinesterase Inhibitors; D013619:Tacrine; D000110:Acetylcholinesterase; D003545:Cysteine
keywords: Alzheimer's disease; S-allylcysteine; S-propargylcysteine; acetylcholinesterase inhibitors; anti-Aβ aggregation; antineurodegeneratives; tacrine