Novel multi-target directed ligands as drug candidates against Alzheimer’s disease

Abstract

Alzheimer’s disease (AD) is the main neurodegenerative disorder and one of the most important health-care problems worldwide, because of its high prevalence and personal and economic impact. To aggravate this situation, current treatments are only symptomatic, but do not prevent, halt, or delay the disease progression. In the light of the multiple mechanisms involved in its pathogenesis, such as dysfunction of cholinergic and glutamatergic neurotransmitter systems, amyloid and tau pathologies, or oxidative stress, among others, the traditional medicinal chemistry approach of developing drugs based on the reductionist pattern of “one molecule-one target” is being increasingly perceived as ineffective. Alternatively, the so- called multitarget directed ligands (MTDLs), which consist of molecules designed to hit simultaneously different key targets of the complex pathological network, are emerging as a more realistic option to confront the disease. In this context, the purpose of the present PhD Thesis was the design, synthesis and biological evaluation of four novel families of compounds, endowed with multi-target profile, as drug candidates for the treatment of AD: 1) firstly, a family of shogaol–huprine hybrids, with purported dual antioxidant and anticholinesterase activity, with those activities to be imparted by their shogaol-derived and huprine moieties, respectively, and with β-amyloid and tau anti-aggregating activity likely arising from the planar aromatic moieties of their two constituting units; 2) secondly, a second generation of rhein–huprine hybrids designed by modification of the huprine aromatic ring of the lead compound of a previous generation of compounds, developed in our group, to explore the effect of pyridinic ring basicity on the different biological activities, with the hope of identifying an optimized hybrid with favorable activity profile on cholinesterases, β-secretase 1, β-amyloid and tau aggregation, and free radicals, and with reduced basicity, and, hence, with expectable better bioavailability; 3) thirdly, a family of CR-6–tacrine hybrids, which was designed to achieve a dual site binding within both acetylcholinesterase and β-secretase 1, apart from antioxidant activity, by combining a unit of the potent acetylcholinesterase inhibitor 6-chlorotacrine with a moiety derived from CR-6, a potent antioxidant; and 4) finally, a class of benzoadamantane–tacrine hybrids intented to act as acetylcholinesterase inhibitors and NMDA receptor antagonists, to combat neurodegeneration as well as improve memory and cognition. A crucial property for central nervous system drugs, the blood–brain permeability, was additionally assessed for all the abovementioned compounds.