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

Author

Pérez Areales, Francisco Javier

Director

Muñoz-Torrero López-Ibarra, Diego

Tutor

Muñoz-Torrero López-Ibarra, Diego

Date of defense

2017-07-14

Pages

464 p.



Department/Institute

Universitat de Barcelona. Departament de Farmacologia, Toxicologia i Química Terapèutica

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.

Keywords

Desenvolupament de medicaments; Desarrollo de los medicamentos; Drug development; Malaltia d'Alzheimer; Enfermedad de Alzheimer; Alzheimer's disease; Química farmacèutica; Química farmacéutica; Pharmaceutical chemistry

Subjects

615 - Pharmacology. Therapeutics. Toxicology

Knowledge Area

Ciències de la Salut

Documents

01.FJPA_PhD_THESIS.pdf

8.667Mb

02.FJPA_ANNEX_NMR.pdf

4.268Mb

 

Rights

ADVERTIMENT. L'accés als continguts d'aquesta tesi doctoral i la seva utilització ha de respectar els drets de la persona autora. Pot ser utilitzada per a consulta o estudi personal, així com en activitats o materials d'investigació i docència en els termes establerts a l'art. 32 del Text Refós de la Llei de Propietat Intel·lectual (RDL 1/1996). Per altres utilitzacions es requereix l'autorització prèvia i expressa de la persona autora. En qualsevol cas, en la utilització dels seus continguts caldrà indicar de forma clara el nom i cognoms de la persona autora i el títol de la tesi doctoral. No s'autoritza la seva reproducció o altres formes d'explotació efectuades amb finalitats de lucre ni la seva comunicació pública des d'un lloc aliè al servei TDX. Tampoc s'autoritza la presentació del seu contingut en una finestra o marc aliè a TDX (framing). Aquesta reserva de drets afecta tant als continguts de la tesi com als seus resums i índexs.

This item appears in the following Collection(s)