Carregant...
Fitxers
Tipus de document
TesiVersió
Versió publicadaData de publicació
Si us plau utilitzeu sempre aquest identificador per citar o enllaçar aquest document: https://hdl.handle.net/2445/106292
Novel approaches toward anti-Alzheimer and antiprotozoal drug candidates
Títol de la revista
Autors
ISSN de la revista
Títol del volum
Resum
[eng] This PhD Thesis pursues the development of novel anti-Alzheimer and antiprotozoal drug candidates upon exploitation of three different novel approaches: Multitarget therapies, Drug repurposing, and Validation of a novel anti-malarial target. The work carried out in the frame of this PhD Thesis has followed three research lines, thus dividing the next report on three main objectives, namely the development of novel diseasemodifying anti‐Alzheimer agents, novel potential 4-aminoquinoline-based anti tripanosomatid compounds, and so far unexplored substrate analog PfG6PD inhibitors for the treatment of malaria. In the context of the anti‐Alzheimer therapeutic strategies, the innovative so‐called Multi‐ Target Directed Ligands (MTDLs) approach has inspired the structure‐based design and synthesis of two novel classes of hybrid compounds endowed with additional key target interactions beyond cholinesterases, whose modulation has shown to only confer a relief of the very late symptoms of the disease. On the one hand, rhein-huprine hybrids combine the activity of the potent catalytic anionic site (CAS) AChE inhibitor, huprine Y, with that of an anthraquinone fragment derived from rhein to afford a tau antiaggregating effect, apart from the conventional effects derived from dual site AChE interaction. Levetiracetam-based hybrids, on the other hand, comprise, apart from a CAS AChE inhibitor unit, a moiety related to the antiepileptic drug levetiracetam which tackles the Aβ-induced aberrant epileptiform activity across the neuronal network. Regarding HAT and malaria treatment, current registered drugs are problematic, most of them display a range of toxic side effects, require strict and complicated parenteral administration regimens and produce resistances that undermine clinical effectiveness. For this reason, there is an acute need to find novel drugs that can circumvent the limitations of existing therapies. In the context of this PhD Thesis, drug repurposing and further optimization of 4 aminoquinoline based compounds has been considered as a useful approach to potentially speed up the drug development in the HAT field. We have demonstrated that homodimerization, heterodimerization, and side chain modification of the anti-Alzheimer investigational 4- aminoquinoline derivative huprine Y can result in potent brain permeable antitrypanosomal agents, with decreased but still significant anticholinesterasic activity. On the other hand, the bifunctional Plasmodium falciparum glucose-6-phosphate dehydrogenase-6- phosphogluconolactonase enzyme (PfGluPho) has recently emerged as attractive druggable alternative for the development of innovative antimalarial therapeutic strategies. Starting from a homology model of PfG6PD (G6PD domain of PfGluPho), a new family of selective substrate analog-based inhibitors against the parasite PfG6PD active site has been designed and synthesized, on the basis of the structural differences found at the catalytic site of the parasite and human enzymes.
Descripció
Matèries
Matèries (anglès)
Citació
Citació
SOLA, Irene. Novel approaches toward anti-Alzheimer and antiprotozoal drug candidates. [consulta: 4 de desembre de 2025]. [Disponible a: https://hdl.handle.net/2445/106292]