Načrtovanje, sinteza in biokemijsko vrednotenje derivatov 8-hidroksikinolina kot ligandov z multiplim delovanjem za zdravljenje Alzheimerjeve bolezni

Subašič, Dimitrij (author), Gobec, Stanislav (mentor), Knez, Damijan (comentor)

Alzheimerjeva bolezen (AB), odkrita leta 1907, spada med kronične progresivne nevrodegenerativne bolezni. Predstavlja kar 60 do 80 % vseh oblik demenc. Najbolj pogosti pacienti so starostniki. Prizadene kar 10 % ljudi po 70. letu starosti, s staranjem pa se ta delež še povečuje. AB je zapletena bolezen, ki vključuje veliko različnih faktorjev. Eden izmed glavnih je pomanjkanje živčnega prenašalca acetilholina v nevronih. Za razgradnjo acetilholina v centralnem živčevju skrbita holinesterazi. Poznamo acetilholin esterazo (AChE) in butirilholin esterazo (BChE). Kljub temu da AChE razgradi večino acetilholina pa pri Alzheimerjevi boleznni BChE dobiva vedno večjo vlogo, saj raziskave dokazujejo, da je z napredovanjem bolezni BChE odgovorna za vedno večji delež razgrajenega acetilholina v nevronih. Med ostalimi pomembnimi faktorji sta oksidativni stres in določeni kovinski ioni, saj s tvorbo reaktivnih kisikovih in dušikovih zvrsti pripomorejo k poškodbam v nevronih in posledično k nevrodegeneraciji. AB kot tudi demenca sta večfaktorski bolezni kateri težko zdravimo samo z enim pristopom. Za uspešno zdravljenje oz. preprečevanje je potrebno AB obvladovati z večimi različnimi prijemi – tako farmakološkimi kot tudi nefarmakološkimi. V okviru magistrske naloge smo sintetizirali več spojin z multiplim delovanjem za zdravljenje Alzheimerjeve bolezni. Na podlagi strukture nedavno odkritega zaviralca encima BChE smo optimizirali spojine tako, da smo na mesto 3 piperidina uvedli različne substituente in nato sintetizirane spojine ovrednotili z biokemijskimi testi. Spojine 45, 49, 43b in 42 so pokazale dobro zaviralno delovanje na BChE v nanomolarnem območju z vrednostmi IC50, ki so manjše od spojine zadetka (IC50 = 80,0 nM). Kot najmočnejši zaviralec se je izkazala spojina 45 z vrednostjo IC50 = 5,58 nM. Vse spojine selektivno zavirajo BChE. Spojini 45 in 44 izkazujeta tudi antioksidativno delovanje, kar smo ovrednotili z DPPH testom. Iz dobljenih rezultatov ThT testa smo videli, da nobena izmed spojin ne zavira agregacije Aß1–42. Z vidika multiplega delovanja je najbolj obetavna spojina 45, ki predstavlja dobro odskočno desko za nadaljnje načrtovanje in optimizacijo spojin z multiplim delovanjem za terapijo AB.

• Language: Slovenian
• Keywords: Alzheimerjeva bolezen, butirilholin esteraza, multifunkcionalni ligandi, 8-hidroksikinolin
• Work type: Master's thesis/paper
• Organization: FFA - Faculty of Pharmacy
• Year: 2019
• PID: 20.500.12556/RUL-110775
• Publication date in RUL: 19.09.2019

Secondary language

• Language: English
• Title: Design, synthesis and biochemical evaluation of 8-hydroxyquinoline derivatives as multifunctional ligands in the treatment of Alzheimer's disease

Abstract

Alzheimer's disease (AD), discovered in 1907, is a chronic progressive neurodegenerative disease that represents 60 – 80 % of all forms of dementia. Most commonly affected are the elderly. It affects 10 % of people after 70 years of age and the percentage increases with age. AD is a complicated disease, which is characterized by many different factors. One of the main factors is the deficiency in levels of neurotransmitter acetylcholine, located in the neurons. In the central nervous system there are two cholinesterases, which are responsible for the decomposition of acetylcholine – acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Although AChE accounts for the majority of decomposed acetylcholine, in AD the significance of BChE rises. With the progression of the disease, the BChE is accountable for bigger and bigger share of decomposed acetylcholine in neurons. Among other important factors are oxidative stress and metal ions. They are responsible for the production of reactive oxygen and nitrogen species, which strongly contributes to the damages in the neurons and to the neurodegeneration. AD is a multifactorial disease, which is almost impossible to successfully treat with only one approach. For successful treatment it is necessary to tackle the disease with a number of different approaches – both pharmacological and nonpharmacological. The subject of this master thesis is the synthesis and biochemical evaluation of a number of different multifunctional compounds for the treatment of Alzheimer's disease. On the basis of recently discovered inhibitor of BChE, we optimized the structure by variating the substituents on position of piperidin ring. Compounds 45, 49, 34b and 42 inhibit BChE in the nanomolar range with IC50 value lower than the hit compound (IC50 = 80,0 nM). The most promising inhibitor is compound 45 with IC50 value of 5,58 nM. All synthesized compounds selectively inhibit BChE. Compounds 45 and 44 also showed antioxidant activity, which was evaluated by the DPPH assay. From the results gathered with ThT test we can conclude, that these compounds do not inhibit the aggregation of Aβ1–42. Nonetheless, compound 45 represents a good basis for further development and design of multifunctional compounds for the treatment of Alzheimer’s disease.

• Keywords: Alzheimer's disease, butyrylcholineesterase, multifunctional ligands, 8-hydroxyquinoline