[enoviti magistrski študijski program farmacija]
Urša Jarc (Author), Stanislav Gobec (Mentor)

Abstract

Butirilholin-esteraza (BChE) je encim, katerega koncentracija se z napredovanjem Alzheimerjeve bolezni značilno poviša, s čimer postane pomembna tarča v zdravljenju poznih stadijev te bolezni. Izvedli smo strukturno manipulacijo benzilnega obroča spojine 2, selektivnega zaviralca BChE, z namenom razumevanja in izboljšanja njenih lastnosti. Benzilni obroč smo tako zamenjali s p-F, m-F, p-CN, m-CN in p-NMe2 benzilnim obročem ter ovrednotili lastnosti teh spojin. Vse spojine so selektivni zaviralci BChE in jo večinoma zavirajo v nanomolarnih koncentracijah. Najaktivnejša je spojina 4 (IC50 = 49,1 nM), kar je še vedno slabše od spojine 2 (IC50 = 7,2 nM), najmanj aktivna pa spojina 5 (IC50 = 1463,9 nM). Načrtovane in sintetizirane spojine smo ovrednotili tudi na podlagi predvidenih farmakokinetičnih lastnosti, kjer smo ugotovili, da imajo vse spojine, tudi spojina 2, primerne farmakokinetične lastnosti, tako da lahko predvidimo njihovo prehajanje gastrointestinalne in krvno-možganske pregrade. Spojina 2 ostaja obetavna struktura v razvoju novih zaviralcev BChE in informacije o vplivu substitucije benzilnega fragmenta na aktivnost spojine bodo koristne pri nadaljnji optimizaciji spojine 2.

Keywords

holin-esteraze;naftalensulfonamidi;sinteza benzilnih derivatov;sinteza naftalensulfonamidov;biokemijska analiza;farmakokinetika;t-butil karbamatna zaščitna skupina;

Data

Language: Slovenian
Year of publishing:
Typology: 2.09 - Master's Thesis
Organization: UL FFA - Faculty of Pharmacy
Publisher: [U. Jarc]
UDC: 615.2:616.894-085(043.3)
COBISS: 3816817 Link will open in a new window
Views: 1063
Downloads: 262
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Other data

Secondary language: English
Secondary title: Design, synthesis and evaluation of novel naphtalenesulfonamides as potential cholinesterase inhibitors
Secondary abstract: Butyrylcholinesterase is an enzyme whose concentration increases significantly with the progress of the Alzheimer's disease, which makes it a promising drug target in the late stages of the disease. In order to understand and improve the properties of a selective BChE inhibitor, compound 2, we performed a structural manipulation of the benzyl moiety. We thus replaced the benzyl moiety with p-F, m-F, p-CN, m-CN and p-NMe2 benzyl moiety and evaluated the properties of the new compounds. All compounds are selective BChE inhibitors and mainly exert their inhibition in nanomolar concentration range. Compound 4 is the most active (IC50 = 49.1 nM) while compound 5 is the least active BChE inhibitor (IC50 = 1463.9 nM). Both of these activities are lower than IC50 of the initial compound 2, being 7.2 nM. Designed and synthesized compound were also evaluated on the basis of their theoretical pharmacokinetic properties. The analysis showed that all the compounds, including compound 2, have appropriate pharmacokinetic properties and are thus likely to cross both the gastrointestinal tract and the blood-brain barrier. Compound 2 remains a promising compound in the development of novel BChE inhibitors and the obtained information about the influence of the substituted benzyl moiety on compound’s performance can be used in further structural optimization of the compound 2.
Secondary keywords: Alzheimerjeva bolezen;
Type (COBISS): Master's thesis/paper
Thesis comment: Univ. Ljubljana, Fak. za farmacijo
Pages: 51 f.
ID: 12050913