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Načrtovanje, sinteza in vrednotenje novih piperidinov kot potencialnih zaviralcev butirilholin-esteraze in monoamin-oksidaze B : enoviti magistrski študij farmacije
Lipušček, Julija (Author), Gobec, Stanislav (Mentor) More about this mentor... This link opens in a new window

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Abstract
S podaljševanjem življenjske dobe se število ljudi obolelih z Alzheimerjevo boleznijo (AB) povečuje. Posledično se razvijajo novi pristopi k zdravljenju bolezni, za nastanek katere so pomembni različni dejavniki. Koncentracija in encimska aktivnost BChE v možganih bolnikov z AB z napredovanjem bolezni naraščata in postaneta odgovorna za hidrolizo večine nevrotransmitorja acetilholina, ki v telesu igra pomembno vlogo pri tvorjenju spomina in učenju. Nevroprotektivni učinki, ki so prav tako pomembni pri zdravljenju AB, pa so posledica zaviranja MAO-B. Zaradi težnje po razvoju spojin, ki bi delovale na več faktorjev hkrati, smo se odločili sintetizirati in ovrednotiti spojine, ki združujejo lastnosti zaviranja butirilholin-esteraze (BChE) in monoamin-oksidaze B (MAO-B). Sintetizirali smo 6 disubstituiranih derivatov piperidina, kjer smo variirali disubstitucijski vzorec piperidina (1,3- in 1,4-disubstituirani) ter dolžino verige na sulfonamidnem dušiku (-H, -(CH2)2-OMe, -(CH2)3-OMe). N-propargilaminska skupina, ki smo jo pripeli na piperidnski dušik, pa je odločilna za vezavo na MAO-B. Vsem sintetiziranim spojinam smo izmerili zaviralno aktivnost na holin-esterazah in MAO, z željo po selektivni vezavi na BChE in MAO-B. Spojina 6 se je izkazala kot selektivni zaviralec BChE z IC50 = 2559,7 nM in zaviralec MAO-B z IC50 = 43,93 μM. Spojina 6 ima tudi vse fizikalno-kemijske lastnosti, ki so zahtevane za napoved uspešnega prehoda krvno-možganske pregrade in tako predstavlja novo spojino vodnico za nadaljnjo optimizacijo.

Language:Slovenian
Keywords:sinteza t-butil spojin encimski testi sinteza piperidina vrednotenje zaviralne aktivnosti holinergična hipoteza butirilholin-esteraza
Work type:Master's thesis/paper (mb22)
Tipology:2.09 - Master's Thesis
Organization:FFA - Faculty of Pharmacy
Year:2015
Publisher:[J. Lipušček]
Number of pages:VI, 49 f.
UDC:543.057:616.894(043.3)
COBISS.SI-ID:3981681 This link opens in a new window
Views:188
Downloads:52
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Secondary language

Language:English
Title:Design, synthesis and evaluation of novel pyperidines as potential butyrylcholinesterase and monoamine oxidase B inhibitors
Abstract:
With increased life expectancy the number of people with Alzheimer disease is growing. Consequently, new approaches for treatment of Alzheimer's disease are being developed. Concentration and enzymatic activity of BChE in the brain of a patient with Alzheimer’s disease increases with the deterioration of the disease and is responsible for the breakdown of most of acetylcholine, a neurotransmitter responsible for memory and learning. Neuroprotective properties are also very important in Alzheimer disease treatment and are a result of MAO-B inhibition. There are many different factors involved in developing Alzheimer’s disease and therefore multi-target molecules are interesting as new treatment strategies. With this in mind we synthesised and evaluated molecules with both BChE and MAO-B inhibition properties. We synthesized 6 piperidine compounds and evaluated their ChE and MAO-B inhibition. BChE and MAO-B selective inhibition was desired. Molecules were 1,3-disubstituted and 1,4-disubstituted piperidines with -H, -(CH2)2-OMe or -(CH2)3-OMe as a substituent on the sulfonamide. N-propargylic group is required for MAO-B inhibiton. Compound 6 was evaluated as a selective BChE inhibitor with IC50 = 2559,7 nM, and MAO-B inhibitor with IC50 = 43,93 μM. Compound 6 also has all the necessary physicochemical properties that are required to predict successful blood-brain barrier permeability. This compound represents a promising new lead compound for further optimisation.


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