Vpliv zamenjave aromatskega obroča v indolinskih zaviralcih butirilholin esteraze in z mitogenom aktivirane kinaze p38α

Bevk, Ana (author), Obreza, Aleš (mentor), Košak, Urban (co-mentor)

Magistrska naloga obravnava novejši pristop k zdravljenju Alzheimerjeve bolezni (AB) z načrtovanjem in sintezo novih dvojnih zaviralcev, ki so usmerjeni proti dvema ključnima encimoma butirilholin esterazi (BChE) in z mitogenom aktivirani kinazi p38α (p38α MAPK). Alzheimerjeva bolezen je nevrodegenerativna motnja, za katero je značilen upad kognitivnih sposobnosti in je tesno povezana z disregulacijo holinergične nevrotransmisije in nevrovnetnih procesov, ki jih posreduje p38α MAPK. Zaviranje BChE izboljša kognitivne funkcije zaradi povečanja koncentracije živčnega prenašalca acetilholina, zaviranje kinaze p38α MAPK pa zmanjša nevrovnetje in hiperfosforilacijo proteina tau, kar bi lahko izboljšalo klinične znake, ki se kažejo pri AB. Na osnovi selektivnega zaviralca p38 MAPK, spojine ARRY-371797, smo načrtovali in sintetizirali pet novih spojin, označenih s številkami 9, 10, 16, 22 in 28 v šeststopenjski sintezi, pri čemer smo izhajali iz metil 2-fluoro-4-metil-5-nitrobenzoata. Naše končne spojine se razlikujejo od spojine ARRY-371797 v aromatskih substituentih, ki zamenjajo 2,4-difluorofenilno skupino v spojini vodnici. Z novimi substituenti smo želeli ohraniti ali povečati jakost zaviranja p38α MAPK in BChE. Spojine smo očistili, potrdili njihovo strukturo s spektroskopskimi metodami in jim izmerili aktivnost s pomočjo biokemijskih testiranj na rekombinantnih encimih. Izmed vseh zaviralcev se je za najobetavnejšega izkazala spojina 9, ki zavira človeško (h)BChE z IC50 vrednostjo 6,4 µM in p38α MAPK z IC50 = 0,28 µM.

• Language: Slovenian
• Keywords: Nevrodegenerativne bolezni, Alzheimerjeva bolezen, BChE, p38α MAPK, načrtovanje dvojnih zaviralcev
• Work type: Master's thesis/paper
• Organization: FFA - Faculty of Pharmacy
• Year: 2024
• PID: 20.500.12556/RUL-154911
• Publication date in RUL: 08.03.2024

Secondary language

• Language: English
• Title: Influence of aromatic replacement in indoline inhibitors of butyrylcholinesterase and mitogen-activated protein kinase p38α

Abstract

This thesis addresses a novel approach to the treatment of Alzheimer's disease (AD) by the design and synthesis of novel dual inhibitors, targeting two key enzymes butyrylcholinesterase (BChE) and mitogen-activated kinase p38α. Alzheimer's disease is a neurodegenerative disorder characterised by cognitive decline and is closely associated with dysregulation of cholinergic neurotransmission and neuroinflammatory processes mediated by p38α MAPK. Inhibition of BChE improves cognitive function by increasing the concentration of the neurotransmitter acetylcholine, inhibition of p38α MAPK kinase reduces neuroinflammation and hyperphosphorylation of tau protein, which could improve the clinical signs manifested in AD. Based on a selective p38 MAPK inhibitor, compound ARRY-371797, we designed six new compounds, labelled as 9, 10, 16, 22, 28. Based on a literature search, we developed a six-step synthesis starting from methyl 2-fluoro-4-methyl-5-nitrobenzoate. Our final compounds differ from compound ARRY-371797 in 4 substituents replacing the 2,4-difluorophenyl group. With the new substituents we wanted to maintain or increase the inhibition potency of p38α MAPK and BChE. The compounds were purified and their structure confirmed by spectroscopic methods and their residual activity determined by biochemical assays on recombinant enzymes. Among all inhibitors, compound 9 was found to be the most promising with an IC50 value of 6.4 µM against human (h)BChE and with and IC50 = 0.28 µM against p38α MAPK.

• Keywords: Neurodegenerative diseases, Alzheimer's disease, BChE, p38α MAPK, design of dual inhibitors