Sinteza derivatov 4-fenetil-1-(prop-2-in-1-il)piperidina s hidroksi in karbamatno skupino kot zaviralcev monoamin oksidaz in holin esteraz

Mazej, Tjaša (author), Sova, Matej (mentor)

Alzheimerjeva bolezen je progresivna nevrodegenerativna motnja, ki jo spremlja izguba spomina, vedenjske spremembe in upad kognitivnih funkcij. Z več patofiziološkimi mehanizmi pogojen nastanek bolezni nakazuje na smiselnost načrtovanja ligandov s hkratnim delovanjem na več terapevtskih prijemališč. Med aktualnimi in terapevtsko zanimivimi tarčami so encimi monoamin oksidaze (MAO) in holin esteraze (ChE). Na podlagi že znanih zaviralcev teh encimov smo načrtovali in sintetizirali nove zaviralce z dvojnim delovanjem (na MAO in ChE) ter ovrednotili vpliv strukturnih modifikacij na njihovo delovanje. Sintetizirali smo enajst derivatov 4-fenetil-1-(prop-2-in-1-il)piperidina, ki smo jim določili zaviralno delovanje na humani acetilholin in butirilholin esterazi (hAChE in hBChE) ter humani monoamin oksidazi A in B (hMAO-A in hMAO-B). Pri sintezi smo izhajali iz piperidin-4-karboksilne kisline, ki smo jo zaščitili v obliki terc-butil karbamata ter jo preko Weinrebovega amida reducirali do aldehida. Temu je sledila Wittigova reakcija do alkena, redukcija dvojne vezi, odščita karbamata in N-alkiliranje s propargil bromidom do ustreznih derivatov 4-fenetil-1-(prop-2-in-1-il)piperidina. Metoksi derivate smo nadalje z BBr3 odščitili do fenolov, ki smo jih z reakcijo s fenil izocianatom ali N-etil-N-metilkarbamoil kloridom pretvorili v končne karbamate. Vsi sintetizirani derivati so delovali zaviralno na hMAO-B, pri čemer so močnejše delovanje imele spojine z 1,4-disubstitucijo in večjimi hidrofobnimi substituenti. Skupna vsem spojinam je bila propargilaminska skupina, ki najverjetneje tvori kovalentno vez s kofaktorjem encima. Za zaviranje BChE je bila nujna prisotnost karbamatne skupine. Sintetizirali smo tri zaviralce z dvojnim delovanjem (27, 28 in 29), izmed katerih je spojina 29 (IC50 (hBChE) = 4,30 µM, IC50 (hMAO-B)= 8,45 µM) najbolj obetavna za nadaljnjo optimizacijo. Spojina 29 je namreč strukturni analog potrjenih kovalentnih zaviralcev MAO-B, njeno časovno odvisno zaviranje BChE pa nakazuje na kovalenten mehanizem delovanja.

• Language: Slovenian
• Keywords: Alzheimerjeva bolezen, zaviralci, holin esteraze, monoamin oksidaze, 4-fenetil-1-(prop-2-in-1-il)piperidin
• Work type: Master's thesis/paper
• Organization: FFA - Faculty of Pharmacy
• Year: 2021
• PID: 20.500.12556/RUL-125072
• Publication date in RUL: 04.03.2021

Secondary language

• Language: English
• Title: Synthesis of 4-phenethyl-1-(prop-2-yn-1-yl)piperidine derivatives containing hydroxyl and carbamate groups as inhibitors of monoamine oxidases and cholinesterases

Abstract

Alzheimer’s disease is a progressive neurodegenerative brain disorder characterized by memory deterioration, behavioural changes, and impaired cognitive functions. The multifactorial pathogenesis confirms the importance of developing multitarget directed ligands capable of modulating multiple therapeutic pathways. Currently, interesting therapeutic targets include the enzymes monoamine oxidases (MAO) and choline esterases (ChE). Based on the known inhibitors of these enzymes, we designed and synthesized new dual inhibitors of MAO and ChE and evaluated their structure-activity relationship. We synthesized eleven derivatives of 4-phenethyl-1-(prop-2-in-1-il)piperidine and determined their inhibitory potencies against human acetylcholine and butyrylcholine esterase (hAChE and hBChE) and human monoamine oxidases A and B (hMAO-A and hMAO-B). The starting reagent was piperidine 4 carboxylic acid, which was protected with tert-butyl carbamate group and reduced into aldehyde via Weinreb’s amide. The aldehyde was then subjected to Wittig reaction to form an alkene. Following the double bond reduction, removal of the protecting carbamate group and N-alkylation with propargyl bromide, we obtained corresponding derivatives of 4-phenethyl-1-(prop-2-in-1-il)piperidine. The derivatives with methoxy substituent were additionally demethylated with BBr3 to form phenols, which were then reacted with phenyl isocyanate or N-ethyl-N-methylcarbamoyl chloride to form final carbamates. All of the synthesized compounds inhibited hMAO-B and 1,4-disubstituted derivatives with larger hydrophobic substituents exhibited superior inhibitory properties. Propargylamine moiety was present in all compounds and most likely formed a covalent bond with the enzyme’s cofactor. For the hBChE inhibition, the presence of carbamate moiety was found as essential. We synthesized three dual inhibitors (27, 28 in 29) and among them, the most promising compound for further optimization is 29 (IC50 (hBChE) = 4.30 µM, IC50 (hMAO B) = 8.45 µM). The compound 29 is a structural analogue of confirmed covalent inhibitors of MAO-B and its time dependant inhibition of BChE implies a covalent mechanism of inhibition.

• Keywords: Alzheimer’s disease, inhibitors, choline esterase, monoamine oxidase, 4-phenethyl-1-(prop-2-in-1-il)piperidine