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Raziskovanje kemijskega prostora dvojnih zaviralcev kinaze p38ɑ MAP in butirilholin esteraze s piridazinskim skeletom = Chemical space exploration of p38ɑ MAP kinase and butyrylcholinesterase dual inhibitors with piridazine scaffold : Uniform Master's Study Programme PharmacyMikuletič, AnaAlzheimerjeva bolezen je kronična nevrodegenerativna motnja, ki vodi v upad kognitivnih funkcij in nastanek nevropsihiatričnih simptomov. Poznamo več možnih patofizioloških mehanizmov nastanka ... bolezni, ki kažejo na smiselnost raziskovanja novih zdravilnih učinkovin z multiplim delovanjem. Aktualni terapevtski tarči sta butirilholin esteraza (BChE), ki jo povezujemo s poslabšanjem kognitivnih funkcij, ter kinaza p38α MAP (p38ɑ MAPK), ki je povezana z nevrovnetjem in prispeva k propadanju nevronov. Na osnovi spojine MW150, selektivnega zaviralca p38α MAPK, smo načrtovali in sintetizirali dvojne zaviralce p38ɑ MAPK in BChE s piridazinskim, 5-aminopirazolnim in morfolin-3-onskim ogrodjem. Pri sintezi derivatov piridazina smo izhajali iz Weinrebovega amida, ki smo ga preko nukleofilne adicije organolitijevega reagenta pretvorili v keton. Sledila je reakcija nukleofilne substitucije z etil bromoacetatom, kjer smo dobili 4-ketoester, ki smo ga pretvorili do cikličnega hidrazida in nato oksidirali do piridazin-6-ona. Slednjega smo s fosforil kloridom pretvorili v 6-kloropiridazin, na katerega pa smo z namenom raziskovanja odnosa med strukturo in delovanjem pripenjali različne amine. Derivate 5-aminopirazola smo sintetizirali preko aktiviranega N-hidroksisukcinimidnega estra, ki smo ga pretvorili v 2-cianoketon, tega nadalje v β-kloroakrilonitril, sledila pa je kondenzacija do 5-aminopirazola 35. Sinteza morfolin-3-ona 44 je potekala v treh stopnjah, najprej smo z nukleofilno adicijo nitrita na mesto α ketona uvedli oksim, ki smo ga v naslednji stopnji reducirali do amina in nato v dveh zaporednih stopnjah zaprli do morfolin-3-onskega obroča. Sintetizirali smo 15 spojin, ki smo jim s spektroskopskimi in kromatografskimi metodami potrdili identiteto in čistost ter ovrednotili vpliv strukturnih modifikacij na zaviralno delovanje na človeški acetilholin esterazi (hAChE), hBChE in p38α MAPK. Večina sintetiziranih derivatov je zavirala katalitično aktivnost kinaze p38α MAPK, medtem ko je hBChE zaviralo manj spojin. Najmočnejše in uravnoteženo zaviralno delovanje na obeh tarčah je imel piridazin 15 [IC50(hBChE) = 39,9 ± 4,8 nM; IC50(p38α MAPK) = 127 ± 12 nM].Type of material - master's thesis ; adult, seriousPublication and manufacture - Ljubljana : [A. Mikuletič], 2022Language - slovenianCOBISS.SI-ID - 124231171
Author
Mikuletič, Ana
Other authors
Knez, Damijan, farmacevt
Topics
Alzheimerjeva bolezen |
Farmacevtska kemija |
butirilholin esteraza |
MW150 |
nevrovnetje |
p38α MAPK
Library/institution |
City | Acronym | For loan | Other holdings |
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Faculty of Pharmacy, Ljubljana | Ljubljana | FFALJ |
reading room 1 cop.
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Database name | Field | Year |
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Links to authors' personal bibliographies | Links to information on researchers in the SICRIS system |
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Mikuletič, Ana | |
Knez, Damijan, farmacevt | 36438 |
Source: Personal bibliographies
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