Sinteza 3-vinilpiridinskih in stirenskih zaviralcev ligaz Mur in monoamin oksidaz B

Lah, Vid (author), Frlan, Rok (mentor)

Bakterijska odpornost na protibakterijske učinkovine je naraven pojav, ki je v naravi prisoten že od nastanka bakterij. Uporaba pri kirurških postopkih in okužbah je postala stalnica, s tem pa tudi vse večji razvoj bakterijske odpornosti, ki jo danes Svetovna zdravstvena organizacija šteje med večje grožnje javnemu zdravstvu, zato je razvoj novih skupin protibakterijskih učinkovin nujen. Ena izmed največjih razlik med bakterijsko in človeško celico je celična stena pri bakterijskih celicah, ki ji pomaga pri mehanski trdnosti in vzdrževanju osmotskega pritiska. Glavni gradnik je peptidoglikan, pri njegovi sintezi pa sodelujejo tudi ligaze Mur, ki so še dokaj neraziskane tarče za razvoj protibakterijskih učinkovin. Alzheimerjeva bolezen je nevrodegenerativna bolezen, katere glavni simptomi so pozabljivost, anksioznost, motorične disfunkcije in težave s komunikacijo. Njen nastanek še ni popolnoma raziskan, poznamo več teorij, ki razlagajo kako bolezen nastane, vendar znanstveniki niso enotnega mnenja. Po amiloidni hipotezi je za nastanek krivo nabiranje amiloidnega prekurzorskega proteina β, ki v možganih agregira in kasneje tvori amiloidne lehe. Trenutno zdravljenje poteka simptomatsko, kar pomeni, da samo zavira napredek bolezni, ne poznamo pa še zdravila, ki bi bolezen preprečila oziroma popolnoma ustavila. Monoamin oksidaza je odgovorna za homeostazo bioloških aminov, s pomočjo oksidativne deaminacije nadzira njihovo koncentracijo v telesu. Zaviranje monoamin oksidaze B je povečalo razgradnjo amiloidnega prekurzorskega proteina s povečanjem aktivnosti α-sekretaze. Namen magistrske naloge je bil načrtovanje in sinteza novih 3-vinilpiridinskih in stirenskih zaviralcev ligaz Mur in monoamin oksidaz B. Biološke teste smo izvedli na 8 spojinah, ki smo jim izmerili rezidualno aktivnost in srednjo zaviralno aktivnost. Izhajali smo iz spojin zadetkov, ki so bile sintetizirane na Katedri za farmacevtsko kemijo, Fakultete za farmacijo, Univerze v Ljubljani. Spojine, ki bi lahko imele zaviralno delovanje na ligaze Mur so se izkazale kot neaktivne. Najboljše zaviralno delovanje je imel (E)-3-(4-metoksi-2-nitrostiril)benzonitril s srednjo zaviralno koncentracijo 0.98 ± 0.28 µM. Spojina nam daje odlično izhodišče za sintezo novih zaviralcev monoamin oksidaze B in nadaljnje raziskave na tem področju.

• Language: Slovenian
• Keywords: MAO, ligaze Mur, bakterijska odpornost, Alzheimerjeva bolezen, zaviralec
• Work type: Master's thesis/paper
• Organization: FFA - Faculty of Pharmacy
• Year: 2020
• PID: 20.500.12556/RUL-121247
• Publication date in RUL: 02.10.2020

Secondary language

• Language: English
• Title: Synthesis of 3-vinylpyridine and styrene inhibitors of Mur ligases and Monoamine Oxidases B

Abstract

Bacterial resistance to antibacterial agents is a natural phenomenon that has been present in nature since the origin of bacteria. The discovery of antibacterial agent and commercialization revolutionized modern medicine. The use in surgical procedures and infections has become a constant and with it the development of bacterial resistance, which is considered by the World Health Organization to be a major threat to public health. One of the biggest differences between a bacterial and a human cell is the cell wall in bacterial cells, which helps it maintain mechanical strength and osmotic pressure. Mur ligases are involved in its synthesis, which are still relatively unexplored targets for the development of new antibacterial agents. Alzheimer's disease is a neurodegenerative disease whose main symptoms are memory loss, anxiety, motor dysfunction and communication problems. Its origin has not yet been fully explored, several theories explain how the disease occurs, but scientists are not unanimous. According to the amyloid hypothesis, the accumulation of amyloid precursor protein β is responsible for the formation of amyloid plaques in brains. Currently, treatment is symptomatic, which only slows the progression of the disease. Monoamine oxidase is responsible for the homeostasis of biogenic amines. Inhibition of monoamine oxidase B increases the degradation of amyloid precursor protein by increasing α-secretase activity. The purpose of the master's thesis was to the design and synthesize new 3-vinylpyridine and styrene inhibitors of Mur ligase and monoamine oxidase B. Biological tests were performed on 8 compounds, for which residual activity and half maximal inhibitory concentration were measured. We started from compounds that were synthesized at the Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Ljubljana. Compounds that could have an inhibitory effect on Mur ligases were shown to be inactive. ((E)-3-(4-methoxy-2-nitrostyryl)benzonitrile with a half maximal inhibitory concentration of 0.98 ± 0.28 µM had the best inhibitory effect. Compound provides an excellent starting point for the synthesis of new monoamine oxidase B inhibitors and further research in this field.

• Keywords: MAO, Mur ligases, bacterial resistance, Alzheimer's disease, inhibitor