Sinteza triptaminskih derivatov s protimikrobnim delovanjem in z zaviralnim delovanjem na bakterijsko glikoziltransferazo : diplomska naloga

Jakovac, Samo (author), Anderluh, Marko (mentor)

V današnjem času predstavljajo vedno večji problem rezistentne bakterije, ki resno ogrožajo zdravje ljudi. Razširjenost in neprimerna uporaba antibiotikov je ustvarila močan evolucijski pritisk na nastanek bakterij, ki so bodisi naravno odporne proti antibiotikom ali pa imajo možnost za pridobitev odpornosti. Bakterijske infekcije so v razvitem svetu še vedno velik vzrok umrljivosti, zato je nujno potreben napredek na področju sinteze novih protimikrobnih zdravil. V zadnjem času se odkrivajo nove učinkovine z drugačnimi mehanizmi delovanja, kot jih imajo spojine na tržišču. Razlog je predvsem v tem, ker bakterije postajajo multirezistentne. Kot zadnjo linijo obrambe na multirezistentne seve imamo trenutno na voljo le nekaj protimikrobnih učinkovin. Veliko pozornosti se posveča učinkovinam, ki neposredno vplivajo na sintezo celične stene. Peptidoglikan v celični steni predstavlja pomembno tarčo, saj lahko njegovo sintezo blokiramo z inhibicijo več različnih encimov. V zadnjih stopnjah sinteze peptidoglikana sodelujeta glikoziltransferazna in transpeptidazna domena penicilin vezočih proteinov. V okviru diplomskega dela smo načrtovali in sintetizirali inhibitorje bakterijske glikoziltransferaze. Encim glikoziltransferaza polimerizira glikansko verigo z uporabo substrata lipida II. Poznamo dve glavni skupini inhibitorjev bakterijske glikoziltransferaze. V prvi so spojine, ki se vežejo na substrat in prepoznajo strukturne elemente v lipidu II in nastajajočem peptidoglikanu, v drugi pa spojine, ki se vežejo na glikoziltransferazo. Načrtovali in sintetizirali smo derivate triptamina in 5-metoksitriptamina, ki zavirajo glikoziltransferazo predvidoma z vezavo na lipid II. Za identifikacijo spojin smo uporabljali različne metode: npr. NMR, IR, in MS, za preverjanje čistosti spojin pa HPLC. Spojine smo poslali tudi na testiranje citotoksičnosti in protimikrobne učinkovitosti. Rezultati testiranj so pokazali, da imajo nekatere spojine dobro protimikrobno učinkovitost in nizko stopnjo citotoksičnosti.

• Language: Slovenian
• Keywords: protimikrobne učinkovine sintezni postopki zaviralci glikoziltransferaze penicilin derivati triptamina citotoksičnost
• Work type: Undergraduate thesis
• Typology: 2.11 - Undergraduate Thesis
• Organization: FFA - Faculty of Pharmacy
• Place of publishing: Ljubljana
• Publisher: [S. Jakovac]
• Year: 2014
• Number of pages: IX, 63 f.
• PID: 20.500.12556/RUL-121069
• UDC: 577.27+615.015.8(043.2)
• COBISS.SI-ID: 3598705
• Publication date in RUL: 29.09.2020

Secondary language

• Language: English
• Title: Synthesis of tryptamine derivatives with antibacterial activity and inhibitory effect on bacterial glycosyltransferase

Abstract

Nowadays resistant bacteria represents a growing problem which seriously affects human health. Prevalence and inappropriate use of antibiotics has created a strong evolutionary pressure on the emergence of bacteria that are either naturally resistant to antibiotics or have the possibility to acquire resistance. In the developed world bacterial infections are still a major cause of death. This is why the progress in the synthesis of new antimicrobial agents is urgently needed. Recently new active substances with different mechanisms of action are being discovered in comparison to the compounds on the market. The main reason is that bacteria are acquiring multidrug resistance. As a last line of defense for multidrug resistant strains, only a few antimicrobial agents are currently available. A lot of attention is devoted to agents that directly affects cell wall synthesis. Peptidoglycan in the cell wall is an important target, because it can be blocked by inhibiting the synthesis of several different enzymes. Glycosyltransferase and transpeptidase domain of penicillin-binding proteins participate in the final stages of peptidoglycan synthesis. Within the framework of the thesis, we planned and synthesized inhibitors of bacterial glycosyltransferase. Enzyme glycosyltransferase polymerizes the glycan chain using the lipid II substrate. There are two main groups of inhibitors of bacterial glycoslytransferase. In the first one are compounds which bind to the substrate by identifying the structural elements within lipid II and emerging peptidogylcan. In the second one are compounds which bind to glycosyltransferase. We planned and synthesized derivatives of tryptamine and 5-methoxytryptamine, which presumably inhibit glycosyltranferase by binding to lipid II. Various methods for identification such us NMR, IR and MS were used. The purity of the compounds was identified with HPLC. The compounds were also sent for testing cytotoxicity and antimicrobial effectiveness. The test results have shown that some of the compounds have good antimicrobial activity and a low level of cytotoxicity.