Načrtovanje, sinteza in vrednotenje 2-aminopiridinskih in 3,5-dimetilfenolnih zaviralcev ligaz Mur

Debenjak, Tina (author), Frlan, Rok (mentor)

Dan za dnem se odpornost bakterij na klinično uporabne antibiotike povečuje in predstavlja eno največjih groženj za ohranjanje splošnega zdravja ljudi. Eden od načinov zamejevanja bakterijske odpornosti je odkrivanje novih učinkovin, ki bi imele drugačen mehanizem delovanja kot že uveljavljene protibakterijske učinkovine. Biosinteza peptidoglikana je že dolgo časa ena od pomembnejših tarč za delovanje protibakterijskih učinkovin, vendar so v klinični uporabi večinoma učinkovine, ki zavirajo poznejše stopnje biosinteze, citoplazemski del biosinteze peptidoglikana pa je kot tarča še dokaj neizkoriščen. V magistrski nalogi smo se osredotočili na sintezo potencialnih zaviralcev ligaz MurC-F, od ATP odvisnih encimov, ki katalizirajo pripenjanje aminokislin na glikansko verigo. Spojine smo načrtovali na osnovi spojine vodnice 5-(4-(furan-2-il)-2,6-dimetilstiril)-3-(1H-tetrazol-5-il)piridina. Sintetizirali smo spojine dveh vrst: 2-aminopiridinske in 3,5-dimetilfenolne zaviralce ligaz MurC-F. Za sintezo 2-aminopiridinskih zaviralcev ligaz Mur smo se odločili, ker naj bi amino skupina na piridinu prispevala k vezavi v ATP vezavno mesto ligaz Mur. 3,5-dimetilfenolne zaviralce ligaz Mur smo zasnovali s spreminjanjem tetrazolnega in furanskega dela spojine vodnice s funkcionalnimi skupinami iz spojin, ki so se na predhodnih testiranjih izkazale za potencialno učinkovite. Nobena izmed sintetiziranih spojin ni izkazala zaviralne aktivnosti. Še posebej pri 2-aminopiridinskih spojinah se je kot velika ovira pokazala njihova zelo slaba topnost v večini topil, kar je tudi vplivalo na sintezo posameznih spojin. Na osnovi rezultatov bi lahko sklepali, da se 2-aminopiridinske spojine v ATP vezavno mesto ne vežejo na predpostavljen način, da izbrane funkcionalne skupine pri 3,5-dimetilfenolnih spojinah neugodno vplivajo na vezavo v vezavno mesto ter da se spojine s furanskim obročem v strukturi in spojine brez njega v vezavno mesto vežejo na različna načina. Kljub temu so navedena spoznanja pomembna za nadaljnji razvoj novih zaviralcev ligaz Mur, saj usmerjajo njihovo načrtovanje preko drugačnih modifikacij v strukturi.

• Language: Slovenian
• Keywords: peptidoglikan, protibakterijske učinkovine, ligaze Mur, 2-aminopiridin, 3, 5-dimetilfenol
• Work type: Master's thesis/paper
• Organization: FFA - Faculty of Pharmacy
• Year: 2019
• PID: 20.500.12556/RUL-111807
• Publication date in RUL: 14.10.2019

Secondary language

• Language: English
• Title: Design, synthesis and evaluation of 2-aminopyridine and 3,5-dimethylphenol inhibitors of Mur-ligases

Abstract

Bacterial resistance to clinically used antibiotics is growing day by day and it is thus one of the main threats to maintaining health and vitality of people. One of the methods of delimiting bacterial resistance is discovering new substances that function with a mechanism which differs from already established antibacterial substances. Peptidoglycan biosynthesis has been one of the main targets of antibacterial substances for a long time but the main clinically used substances still only inhibit the late stages of biosynthesis while the cytoplasmic part of peptidoglycan biosynthesis remains rather unused. In master’s thesis we focused on synthesis of potential inhibitors of ligases MurC-F, ATP dependent enzymes that catalyse the binding of aminoacids to glycan chain. The solutions have been designed on the base of the lead compound 5-(4-(furan-2-yl)-2,6-dimethylstyryl)-3-(1H-tetrazol-5-yl)pyridine. We have synthesized two types of compounds: 2-aminopyridine and 3,5-dimethylphenol ligase MurC-F inhibitors. The decision for synthesising 2-aminopyridine ligase Mur inhibitors was made on the presumption that the amino group on pyridine contributes to binding to the ATP binding site of ligases Mur. 3,5-dimethylphenol ligase Mur inhibitors have been designed with altering tetrazole and furan part of the lead compound with functional groups from compounds that have proven potentially effective in previous testings. Neither of synthesised solutions displayed an inhibitory activity. Especially 2-aminopyridine compounds showed low solubility in the majority of solvents, which has affected the synthesis of some compounds. Based on the results we can conclude that 2-aminopyridine compounds do not bind in the ATP binding site as proposed and that the selected functional groups of 3,5-dimethylphenol compounds have a negative impact on binding into the binding site and that the compounds with furan functional group bind differentely than the ones without it. Regardless, the findings are important for the further development of new ligase Mur inhibitors by being differently structurally modified.

• Keywords: peptidoglycan, antibacterial substances, Mur ligases, 2-aminopyridine, 3, 5-dimethylphenol