enoviti magistrski študijski program Farmacija
Tjaša Novak (Avtor), Marko Anderluh (Mentor)

Povzetek

Odpornost bakterij predstavlja vedno večji problem v zdravstvu, zato je ključnega pomena razvoj novih protibakterijskih učinkovin, ki bi lahko delovale na nove terapevtske tarče ali pa na že obstoječe tarče z novim mehanizmom delovanja. Bakterijska DNA giraza, ki je sestavljena iz dveh podenot A in dveh podenot B je validirana tarča za razvoj novih protibakterijskih učinkovin. V klinični praksi se kot zaviralci podenote A DNA giraze uporabljajo fluorokinoloni, zaviralci podenote B DNA giraze trenutno v klinični praksi niso prisotni. V okviru magistrske naloge smo načrtovali spojine s potencialnim zaviralnim delovanjem na podenoto B DNA giraze. Sintetizirali smo 8 končnih spojin z aminopiperidinskim osnovnim skeletom, ki smo ga na prvem terminalnem mestu razširili z dibromopirolnim ali indolnim fragmentom. Na drugo terminalno mesto smo pripeli alifatski fragment s prosto karboksilno skupino in njegov analog z metilno estrsko skupino, piperidin-4-aminsko mesto pa smo substituirali z alilnim ali benzilnim fragmentom. Vse končne spojine smo ovrednotili z in vitro testom na izoliranem encimu. Ugotovili smo, da je za zaviralno delovanje ugoden dibromopirolni fragment. Močnejše interakcije z aminokislinskim ostankom Arg136 na vhodu v vezavno mesto tvorijo spojine s prosto karboksilno skupino. Uvedba lipofilnih fragmentov na piperidin-4-aminsko mesto ne omogoča ugodnega umeščanja spojin v aktivno mesto, saj so prekinjene ključne interakcije z Asp73 in ohranjeno molekulo vode. Kot referenco smo sintetizirali 2 nesubstituirani spojini s 3,4-dikoro-5-metilpirolnim fragmentom, ki sta pokazali močno zaviralno aktivnost za encim DNA giraza iz bakterije E.coli. Pridobljeni rezultati predstavljajo pomemben prispevek k poznavanju povezave med strukturo in delovanjem omenjene serije spojin.

Ključne besede

bakterijska odpornost;N-alkilirani piperidin-4-amini;zaviralci;protibakterijske učinkovine;sinteze učinkovin;

Podatki

Jezik: Slovenski jezik
Leto izida:
Tipologija: 2.09 - Magistrsko delo
Organizacija: UL FFA - Fakulteta za farmacijo
Založnik: [T. Novak]
UDK: 615.015.8:543.057(043.3)
COBISS: 4324721 Povezava se bo odprla v novem oknu
Št. ogledov: 399
Št. prenosov: 87
Ocena: 0 (0 glasov)
Metapodatki: JSON JSON-RDF JSON-LD TURTLE N-TRIPLES XML RDFA MICRODATA DC-XML DC-RDF RDF

Ostali podatki

Sekundarni jezik: Angleški jezik
Sekundarni naslov: Synthesis of N-alkylated piperidin-4-amine as potential inhibitors of DNA gyrase B
Sekundarni povzetek: Bacterial resistance represents a rising problem in public healthcare, consequently the key factor is the development of new antibacterial drugs, that would inhibit new therapeutic targets or existing targets with novel mechanisms of action. Bacterial DNA gyrase, consisting of two subunits A and two subunits B is a validated target for the development of new antibacterial drugs. In clinical practice fluoroquinolones are used as inhibitors of DNA gyrase A subunit, DNA gyrase B subunit inhibitors are not present in current clinical practice. In our thesis we have designed compounds with a potential inhibitory activity on the DNA gyrase B subunit. We have synthesized 8 compounds with aminopiperdine scaffold that was at the first terminal site expanded with dibromopyrrole or indole fragments. At the second terminal site we attached aliphatic fragment with a free carboxyl group and its methyl ester analogues, while piperdin-4-amine was substituted with an allyl or benzyl fragment. All final synthesized compounds were evaluated with an in vitro assay on the isolated enzyme. We have discovered that dibromopyrrole fragment is the most important for strong inhibitory activity. Compounds with a carboxyl group have formed stronger interactions with amino acid residue Arg136 at the entrance of the binding site. Substitution of piperdin-4-amine with lipophilic fragments disables optimal conformation in the active site of DNA gyrase B enzyme, because the key interactions with Asp73 and the conserved water molecule are discontinued. As reference we synthesized two unsubstituted compounds with 3,4-dichloro-5-methyl pyrrole fragment. They showed good inhibitory activity for enzyme DNA gyrase from E.coli. The results represent an important contribution to structure-activity relationship of these series of compounds.
Sekundarne ključne besede: Bakterijska rezistenca;
Vrsta dela (COBISS): Magistrsko delo/naloga
Komentar na gradivo: Univ. Ljubljana, Fak. za farmacijo
Strani: IX, 62 f.
ID: 12044626