industrijska farmacija
Barbara Herlah (Avtor), Nace Zidar (Mentor)

Povzetek

Nalezljive bolezni že od nekdaj oblikujejo človeško populacijo na svetu. Ko so v začetku 20. stoletja odkrili penicilin in druge protibakterijske učinkovine in je že kazalo, da smo s človeško inovativnostjo dokončno premagali in uničili patogene, so se razvili na antibiotike odporni bakterijski sevi. Odpornost bakterij na protibakterijske učinkovine postaja vsak dan večji svetovni problem in je grožnja svetovnemu prebivalstvu. Zelo problematično je ravno dejstvo, da vedno več bakterij postaja odpornih na številne različne učinkovine, razvoj novih pa je počasen in zahteva veliko energije in sredstev. Zaradi tega je zelo pomembno odkrivanje novih zdravil, ki bi delovala prek novih mehanizmov delovanja ali pa na do sedaj še neizkoriščena vezavna mesta na že obstoječih tarčah. V okviru magistrske naloge smo želeli sintetizirati spojine, ki bi zavrle bakterijsko rast preko delovanja na podenoto B encima DNA-giraza. Na trgu namreč še ni nobene učinkovine s podobnim mehanizmom delovanja. Sintetizirali smo dve seriji spojin, in sicer piperazinske ter piperidinske derivate, njihovo zaviralno aktivnost pa smo preverili z encimskim testom na encimih DNA-giraza in topoizomeraza IV iz bakterij Escherichia coli in Staphylococcus aureus. Izvedli smo tudi protibakterijsko testiranje na devetih različnih po Gramu pozitivnih in po Gramu negativnih bakterijskih sevih. Rezultati testov so nam omogočili, da preučimo odnos med strukturo in delovanjem spojin. Ugotovili smo, da v splošnem piperidinski analogi izkazujejo boljšo aktivnost na encima DNA-giraza iz E. coli ter S. aureus kakor piperazinski analogi. Predvidevali smo, da bodo imele spojine s prostimi karboksilnimi skupinami ter spojine s hidrazidnimi skupinami bistveno boljše aktivnosti kot njihovi analogi z metilnimi estrskimi skupinami zaradi možnosti tvorbe dodatnih interakcij, vendar pa temu ni bilo tako. Izmed vseh sintetiziranih spojin največjo aktivnost izkazuje spojina 11, ki v svoji strukturi vsebuje 5-okso-4,5-dihidro-1,3,4-oksadiazolni obroč. Predvidevamo, da je razlog za njeno visoko aktivnost, možnost tvorbe več vodikovih vezi, pa tudi možnost interakcij s solnim mostičkom v vezavnem mestu encima. Iz rezultatov protibakterijskega testiranja lahko sklenemo, da večina spojin močneje zavira rast po Gramu pozitivnih kakor po Gramu negativnih bakterij. Številne spojine izkazujejo zelo dobro protibakterijsko delovanje, vendar se je tudi tukaj spojina 11 izkazala najbolje, saj je pri sedmih od devetih bakterijskih sevov pri koncentraciji 50 μM izkazovala več kot 93 % zaviranje rasti bakterij.

Ključne besede

DNA giraza;N-fenilpirolamid;protibakterijske učinkovine;piperidin;piperazin;

Podatki

Jezik: Slovenski jezik
Leto izida:
Tipologija: 2.09 - Magistrsko delo
Organizacija: UL FFA - Fakulteta za farmacijo
Založnik: [B. Herlah]
UDK: 543.057:615.015.8(043.3)
COBISS: 4533105 Povezava se bo odprla v novem oknu
Št. ogledov: 470
Št. prenosov: 85
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 and evaluation of piperazine and piperidine substituted N-phenylpyrrolamides as inhibitors of DNA gyrase B
Sekundarni povzetek: Infectious diseases have always been affecting the population throughout the world. When penicillin and other antibacterial agents were discovered in the beginning of the 20th century, and it appeared as if humans had finally controlled and destroyed pathogens, antibiotic-resistant bacterial strains began to develop. The resistance of bacteria to antibacterial agents is a major global problem, and is one of the biggest threat to the world's population. A very daunting fact is that more and more bacteria are becoming resistant to an increasing number of different active ingredients, however, the development of new antibacterial agents is a slow process and requires a lot of energy and resources. For this reason, the discovery of new agents that would work through new mechanisms of action or that would bind to yet-unused binding sites on already existing targets, is very important. For this master's thesis, we wanted to synthesize compounds that would inhibit bacterial growth with the mechanism of action on subunit B of DNA gyrase enzyme. Currently, there are no active substances on the market yet that would inhibit the growth of bacteria with a similar mechanism of action. Two series of compounds were synthesized, i.e. piperazine and piperidine derivatives, and their inhibitory activity was evaluated by an enzyme assay on DNA gyrase and topoisomerase IV enzymes from bacteria Escherichia coli and Staphylococcus aureus. We also carried out antibacterial testing on nine different Gram-positive and Gram-negative bacterial strains. The results of the tests allowed us to examine the structure-activity relationship of the compounds. We have discovered that, in general, piperidine derivatives exhibit better activity on the DNA gyrase enzyme from E. coli and S. aureus compared to piperazine derivatives. We assumed that derivatives possessing free carboxylic acid groups and hydrazide groups would be significantly more active than their methyl ester analogues due to the possibility of forming additional interactions with the enzyme, but this is not the case. Among all synthesized compounds, compound 11 containing a 5-oxo-4,5-dihydro-1,3,4-oxadiazole ring in its structure exhibits the highest activity. We assume that the reason for its high activity is the possibility of forming more hydrogen bonds, as well as the possibility of interactions with the salt bridge at the binding site of the enzyme. From the results of the antibacterial tests, it can be concluded that most compounds are more active against Gram-positive bacteria than against Gram-negative bacteria. Many compounds have shown very good antibacterial activity, however, compound 11 has proved to be the best, because at 50 μM concentration it inhibited bacterial growth in seven out of nine bacterial strains for more than 93 %.
Sekundarne ključne besede: Bakterijska rezistenca;
Vrsta dela (COBISS): Magistrsko delo/naloga
Komentar na gradivo: Univ. Ljubljana, Fakulteta za farmacijo
Strani: XI, 61 f.
ID: 13275162