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Sinteza novih hidroksamskih kislin kot potencialnih zaviralcev MurD : [enoviti magistrski študij farmacije]
Saje, Katja (Author), Anderluh, Marko (Mentor) More about this mentor... This link opens in a new window, Sosič, Izidor (Co-mentor)

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Abstract
Infekcije so še vedno eden izmed najpogostejših vzrokov smrti na svetu in kljub nekaterim uspešnim antibiotičnim zdravilom se zaradi večanja rezistence bakterij pojavljajo potrebe po novih zdravilih, ki bi z različnimi mehanizmi učinkovito delovale v boju proti bakterijami. Ena izmed možnih tarč za protibakterijsko delovanje so encimi iz družine Mur ligaz (MurC-MurF), ki sodelujejo v biosintezi peptidoglikana, nujnega gradnika bakterijske celične stene. V okviru magistrske naloge smo želeli pripraviti potencialne zaviralce encima MurD, ki je odgovoren za pripenjanje aminokisline D-Glu na nastajajočo peptidno verigo UDP-MurNAc-pentapeptida, prekurzorja, ki se vgradi v obstoječi peptidoglikan. Pri načrtovanju novih spojin smo izhajali iz struktur znanih zaviralcev, ki smo jih kemijsko modificirali z uvedbo hidroksamskih kislin. Sintetizirali smo tri končne spojine in jim izmerili zaviralno aktivnost na encimu MurD, izoliranem iz bakterije Escherichia coli. Za učinkovito se je izkazala spojina metil 2-(6-butoksinaftalen-2-sulfonamid)-4-(hidroksikarbamoil)benzoat (13). Poskusili smo sintetizirati tudi že znan zaviralec z vezanim kateholatnim sideroforom, ki bi izboljšal prehod skozi bakterijsko membrano, vendar žal sinteza ni uspela.

Language:Slovenian
Keywords:protimikrobne učinkovine Mur ligaze peptidoglikan sinteza hidroksamskih kislin ligaza MurD ligaza MurF ligaza MurC siderofori
Work type:Master's thesis/paper (mb22)
Tipology:2.09 - Master's Thesis
Organization:FFA - Faculty of Pharmacy
Year:2013
Publisher:[K. Saje]
Number of pages:VI, 57 f.
Place:Ljubljana
UDC:615.28(043.3)
COBISS.SI-ID:3511665 This link opens in a new window
Views:956
Downloads:201
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Secondary language

Language:English
Title:Synthesis of novel hydoxamic inhibitors of MurD
Abstract:
Infections still represent one of the leading causes of death in the world despite some successful antibiotics available. Due to the increasing resistance of bacteria, compounds with novel mechanisms of action are urgently needed in the fight against bacteria. One of the possible targets for antibacterial activity is the enzyme family Mur ligases (MurC-MurF) that are involved in the biosynthesis of peptidoglycan, an essential component of the bacterial cell wall. In the thesis, we wanted to prepare new potential inhibitors of MurD, which is an enzyme responsible for the attachment of amino acid D-Glu in the nascent peptide chain of UDP-MurNAc-pentapeptide, the precursor that is incorporated into the preexisting peptidoglycan. The design of new compounds was based on the structure of known inhibitors that have been chemically modified by the introduction of hydroxamic acids. We synthesized three final compounds and measured their inhibitory activities on the MurD enzyme isolated from Escherichia coli. Compound methyl 2-(6-butoxynaphthalene-2-sulfonamide)-4-(hydroxycarbamoyl) benzoate (13) proved to be effective. We also tried to synthesize an inhibitor possessing catecholate-type siderophore to improve passage through the bacterial membrane synthesis but unfortunately the synthesis was not successful.

Keywords:antibacterial drugs peptidoglycan Mur ligases hydroxamic acids MurD inhibitors siderophores

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