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Sinteza derivatov triazola in alfa-cianocimetne kisline kot zaviralcev undekaprenil pirofosfat sintaze
ID Klenovšek, Maša (Author), ID Sova, Matej (Mentor) More about this mentor... This link opens in a new window

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Abstract
Peptidoglikan je kompleksen heteropolimer, ki obkroža citoplazemsko membrano. Sestavljen je iz linearnih polisaharidnih verig, prečno premreženih s kratkimi peptidi. Undekaprenil difosfat (UPP) ima vlogo nosilca lipidov pri biosintezi peptidoglikana. Encim, ki katalizira sintezo UPP, je undekaprenil difosfat sintaza (UPPS). Zaradi te ključne vloge pri biosintezi bakterijskih peptidoglikanov je UPPS zanimiva tarča za zdravilne učinkovine. V sklopu magistrske naloge smo načrtovali in sintetizirali derivate triazola in alfa-cianocimetne kisline, ki so bili predhodno odkriti z virtualnim rešetanjem, kot potencialne zaviralce UPPS. Uporabili smo dve različni večstopenjski sintezni poti. Sinteza derivatov alfa-cianocimetne kisline je obsegala Willamsovo sintezo etra, Knoevenaglovo kondenzacijo, hidrolizo estra do karboksilne kisline ter sintezo amida iz antranilne kisline preko kislinskega klorida. Sinteza derivatov triazola pa je potekala preko acilhidrazida do tiolnega derivata, ki ga potem z ustreznim alkil bromidom alkiliramo do končnega produkta. Spojin, pridobljenih z virtualnim rešetanjem, nam ni uspelo sintetizirati. Težavo nam je predstavljala zadnja stopnja hidrolize estra do karboksilne kisline. Vendar pa nam je v primeru derivatov alfa-cianocimetne kisline uspelo postaviti postopek do ustreznih estrov, nadaljnja optimizacija hidrolize do karboksilnih kislin pa bo izziv za prihodnost. Pri derivatih triazola pa nam ni uspelo alkilirati tiolne skupine. Sintetiziranim derivatom smo s pomočjo biokemijskega testiranja na encimu UPPS določili zaviralno aktivnost. Nobena izmed spojin se ni izkazala kot zaviralec, smo pa na podlagi biokemijskega testiranja potrdili, da je za zaviralno delovanja encima UPPS pri derivatih alfa-cianocimetne kisline potrebna prosta karboksilna skupina.

Language:Slovenian
Keywords:encim UPPS, zaviralci, protibakterijske učinkovine, alfa-cianocimetna kislina
Work type:Master's thesis/paper (mb22)
Organization:FFA - Faculty of Pharmacy
Year:2021
Publication date in RUL:03.03.2021
Views:210
Downloads:41
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Secondary language

Language:English
Title:The synthesis of triazole and alpha-cyanocinnamic acid derivatives as inhibitors of undecaprenyl pyrophosphate synthase
Abstract:
Peptidoglycan is a complex heteropolymer that surrounds the cytoplasmic membrane. It consists of linear polysaccharide chains cross-linked with short peptides. Undecaprenyl diphosphate (UPP) acts as a lipid carrier in peptidoglycan biosynthesis. The enzyme that catalyzes the synthesis of UPP is an undecaprenyl diphosphate synthase (UPPS). Due to its key role in the biosynthesis of bacterial peptidoglycans, UPPS represents an interesting target for drug design. As part of our master's thesis, we designed and synthesized derivatives of triazole and alpha-cyanocinnamic acid, which were previously discovered by virtual screening, as potential UPPS inhibitors. We used two different multistep synthetic pathways. The synthesis of derivatives of alpha-cyanocinnamic acid included the Williamson ether synthesis, Knoevenagel condensation, ester hydrolysis to carboxylic acid and amide synthesis from anthranilic acid via acid chloride method. On the other hand, the synthesis of triazole derivatives, proceeded via acylhydrazide to the thiol derivative, which can be alkylated with corresponding alkyl bromide to the final product. We were unable to synthesize the compounds obtained by virtual screening. The main problem was the last step of ester hydrolysis to a carboxylic acid. Nevertheless, in the case of alpha-cyanocinnamic acid derivatives, we were able to develop the synthetic procedure to corresponding esters; further optimization of hydrolysis to carboxylic acids will be a challenge for the future. In the case of triazole derivatives, we could not alkylate the thiol group. The inhibitory activity of some synthesized compounds on the UPPS enzyme was determined by biochemical evaluation. None of the compounds exhibited any inhibitory activity; however, based on the results obtained from biochemical assay we showed that a free carboxyl group is essential for the inhibitory activity of alpha-cinnamic acid derivatives on the UPPS enzyme.

Keywords:UPPS enzyme, inhibitors, antibacterial agents, alpha-cyanocinnamic acid

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