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Fumonizini B serije (B1, B2 i B3) se najčešće nalaze u žitaricama ihrani od žitarica, ali je potvrđeno njihovo prisustvo i u različitimvrstama voda. Fumonizini mogu negativno uticati na zdravlje ljudi iživotinja te se teži iznalaženju efikasne metode za njihovo uklanjanje.U tom cilju, ispitana je efikasnost razgradnje fumonizina u vodenojsredini primenom direktne i indirektne fotolize. Na primerudirektne fotolize fumonizina B1 (FB1) ispitani su optimalni usloviu pogledu početne pH-vrednosti primenom UV i simuliranog sunčevogzračenja (SSZ). Pri indirektnoj fotolizi primenjena su dva tretmana, uprisustvu H2O2, odnosno . I u ovom slučaju tretmani suoptimizovani u pogledu početne pH-vrednosti, kao i koncentracijeH2O2, odnosno takođe primenom UV i SSZ. Nadalje, ispitana jeefikasnost direktne i indirektne (H2O2) fotolize fumonizina B2(FB2) primenom UV i SSZ, na dve pH-vrednosti. Jedna pH-vrednost jeodabrana pri kojoj je razgranja najekonomičnija (pH 8), a druga prikojoj je razgradnja najefikasnija (pH 4). Ispitan je i sinergističkiuticaj između FB1 i FB2 tokom direktne i indirektne (UV/H2O2,odnosno UV/ ) fotolize. Najefikasnija metoda fotolize (UV/H2O2)je primenjena i za ispitivanje efikasnosti razgradnje fumonizina B3(FB3). Takođe je ispitana i efikasnost fotokatalitičke razgradnjeprimenom TiO2 Degussa P25, TiO2 Wackherr i ZnO kao fotokatalizatorai UV zračenja. Nađeno je da je fotokatalitička razgradnja FB1 i FB3primenom TiO2 Wackherr kao fotokatalizatora pri prirodnom pH (oko8) najefikasniji tretman za njihovo uklanjanje iz vodene sredine.Međutim, u slučaju FB2 fotokataliza se nije pokazala pogodna za njegovufotorazgradnju, jer primenom sva tri fotokatalizatora dolazi donjegove potpune adsorpcije.Nadalje, ispitan je uticaj tipova voda (matriksa) na brzinu razgradnjeFB1 primenom UV, UV/H2O2 i UV/ tretmana. Isto tako, da bi seispitao uticaj pojedinih jona čija je koncentracija u odabranimtipovima voda bila najviša, kao i huminske kiseline ispitan je injihov uticaj dodavanjem u reakcionu smešu količine koja odgovaraispitivanim vodama. Uticaj jona i huminske kiseline na efikasnostrazgradnje FB1 je ispitan primenom UV i UV/H2O2 tretmana.Citotoksična aktivnost standardnih rastvora različitihkoncentracija sva tri fumonizina ispitana je na četiri ćelijskelinije: Neuro-2a, MRC-5, H-4-II-E i BHK. Ispitan je i citotoksičniuticaj nastalih intermedijera nakon primene različitih tretmana zauklanjanje FB1, FB2 i FB3 na rast sve četiri ćelijske linije., Fumonisins of the B series (B1, B2 and B3) are most often found in cereals andcereal foods, but their presence has also been confirmed in various types ofwater. Fumonisins can adversely affect human and animal health, and effortsare being made to find an effective method to eliminate them. To this end, theefficiency of fumonisin degradation in the aqueous medium was investigatedusing direct and indirect photolysis. On the example of direct photolysis offumonisin B1 (FB1), the optimal conditions in terms of initial pH value wereexamined using UV and simulated solar radiation (SSR). In indirectphotolysis, two treatments were applied, in the presence of H2O2, respectively.In this case, the treatments were also optimized in terms of the initial pHvalue, as well as the concentration of H2O2, i.e. by using UV and SS radiation.Furthermore, the efficiency of direct and indirect (H2O2) photolysis offumonisin B2 (FB2) was examined under UV and SS radiation, at two pHvalues. One pH value was chosen at which degradation is the most economical(pH 8), and the other at which degradation is the most efficient (pH 4). Thesynergistic effect between FB1 and FB2 during direct and indirect (UV/H2O2and UV/ ) photolysis was also investigated. The most efficient methodof photolysis (UV/H2O2) was further used to test the degradation efficiency offumonisin B3 (FB3). In addition, the efficiency of photocatalytic degradationwas investigated using TiO2 Degussa P25, TiO2 Wackherr and ZnO asphotocatalysts under UV radiation. Photocatalytic degradation of FB1 and FB3using TiO2 Wackherr as photocatalysts at natural pH (about 8) was found tobe the most effective treatment for their removal from the aquaticenvironment. However, in the case of FB2, photocatalysis did not prove to besuitable for its photodegradation, because the use of all three photocatalystsleads to its complete adsorption.Furthermore, the influence of water types (matrix) on the rate of FB1degradation using UV, UV/H2O2, and UV/ treatments was investigated.Also, in order to examine the influence of individual ions whose concentrationin the selected types of water was the highest, as well as humic acids, theirinfluence was examined by adding to the reaction mixture an amountcorresponding to the tested waters. The effect of ions and humic acid on thedegradation efficiency of FB1 was investigated using UV and UV/H2O2treatments.The cytotoxic activity of the standard solutions of different concentrations ofall three fumonisins was examined on four cell lines: Neuro-2a, MRC-5, H-4-II-E and BHK. The cytotoxic effect of the resulting intermediates afterapplication of different treatments to remove FB1, FB2 and FB3 on the growthof all four cell lines was also examined..&nbsp

This work presents the fabrication and tensile testing of polyamide specimens fabricated by selective laser sintering (SLS). Two geometries are considered: SENT (Single Edge Notched Tension) and PRNT (Pipe Ring Notched Tension) specimens. Experimental testing of these specimens is a step in development of a new method for testing of properties of the pipeline materials. The samples were produced by SLS (Selective Laser Sintering) additive production technique. The samples were made from polyamide PA12 on EOS Formiga P100 machine (fabrication parameters: laser power 30 W, print layer height 0.1 mm, scanning speed 1.6-5 m/s, operating temperature 170⁰C). Testing was performed in the displacement control on a universal tensile testing machine Shimadzu AGS - X. On this machine, the values of force as well as the values of stress and strain were obtained directly from the Trapezium X software. Special attention in this work is devoted to two important aspects: fixing of the ring specimen for testing and influence of friction between the specimen and the tool. The results obtained on the examined specimens indicate that this study is a valuable contribution for further development and verification of the new fracture resistance testing procedure for different pipeline materials.

Serotonin 5HT1a receptors belongs to a class G-protein coupled receptors and it is widely recognized as one of the targets for treating neurological disorders such depression and schizophrenia. N-arylpiperazine structural motif is present in many compounds with pronounced 5HT1a activity including recently approved aripiprazole for the treatment of the major depressive disorder.

Alzheimer's disease (AD) is a serious, neurodegenerative disease, characterized with a progressive loss of cognitive and behavioral functions leading to fatal outcome. Tacrine belongs to a class of cholinesterase inhibitors(ChEls) and it is the first ChEI marketed for the treatment of AD symptoms.

Alzheimer's disease (AD) is a progressive, neurodegenerative disorder characterized by deterioration of cognitive skills and it is the most abundant form of dementia according to the World Health Organization (WHO).1 Tacrine belongs to a class of acetylcholinesterase inhibitors (AChEIs) and it was formerly used in the treatment of AD symptoms. Albeit no longer in clinical use due to its hepatotoxicity, tacrine ring system is extensively investigated as pharmacophore in novel AChEIs, many of which showed improved pharmacological profile in the preclinical studies.2 Here we present optimized synthetic pathway and pharmacological evaluation of three novel tacrine derivatives (5, 6 and 7), possessing functionalized piperidine connected with tacrine via five methylene groups alkyl chain

Alzheimer’s disease (AD) is a neurodegenerative disease which affects over 50 milion people worldwide.1) AD mainly affects people ages 65 and above. Symptoms are memory loss, decline in learning capacity, and language problems. One of currently available treatments for Alzheimer's disease consists of Cholinesterase (ChEIs) inhibitors, which raise acetylcholine levels in the brain. The drugs currently approved by the FDA for this purpose are donepezil, rivastigmine and galantamine. As a part of our research we designed and synthesized seven novel compounds (6a-g) as potential acetylcholinesterase inhibitors (AChEIs). The compounds contain N-benzyl piperidine moiety, which is common in many inhibitors including donepezil,2) and N-aryl piperazine moieties.

Herein, we report on the synthesis and pharmacological evaluation of ten novel fluorinated cinnamylpiperazines as potential monoamine oxidase B (MAO-B) ligands. The designed derivatives consist of either cinnamyl or 2-fluorocinnamyl moieties connected to 2-fluoropyridylpiperazines. The three-step synthesis starting from commercially available piperazine afforded the final products in overall yields between 9% and 29%. An in vitro competitive binding assay using l-[3H]Deprenyl as radioligand was developed and the MAO-B binding affinities of the synthesized derivatives were assessed. Docking studies revealed that the compounds 8–17 were stabilized in both MAO-B entrance and substrate cavities, thus resembling the binding pose of l-Deprenyl. Although our results revealed that the novel fluorinated cinnamylpiperazines 8–17 do not possess sufficient MAO-B binding affinity to be eligible as positron emission tomography (PET) agents, the herein developed binding assay and the insights gained within our docking studies will certainly pave the way for further development of MAO-B ligands.

U okviru ove disertacije dizajnirano je 30 anilidopipredina, analoga jakog -opioidnog agonista i kliničkog analgetika fentanila. Razvijen je efikasan sintetički put za njihovo dobijanje, a sintetisana jedinjenja mogu se podeliti u dve serije. U okviru prve serije sintetisano je 13 novih analoga fentanila sa različitim azotnim grupama u položaju C3 piperidinskog prstena. Takođe je optimizovana sinteza dva prethodno sintetisana biciklična analoga fentanila. Jedinjenja prve serije predstavljaju prve poznate analoge fentanila sa azotnim grupama u položaju C3. U okviru druge serije sintetisano je 15 novih analoga fentanila, koji su u položaju N1 povezani sa pojedinim N-arilpiperazinima preko linearnih alkil mostova različitih dužina. Jedinjenja druge serije dizajnirana su da budu potencijalni heterobivalenti ligandi, jer sadrže anilidopiperidinsko jezgro fentanila kao -opioidnu agonističku farmakoforu, a N-arilpiperazin kao D2-dopaminergičku, agonističku farmakoforu. Analgetička aktivnost svih 30 jedinjenja ispitana je in vivo. Samo četiri jedinjenja, sva iz prve serije, pokazala su analgetičku aktivnost. Najaktivnije jedinjenje, oko 1,8 puta manje aktivno od fentanila, karakterišu brzo i kratko dejstvo analgetičkog efekta, pa se stoga može potencijalno iskoristiti u različitim farmacutskim formulacijama za tretman bola. Afinitet vezivanja jedinjenja druge serije za dopaminergčke D2 receptore ispitan je in vitro testovima kompeticije koristeći 3H spiperon kao radioaktivni ligand. Odsustvo analgetičke aktivnosti i slab afinitet vezivanja za dopaminergičke D2 receptore, ukazuje da jedinjenja druge serije ne mogu poslužiti kao heterobivalentni ligandi. Preliminarna doking analiza urađena je za jedinjenja koja su pokazala farmakološku aktivnost. This PhD thesis encompasses the design of 30 anilidopiperidines, as analogues of potent -opioid agonist and clinical analgesic, fentanyl. All compounds were prepared by the novel and effcient synthetic routes, and can be divided in two series. In the first series, 13 new analogues of fentanyl with various nitrogen groups in the C3 position of the piperidine ring were synthesized. In addition, the synthesis of two bicyclic analogues of fentanyl, previously synthesized by our group, was optimized. The compounds of the first series represent the first known fentanyl analogues possessing any nitrogen substituent at C3 position of the piperidine ring. The second series involved preparation of 15 new compounds consisting of fentanyl moiety and several arylpiperazine groups joined by the respective secondary nitrogens, via the variable-length alkyl linkers. The compounds were designed to be potential heterobivalent ligands, since they include both the fentanyl core, as the -opioid agonist pharmacophore, and N-arylpiperazine moiety as the D2-dopaminergic agonist pharmacophore. The analgesic activity of 30 compounds was tested in vivo. Only four compounds, all from the first series, showed analgesic activity. The most potent of them was 1.8 times less potent analgesic than fentanyl, with fast onset and short duration of analgesic effect, which makes this compound potentially suitable for different pharmacological formulation in the pain treatment. Binding affinity of the compounds of the second series towards dopaminergic D2 receptors was determined by in vitro competitive assay, using 3H spiperon as radioactive ligand. Compounds of the second series were found to be inactive as analgesics and with low affinity towards dopaminergic D2 receptors. Therefore, the compounds do not represent heterobivalent ligands. Preliminary docking analysis was performed for the pharmacologically active compounds.

The inhibitory activities of selected cyclic urea and carbamate derivatives (1–13) toward a-glucosidase(a-Gls) in in vitro assay were examined in this study. All examined compounds showed higher inhibitory activity (IC50) against a-Gls compared to standard antidiabetic drug acarbose. The most potent was benzyl (3,4,5-trimethoxyphenyl)carbamate (12) with IC50=49.85± 0.10μM.In vitrocytotoxicity of the investigatedcompounds was tested on three human cancer cell lines HeLa, A549 and MDA-MB-453 using MTT assay.The best antitumour activity was achieved with compound2(trans-5-phenethyl-1-phenylhexahydro-1H-imi-dazo[4,5-c]pyridin-2(3H)-one) against MDA-MB-453 human breast cancer cell line (IC50=83.41± 1.60μM).Cyclic ureas and carbamates showed promising anti-a-glucosidase activity and should be further tested as potential antidiabetic drugs. The PLS model of preliminary QSAR study indicated that, in planing the future synthesis of more potent compounds, the newly designed should have the substituents capable of polar interactions with receptor sites in various positions, while avoiding the increase of their lipophilicity.

The aim of this study was to develop highly specific radiofluorinated ligands for quantitative positron emission tomography (PET) imaging of monoamine oxidase-B (MAO-B) in brain. A series of 8 fluoro derivatives of 1-cinnamyl-4-arylpiperazine were synthesized by standard methods of organic synthesis. The affinity of the compounds was determined in a competitive binding assay using L-[3H] deprenyl as radioligand on rat brain homogenates. The KD of the radioligand was determined by homologous competition. An efficient, three-step procedure for the synthesis of the potential MAO-B ligands was developed. A competitive binding assay was established, using L-[3H]deprenyl as the radioligand, and rat brain membrane homogenate. The compounds were screened (three concentrations 10-9, 10-7 and 10-5) for their MAO-B affinity. We successfully synthesized a series of fluorinated MAO-B ligands. Unfortunately, their affinities toward MAO-B have proved to be rather low. To increase the affinity further modifications are needed.

A scalable, cost-efficient and simple synthetic pathway towards potential bivalent opioid/dopamine receptor ligands was developed and optimized. Three novel compounds that contain both opioid and dopamine pharmacophores linked by the four methylene group chain were synthesized in 33, 35 and 39 % overall yield after a four-step synthetic route starting from three commercially available N-aryl piperazines. The anilino piperidine precursor was easily prepared in three steps, as previously published, starting from 4- piperidone. The synthesis presented in this paper could be of interest for heterocyclic and general organic chemistry. The newly designed compounds possessing two pharmacophores, opioid and D2/D3, are potentially useful pharmacological probes. Of particular interest would be the simultaneous binding to both opioid and D2/D3 receptors, and the resulting pharmacological responses may be useful for the further understanding of tolerance and dependence phenomena in opioid clinical use and/or abuse. Три нова једињења, која садрже опиоидну и допаминску фармакофору, спојене преко четири метиленске групе, синтетисанa су у четири фазе у укупном приносу од приближно 35 %, полазећи од три комерцијално доступна N-арилпиперазина. Анилино- пиперидински прекурсор је добијен у три једноставне реакционе фазе, полазећи од 4-пиперидона, према познатој литературној методи. Синтеза приказана у овом раду може бити од значаја за хетероцикличну и органску хемију у целини. Новосинтетисана једињења која поседују две фармакофоре, опиоидну и Д2/Д3, су потенцијално корисни супстрати за фармаколошка испитивања. Од посебног интереса може бити истовремено везивање за опиоидне и Д2/Д3 рецепторе, а резултујући фармаколошки одговор био би користан у даљем разумевању толеранције и зависности, као феномена везаних за кли- ничку употребу и/или злоупотребу опијата.