Derivati etanolamina kao jonske tečnosti i prekursori biološki i katalitički aktivnih Pd(II)-kompleksa

Poslednjih godina jonske tečnosti privlače veliku pažnju, kako nauke tako i industrije. Početak njihove primene neki nazivaju “zelenom“ hemijskom revolucijom. U prilog tome svedoči neprekidan porast broja do sada objavljenih radova i patenata iz ove oblasti (više od 10000 radova i više od 2000 patenata). Ova nova grupa jedinjenja može uticati na smanjenje upotrebe toksičnih i zagađujućih organskih rastvarača zbog njihovih jedinstvenih fizičko-hemijskih karakteristika i mogućnosti da se primene u različitim sintezama. Termini kao što su stopljene soli, nevodene jonske tečnosti I tečne organske soli se, takođe, koriste da bi se opisala ova jonizovana jedinjenja koja su tečna na sobnoj temperaturi, suprotno neorganskim solima koje se tope na izuzetno visokim temperaturama. Zbog svih ovih osobina koje pokazuje ova interesantna grupa jedinjenja, u okviru ove disertacije izvršena je sinteza i karakterizacija nekih novih jonskih tečnosti na bazi derivata etanolamina. Za većinu organskih reakcija koje su tradicionalno katalizovane uobičajenim kiselinama i bazama, mogu se kao katalizatori upotrebiti i odgovarajuće jonske tečnosti. Aldolna kondenzacija, Knevenagelova, Majklova, Manihova, Henrijeva, Dils-Alderova i Fridel-Kraftsova reakcija su samo neke od njih. U okviru ove disertacije ispitana je katalitička uloga nekih etanolaminskih jonskih tečnosti u Manihovoj reakciji, kao i njihov uticaj na stereohemiju dobijenih proizvoda. Metodama funkcionala gustine ispitan je mehanizam odvijanja ove reakcije. Jedan od najvećih izazova organske hemije je svakako stvaranje S–S veze. Međutim, ugljenik je stabilan i atomi ugljenika ne reaguju lako jedan sa drugim. Sinteza jednostavnih organskih jedinjenja više nije problematična, ali pri sintezama složenijih molekula dolazi do stvaranja velikog broja nusproizvoda. Razvojem paladijum-katalizovanih reakcija rešen je taj problem. U ovim reakcijama atomi ugljenika se vezuju za paladijum, nakon čega dolazi do pokretanja hemijske rekcije. Hekova, Negišijeva, Suzukijeva, Stilova i Sonogaširina reakcija su naročito poznate paladijum-katalizovane reakcije koje se izvode u jonskim tečnostima. Pokazalo se da su ovakve reakcije vrlo efikasne i da ne dolazi do taloženja elementarnog paladijuma, odnosno gubitka katalizatora. U svetlu ovih činjenica, u okviru ove disertacije testiran je uticaj nekih etanolaminskih jonskih tečnosti na tok reakcija Hekovog tipa i ispitivan mehanizam formiranja prekatalitički aktivne Pd(II)-vrste, neophodne za njihovo odvijanje. Pokazalo se da su upotrebljene jonske tečnosti odličan reakcioni medijum, i da su efikasni ligandi za formiranje Pd(II), odnosno Pd(0), kompleksa kao katalizatora. Na osnovu literaturnih podataka moglo se zaključiti da su se neki od Pd(II)- kompleksa pokazali kao dobri antimikrobni agensi, ali da njihova antitumorska aktivnost nije naročito izražena. Takođe, poznato je da kompleksi paladijuma(II) katalizuju selektivnu hidrolizu amidne veze u peptidima i proteinima, pri vrlo blagim reakcionim uslovima. Prema tome, oni se mogu smatrati i obećavajućim agensima za selektivnu hidrolizu peptidne veze, odnosno mogu se koristiti kao efikasne metalopeptidaze. Imajući ovo u vidu, testirana je katalitička uloga dietanolamonijum-tetrahlorido-paladat(II)-kompleksa ([HDEA]2[PdCl4]) u hidrolitičkim reakcijama sa N-acetilovanim derivatima L-histidil-glicina (AcHis-Gly) i L-metionil-glicina (AcMet-Gly). Takođe, ispitivana je i antimikrobna aktivnost nekih jonskih tečnosti i Rd(II)-kompleksa dobijenih iz njih.For last two decades ionic liquids attract great attention from both science and industry. The beginning of their application is marked as new “green” chemical revolution. This is demonstrated by the continually growing number of publications and patents (currently > 10000 and > 2000, respectively). This new class of compounds can reduce the usage of toxic and polluting organic solvents, due to their unique physico-chemical properties, and their ability to be applied in different synthesis. Terms such as molten salts, non-aqueous ionic liquids and liquid organic salts are used to describe these ionized compounds which are liquid at room temperature, opposite to inorganic salts which melts at extremely high temperature, aslo. Due to all these properties of which poseses this interesting group of compounds, synthesis and characterization of some new ionic liquids derivatives of ethanolamine was performed in this thesis. Many organic reactions, which are traditionally catalyzed by conventional acids and bases, can be catalyzed by corresponding ionic liquids, also. Reactions such as Aldol condensation, Knoevenagel, Michael, Mannich, Henry, Diels-Ader, Friedel-Crafts reaction, are just some of them. In this dissertation, catalytic role of some ethanolamine ionic liquids is investigated, as well as their impact on the stereoselectivity of the Mannich reaction products. The mechanism of the Mannich reaction was examined using Density Functional Theory (DFT). One of the biggest challenges in organic chemistry is certainly formation of C–C bonds. Carbon atoms are stable, and do not react easily with one another. The synthesis of simple organic compounds has not been problematic, but the synthesis of more complex molecules leads to the formation of a large number of by-products. The development of palladium-catalyzed reactions solved this problem. In these reactions, carbon atoms meet on palladium, after which the chemical reaction begins. Heck, Negishi, Suzuki, Stille and Sonogashira reactions are well known palladium-catalyzed reactions, which are carried out in the presence of ionic liquids. It has been shown that these reactions are very efficient, and appearance of precipitated elemental palladium was not observed, i.e. there was not loss in catalyst activity. In light of this, the effect of some ethanolamine ionic liquids on the Heck type reactions was tested. Also, the mechanism of formation of Pd(II) species necessary for performing these reactions was elucidated. Used ionic liquids were excellent reaction medium and efficient ligands for formation of Pd(II), as well as Pd(0), complexes as catalyst. On the basis of literature data it could be concluded that some Pd(II) complexes act as good antimicrobial agents, but their antitumor activity is not particularly pronounced. Also, it is known that palladium(II) complexes catalyze selective hydrolysis of the amide bonds in peptides and proteins, under very mild conditions. Therefore, they can be considered as promising agents for the selective hydrolysis of peptide bond, and can be used as effective metallopeptidases. Bearing this in mind, catalytic role of diethanolammonium-tetrachloridopalladate(II) complex ([HDEA]2[PdCl4]) was tested in the hydrolytic reaction with N-acetylated derivatives of Lhistidil- glycine (AcHis-Gly) and L-metionil-glycine (AcMet-Gly). The antimicrobial activity of some ionic liquids and Pd(II)-complexes, obtained from them, was examined, also

Supplementary material for the article: Petrović, Z. D.; Đorović, J.; Simijonović, D.; Trifunović, S.; Petrović, V. P. In Vitro Study of Iron Coordination Properties, Anti-Inflammatory Potential, and Cytotoxic Effects of N Salicylidene and N-Vanillidene Anil Schiff Bases. Chemical Papers 2018, 72 (9), 2171– 2180. https://doi.org/10.1007/s11696-018-0419-5

Supplementary material for: [https://doi.org/10.1007/s11696-018-0419-5]Related to published version: [http://cherry.chem.bg.ac.rs/handle/123456789/2190

ANTIRADIKALSKI KAPACITET (E)-N’-1-(2,4-DIOKSO-2H-HROMEN-3(4H)-ILIDENE)ETIL)-4-HIDROKSI-3-METOKSIBENZOHIDRAZIDA

Coumarins are a widespread group of compounds. They have a wide range of physiological effects, from antifungal, through anticoagulant to anticancer, and therefore they have found wide application in the treatment of various diseases. In this paper, the ability of 4-hydroxy-3-methoxy-N'-((E)-1-(2,4-dioxo-2H-chromen- 3(4H)-ylidene)ethyl)benzohydrazide to inactivate ROS was investigated. The analysis of the obtained results showed that the SET-PT (Single Electron Transfer Followed By Proton Transfer) mechanism is non-operative. On the other hand, the thermodynamic parameters describing the HAT *Hydrogen Atom Transfer) and the first step of the SPLET (Sequential Proton Loss-Electron Transfer) mechanism indicate that both mechanisms will be operative. The antiradical capacity of the test compound with the radicals decreases in the following order: •OH> •OCH3> •OC(CH3)3> •OOH> •OOCH3> •OOCH2CH3.Publishe

Supplementary material for the article: Petrović, Z. D.; Đorović, J.; Simijonović, D.; Trifunović, S.; Petrović, V. P. In Vitro Study of Iron Coordination Properties, Anti-Inflammatory Potential, and Cytotoxic Effects of N Salicylidene and N-Vanillidene Anil Schiff Bases. Chemical Papers 2018, 72 (9), 2171– 2180. https://doi.org/10.1007/s11696-018-0419-5

Supplementary material for: [https://doi.org/10.1007/s11696-018-0419-5]Related to published version: [http://cherry.chem.bg.ac.rs/handle/123456789/2190

Evaluation of antioxidant and cytotoxic properties of phenolic N-acylhydrazones: Structure-activity relationship

Cancer is still a relentless public health issue. Particularly, colorectal cancer is the third most prevalent cancer in men and the second in women. Moreover, cancer development and growth are associated with various cell disorders, such as oxidative stress and inflammation. The quest for efficient therapeutics is a challenging task, especially when it comes to achieving both cytotoxicity and selectivity. Herein, five series of phenolic N-acylhydrazones were synthesized and evaluated for their antioxidant potency, as well as their influence on HCT-116 and MRC-5 cells viability. Among 40 examined analogues, 20 of them expressed antioxidant activity against the DPPH radical. Furthermore, density functional theory was employed to estimate the antioxidant potency of the selected analogues from the thermodynamical aspect, as well as the preferable free-radical scavenging pathway. Cytotoxicity assay exposed enhanced selectivity of a number of analogues toward cancer cells. The structure-activity analysis revealed the impact of the type and position of the functional groups on both cell viability and selectivity toward cancer cells

A new efficient domino approach for the synthesis of pyrazolyl-phthalazine-diones. Antiradical activity of novel phenolic products

Pyrazolyl-phthalazine-dione derivatives (PPDs) were synthetized in the ionic liquid catalyzed one-pot multicomponent reaction of acetylacetone, 2,3-dihydrophthalazine-1,4-dione, and different aldehydes in moderate to good yields. Six new PPDs were obtained, and the crystal structure of 2-acetyl-1-(4-fluorophenyl)- 3-methyl-1H-pyrazolo[1,2-b] phthalazine-5,10-dione (PPD-4) was determined. The most interesting structural features of the novel PPD-4 is the formation of a rather short intermolecular distance between the F atom of one molecule and the midpoint of the neighbouring six-membered heterocyclic ring. This interaction arranges all molecules into parallel supramolecular chains. UV-Vis spectra of all PPDs were acquired and compared to the simulated ones obtained with TD-DFT. All synthetized compounds were subjected to evaluation of their in vitro antioxidative activity using a stable DPPH radical. It was shown that PPD-7, with a catechol motive, is the most active antioxidant, while PPD-9, with two neighbouring methoxy groups to the phenolic OH, exerted a somewhat lower, but significant antioxidative potential. The results of DFT thermodynamical study are in agreement with experimental findings that PPD-7 and PPD-9 should be considered as powerful radical scavengers. In addition, the obtained theoretical results (bond dissociation and proton abstraction energies) specify SPLET as a prevailing radical scavenging mechanism in polar solvents, and HAT in solvents with lower polarity. On the other hand, the obtained reaction enthalpies for inactivation of free radicals suggest competition between HAT and SPLET mechanisms, except in the case of the (OH)-O-center dot radical in polar solvents, where HAT is labeled as prefered

In vitro and in silico lipoxygenase inhibition studies and antimicrobial activity of pyrazolyl-phthalazine-diones

The series of pyrazolyl-phthalazine-dione derivatives (PPDs) was subjected to evaluation of their in vitro lipoxygenase (LOX) inhibition and antimicrobial activities. Results obtained for LOX inhibition activities of PPDs showed that all compounds exhibit good to excellent activity, whereby compounds with eudesmic, syringic, vanillic or toluic moiety are the most active. Molecular modelling study was performed to investigate the possible mechanism of action and binding mode of compounds within the LOX active site. Docking results revealed that activity of the examined compounds depends on the functional group ability to create hydrogen bond accepting (HBA) and hydrophobic features (Hy) in the LOX-Ib active site. In addition, all substances were tested for their antibacterial and antifungal activities. The investigated compounds showed better antifungal than antibacterial activity. The highest antifungal activity was on Aspergillus fumigatus ATTC 204305 and Trichoderma viridae ATCC 13233.Publishe

Green One-Pot Synthesis of Coumarin-Hydroxybenzohydrazide Hybrids and Their Antioxidant Potency

Compounds from the plant world that possess antioxidant abilities are of special importance for the food and pharmaceutical industry. Coumarins are a large, widely distributed group of natural compounds, usually found in plants, often with good antioxidant capacity. The coumarin-hydroxybenzohydrazide derivatives were synthesized using a green, one-pot protocol. This procedure includes the use of an environmentally benign mixture (vinegar and ethanol) as a catalyst and solvent, as well as very easy isolation of the desired products. The obtained compounds were structurally characterized by IR and NMR spectroscopy. The purity of all compounds was determined by HPLC and by elemental microanalysis. In addition, these compounds were evaluated for their in vitro antioxidant activity. Mechanisms of antioxidative activity were theoretically investigated by the density functional theory approach and the calculated values of various thermodynamic parameters, such as bond dissociation enthalpy, proton affinity, frontier molecular orbitals, and ionization potential. In silico calculations indicated that hydrogen atom transfer and sequential proton loss–electron transfer reaction mechanisms are probable, in non-polar and polar solvents respectively. Additionally, it was found that the single- electron transfer followed by proton transfer was not an operative mechanism in either solvent. The conducted tests indicate the excellent antioxidant activity, as well as the low potential toxicity, of the investigated compounds, which makes them good candidates for potential use in food chemistry

Biosynthesis and characterization of silver nanoparticles synthesized using extracts of Agrimonia eupatoria L. and in vitro and in vivo studies of potential medicinal applications

This research explores the synthesis, characterization, and biological activities of silver nanoparticles (AgNPs) derived from acetone (AgNPs-acetone) and aqueous (AgNPs-H2O) extracts of Agrimonia eupatoria. The nanoparticles exhibit isometric morphology and uniform size distribution, as elucidated through Transmission Electron Microscopy (TEM) and high-resolution TEM (HRTEM) analyses. The utilization of Scanning Transmission Microscopy (STEM) with High-Angle Annular Dark-Field (HAADF) imaging and energy dispersive spectrometry (EDS) confirms the crystalline nature of AgNPs. Fourier Transform Infrared (FTIR) analysis reveals identical functional groups in the plant extracts and their corresponding AgNPs, suggesting the involvement of phytochemicals in the reduction of silver ions. Spectrophotometric monitoring of the synthesis process, influenced by various parameters, provides insights into the kinetics and optimal conditions for AgNP formation. The antioxidant activities of the plant extracts and synthesized AgNPs are evaluated through DPPH and ABTS methods, highlighting AgNPs-acetone as a potent antioxidant. Third-instar larvae exposed to the extracts have differential effects on DNA damage, with the acetone extract demonstrating antigenotoxic properties. Similarly, biosynthesized AgNPs-acetone displays antigenotoxic effects against EMS-induced DNA damage. The genotoxic effect of water extract and AgNPs-acetone was dose-dependent. Hemolytic potential is assessed on rat erythrocytes, revealing that low concentrations of AgNPs-acetone and AgNPs-H2O had a nontoxic effect on erythrocytes. Cytotoxicity assays demonstrate time-dependent and dose-dependent effects, with AgNPs-acetone exhibiting superior cytotoxicity. Proapoptotic activity is confirmed through apoptosis induction, emphasizing the potential therapeutic applications of AgNPs. The antimicrobial activity of AgNPs reveals concentration-dependent effects. AgNPs-H2O display better antibacterial activity, while antifungal activities are comparable between the two nanoparticle types

Derivati etanolamina kao jonske tečnosti i prekursori biološki i katalitički aktivnih Pd(II)-kompleksa

Poslednjih godina jonske tečnosti privlače veliku pažnju, kako nauke tako i industrije. Početak njihove primene neki nazivaju “zelenom“ hemijskom revolucijom. U prilog tome svedoči neprekidan porast broja do sada objavljenih radova i patenata iz ove oblasti (više od 10000 radova i više od 2000 patenata). Ova nova grupa jedinjenja može uticati na smanjenje upotrebe toksičnih i zagađujućih organskih rastvarača zbog njihovih jedinstvenih fizičko-hemijskih karakteristika i mogućnosti da se primene u različitim sintezama. Termini kao što su stopljene soli, nevodene jonske tečnosti I tečne organske soli se, takođe, koriste da bi se opisala ova jonizovana jedinjenja koja su tečna na sobnoj temperaturi, suprotno neorganskim solima koje se tope na izuzetno visokim temperaturama. Zbog svih ovih osobina koje pokazuje ova interesantna grupa jedinjenja, u okviru ove disertacije izvršena je sinteza i karakterizacija nekih novih jonskih tečnosti na bazi derivata etanolamina. Za većinu organskih reakcija koje su tradicionalno katalizovane uobičajenim kiselinama i bazama, mogu se kao katalizatori upotrebiti i odgovarajuće jonske tečnosti. Aldolna kondenzacija, Knevenagelova, Majklova, Manihova, Henrijeva, Dils-Alderova i Fridel-Kraftsova reakcija su samo neke od njih. U okviru ove disertacije ispitana je katalitička uloga nekih etanolaminskih jonskih tečnosti u Manihovoj reakciji, kao i njihov uticaj na stereohemiju dobijenih proizvoda. Metodama funkcionala gustine ispitan je mehanizam odvijanja ove reakcije. Jedan od najvećih izazova organske hemije je svakako stvaranje S–S veze. Međutim, ugljenik je stabilan i atomi ugljenika ne reaguju lako jedan sa drugim. Sinteza jednostavnih organskih jedinjenja više nije problematična, ali pri sintezama složenijih molekula dolazi do stvaranja velikog broja nusproizvoda. Razvojem paladijum-katalizovanih reakcija rešen je taj problem. U ovim reakcijama atomi ugljenika se vezuju za paladijum, nakon čega dolazi do pokretanja hemijske rekcije. Hekova, Negišijeva, Suzukijeva, Stilova i Sonogaširina reakcija su naročito poznate paladijum-katalizovane reakcije koje se izvode u jonskim tečnostima. Pokazalo se da su ovakve reakcije vrlo efikasne i da ne dolazi do taloženja elementarnog paladijuma, odnosno gubitka katalizatora. U svetlu ovih činjenica, u okviru ove disertacije testiran je uticaj nekih etanolaminskih jonskih tečnosti na tok reakcija Hekovog tipa i ispitivan mehanizam formiranja prekatalitički aktivne Pd(II)-vrste, neophodne za njihovo odvijanje. Pokazalo se da su upotrebljene jonske tečnosti odličan reakcioni medijum, i da su efikasni ligandi za formiranje Pd(II), odnosno Pd(0), kompleksa kao katalizatora. Na osnovu literaturnih podataka moglo se zaključiti da su se neki od Pd(II)- kompleksa pokazali kao dobri antimikrobni agensi, ali da njihova antitumorska aktivnost nije naročito izražena. Takođe, poznato je da kompleksi paladijuma(II) katalizuju selektivnu hidrolizu amidne veze u peptidima i proteinima, pri vrlo blagim reakcionim uslovima. Prema tome, oni se mogu smatrati i obećavajućim agensima za selektivnu hidrolizu peptidne veze, odnosno mogu se koristiti kao efikasne metalopeptidaze. Imajući ovo u vidu, testirana je katalitička uloga dietanolamonijum-tetrahlorido-paladat(II)-kompleksa ([HDEA]2[PdCl4]) u hidrolitičkim reakcijama sa N-acetilovanim derivatima L-histidil-glicina (AcHis-Gly) i L-metionil-glicina (AcMet-Gly). Takođe, ispitivana je i antimikrobna aktivnost nekih jonskih tečnosti i Rd(II)-kompleksa dobijenih iz njih.For last two decades ionic liquids attract great attention from both science and industry. The beginning of their application is marked as new “green” chemical revolution. This is demonstrated by the continually growing number of publications and patents (currently > 10000 and > 2000, respectively). This new class of compounds can reduce the usage of toxic and polluting organic solvents, due to their unique physico-chemical properties, and their ability to be applied in different synthesis. Terms such as molten salts, non-aqueous ionic liquids and liquid organic salts are used to describe these ionized compounds which are liquid at room temperature, opposite to inorganic salts which melts at extremely high temperature, aslo. Due to all these properties of which poseses this interesting group of compounds, synthesis and characterization of some new ionic liquids derivatives of ethanolamine was performed in this thesis. Many organic reactions, which are traditionally catalyzed by conventional acids and bases, can be catalyzed by corresponding ionic liquids, also. Reactions such as Aldol condensation, Knoevenagel, Michael, Mannich, Henry, Diels-Ader, Friedel-Crafts reaction, are just some of them. In this dissertation, catalytic role of some ethanolamine ionic liquids is investigated, as well as their impact on the stereoselectivity of the Mannich reaction products. The mechanism of the Mannich reaction was examined using Density Functional Theory (DFT). One of the biggest challenges in organic chemistry is certainly formation of C–C bonds. Carbon atoms are stable, and do not react easily with one another. The synthesis of simple organic compounds has not been problematic, but the synthesis of more complex molecules leads to the formation of a large number of by-products. The development of palladium-catalyzed reactions solved this problem. In these reactions, carbon atoms meet on palladium, after which the chemical reaction begins. Heck, Negishi, Suzuki, Stille and Sonogashira reactions are well known palladium-catalyzed reactions, which are carried out in the presence of ionic liquids. It has been shown that these reactions are very efficient, and appearance of precipitated elemental palladium was not observed, i.e. there was not loss in catalyst activity. In light of this, the effect of some ethanolamine ionic liquids on the Heck type reactions was tested. Also, the mechanism of formation of Pd(II) species necessary for performing these reactions was elucidated. Used ionic liquids were excellent reaction medium and efficient ligands for formation of Pd(II), as well as Pd(0), complexes as catalyst. On the basis of literature data it could be concluded that some Pd(II) complexes act as good antimicrobial agents, but their antitumor activity is not particularly pronounced. Also, it is known that palladium(II) complexes catalyze selective hydrolysis of the amide bonds in peptides and proteins, under very mild conditions. Therefore, they can be considered as promising agents for the selective hydrolysis of peptide bond, and can be used as effective metallopeptidases. Bearing this in mind, catalytic role of diethanolammonium-tetrachloridopalladate(II) complex ([HDEA]2[PdCl4]) was tested in the hydrolytic reaction with N-acetylated derivatives of Lhistidil- glycine (AcHis-Gly) and L-metionil-glycine (AcMet-Gly). The antimicrobial activity of some ionic liquids and Pd(II)-complexes, obtained from them, was examined, also