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The condensation product of 7-acetyl-6-azaindole and Girard’s T reagent ((E)-2-(2-(1-(1H-pyrrolo[2,3-c]pyridin-7-yl)ethylidene)hydrazineyl)-N,N,N-trimethyl-2-oxoethan-1-aminium, HL ligand) was used as a ligand in the reaction with Cu(BF4)2·6H2O and NaN3. The reaction led to the formation of a binuclear Cu(II) complex containing two end-to-end (di-m-1,3-N3) azide bridges, as well as two NNO-donor hydrazone ligands, forming an axially elongated square pyramidal geometry around each Cu(II) center. This end-to-end (di-m-1,3-N3) azide bridge binding mode has not yet been reported, in Cu(II) complexes containing the NNO-donor hydrazone ligands, which makes the structure of the complex even more interesting for further studies. The com­plex was characterized by elemental analysis, IR spectroscopy and X-ray crys­tal­lography, and it was found that it crystallizes in the triclinic space group P–1 with the asymmetric unit comprising one Cu(II) centre, zwitterionic ligand L, one azide (N3-) ligand and BF4- counter anion. Examination of antimicrobial activity of the complex shows higher antifungal and antibacterial activity towards tested Gram-positive bacteria in comparison to the hydrazone ligand, with the antifungal activity of the complex even being comparable to the act­ivity of amphotericin B.

Fe(III) and Mn(II) complexes with condensation product of thiosemicarbazide and 2-acetylthiazole (HL1, (E)-2-(1-(thiazol-2-yl)ethylidene)hydrazine-1-carbothioamide) have been synthesized and characterized by single-crystal X-ray diffraction, IR spectroscopy, and elemental analysis. In both complexes, the thiosemicarbazone ligand is coordinated in deprotonated form through the NNS donor set of atoms. However, while Fe(III) complex is in the doublet ground state with distorted octahedral geometry, the coordination environment around Mn(II) is distorted trigonal-prismatic, and the sextet state is found to be the ground state. DFT calculations were performed to rationalize spin state preferences, and continuous shape measure describes the deviation from ideal six-coordinated polyhedral geometries in the ground and excited states. Antimicrobial activity (against a panel of Gram-negative and Gram-positive bacteria, two yeast, and one fungal strain), brine shrimp assay, and DPPH radical scavenging activity of both complexes were evaluated, and these results relate to the electronic structure of the complexes.

Interest in Cd complexes has been growing in recent years. Cd complexes are considered a potential solution in the search for novel antibiotics that can fight antimicrobial resistance. In addition, Cd complexes draw attention to material chemistry. The main objective of this work was to prepare the first Cd(II) complexes with anionic forms of pyridine-based thiazolyl hydrazone (THs) ligands HLS2 [(E)-4-(4-methoxyphenyl)-2-(2-[pyridine-2-ylmethylene]hydrazinyl)thiazole] and HLS3 [(E)-2-(2-[pyridine-2-ylmethylene]hydrazinyl)-4-(p-tolyl)thiazole] and perform their structural and spectroscopic characterization, as well as stability in solution and upon heating. Studies related to their biological activities and possible electrochromic applications are also being conducted. Complexes [Cd(HLS2)2] (1) and [Cd(HLS3)2] (2) have been characterized by a single-crystal X-ray diffraction and computational analysis of intermolecular interactions responsible for their solid-state structures was performed. Thermal stability of 1 and 2 in the solid-state was analyzed by TGA/MS, where as their solution stability was determined by the spectrophotometric titration method. Electrochemical and in situ UV–Vis spectroelectrochemical analyses of 1 and 2 were carried out to determine redox mechanisms and the influence of the substituents and electrolytes on their redox responses. The antioxidant capacity of both complexes was tested in antioxidant assays, while their antimicrobial activity was tested against five Gram-positive and four Gram-negative bacteria, as well as against three fungi. The obtained results indicate their potent antioxidant capacity. The antimicrobial activity of investigated compounds on almost all tested bacterial strains was stronger than that of the standard antibiotic erythromycin. The results of docking studies indicate that the minor groove DNA is the possible biological target of 1 and 2.

Earth-abundant, cheap and non-toxic zinc-based coordination compounds are drawing research attention as promising candidates for various applications, such as photoluminescent materials and anticancer agents. In this paper we report six zinc complexes (1–3-NO3 and 1–3-Cl) with pyridyl-based thiazolyl–hydrazone ligands, which differ in the nature of substituents at the ligands' periphery, anion type, and geometry around the metal ion. The complexes were characterized by single-crystal and powder X-ray diffraction analysis, as well as IR and NMR spectroscopy. The symmetrical complexes 2-Cl and 3-Cl, where zinc atoms are located at a two-fold axis, do not exhibit photophysical properties, unlike their asymmetrical analogs 2-NO3 and 3-NO3 with the same complex cation. Asymmetrical pentacoordinated 1-Cl and hexacoordinated 1-NO3 complexes exhibit photophysical properties. An admixture of allowed intra-ligand (1IL) and chloro (X)-to-ligand charge-transfer (1XLCT) electronic transitions is responsible for the fluorescence of the 1-Cl complex. The origin of the emission of the 1-NO3 complex is ascribed to an admixture of 3IL and ligand-to-ligand charge-transfer (3LLCT) forbidden electronic transitions, while for 3-NO3 most electronic excitations are of LLCT character. The thermal stability of the complexes is in accord with the strength of respective intermolecular interactions. The antiproliferative activity of the complexes was in the nanomolar range on some of the investigated cancer cell lines. Contrary to the increase of antiproliferative activity of the complexes in comparison to the free ligands in cancer cell lines, an acute toxicity determined in the brine shrimp assay follows the opposite trend. The overall results suggest that Zn(II) thiazoyl–hydrazone complexes have considerable potential as multifunctional materials.

The biological activity of Cd compounds has been investigated scarce since Cd has been recognized as a human carcinogen. However, the toxicity of cadmium is comparable to the toxicity of noble metals such as Pt and Pd. The paradigm of metal toxicity has been challenged suggesting that metal toxicity is not a constant property, yet it depends on many factors like the presence of appropriate ligands. Studies on anticancer activity of cadmium complexes showed that the complexation of various ligands resulted in complexes that showed better activities than approved drugs. In the present study, cadmium complexes with biologically potent thiazolyl/selenazoyl-hydrazone ligands have been prepared, and tested for their activity against different types of tumor cell models. The complexation of ligands with Cd(II) resulted in a synergistic effect. The antiproliferative activity study revealed that all complexes are more active compared to 5-fluorouracil and cisplatin. The mechanism of tumor cell growth inhibition reveal that selenium-based compounds induce cell death in T-47D (gland carcinoma) cells through apoptosis via caspase-3/7 activation. Additionally, their pro-apoptotic effect was stronger compared to etoposide and cisplatin. Nuclease activity, detected by gel electrophoresis, may be the possible mechanism of anticancer action of investigated complexes.

In this work synthesis, characterization and crystal structures of 1, Zn(II) complex ([ZnL1(NCS)2]), with (E)-1-(2-oxo-2-(2-(quinolin-2-ylmethylene)hydrazinyl)ethyl)pyridin-1-ium chloride (HL1Cl) and 2, Bi(III) complex ([BiHL2Cl4] × 1/2CH3OH), with (E)-N,N,N-trimethyl-2-oxo-2-(2-(1-(thiazol-2-yl)ethylidene)hydrazinyl)ethan-1-aminium chloride (HL2Cl), have been reported. Zn(II) complex possesses a distorted trigonal bipyramidal geometry while surroundings around Bi(III) ion are extended pentagonal bipyramidal. Antimicrobial activity, brine shrimp assay and DPPH radical scavenging activity of both complexes, including previously synthesized complexes with HL2Cl ligand (Zn(II) and Ni(II)) and complexes with (E)-N,N,N-trimethyl-2-oxo-2-(2-(1-(pyridin-2-yl)ethylidene)hydrazinyl)ethan-1-aminium chloride (HL3Cl) (Zn(II), Cu(II), Cd(II), Co(II), Fe(III), Ni(II)), were evaluated. For the most active complexes, cytotoxic activity against five malignant cancer cell lines (HeLa, A375, MCF7, PC-3 and A549) and normal cell line HaCaT, as well as generation of reactive oxygen species (ROS), was tested.

In this work synthesis, characterization and crystal structures of 1, Zn(II) complex ([ZnL1(NCS)2]), with (E)-1-(2-oxo-2-(2-(quinolin-2-ylmethylene)hydrazinyl)ethyl)pyridin-1-ium chloride (HL1Cl) and 2, Bi(III) complex ([BiHL2Cl4] × 1/2CH3OH), with (E)-N,N,N-trimethyl-2-oxo-2-(2-(1-(thiazol-2-yl)ethylidene)hydrazinyl)ethan-1-aminium chloride (HL2Cl), have been reported. Zn(II) complex possesses a distorted trigonal bipyramidal geometry while surroundings around Bi(III) ion are extended pentagonal bipyramidal. Antimicrobial activity, brine shrimp assay and DPPH radical scavenging activity of both complexes, including previously synthesized complexes with HL2Cl ligand (Zn(II) and Ni(II)) and complexes with (E)-N,N,N-trimethyl-2-oxo-2-(2-(1-(pyridin-2-yl)ethylidene)hydrazinyl)ethan-1-aminium chloride (HL3Cl) (Zn(II), Cu(II), Cd(II), Co(II), Fe(III), Ni(II)), were evaluated. For the most active complexes, cytotoxic activity against five malignant cancer cell lines (HeLa, A375, MCF7, PC-3 and A549) and normal cell line HaCaT, as well as generation of reactive oxygen species (ROS), was tested.

In this article, synthesis, spectral and X-ray structure characterization, antimicrobial activity and Brine shrimp test of two new Cu(II) complexes with a salicylaldehyde derivative have been reported. Complexes [Cu(L)(bipy)]BF4·0.5H2O and [Cu2(L)2(phen)2](BF4)2 were obtained in the reaction of Cu(BF4)2·6H2O, deprotonated 4-(diethylamino)−2-hydroxybenzaldehyde ligand (L) and α-diimine (2,2’-bipyridine or 1,10-phenanthroline). The complex with bipyridine is mononuclear, containing one L and one bipyridine ligand in a distorted square-planar cation with a BF4 − anion and lattice water molecule, whereas the complex with phenanthroline is a dinuclear centrosymmetric dimeric cation, containing two L ligands along with two phenanthroline ligands and BF4 − anions. The coordination geometry of each Cu(II) ion can be described as an elongated square pyramid. MS-ESI spectroscopy indicated that [Cu2(L)2(phen)2](BF4)2 is mononuclear in DMSO solution. In vitro antibacterial and antifungal activity was tested against four Gram-positive, four Gram-negative bacteria and three fungal strains. Complexes showed significantly stronger antibacterial activities than parent ligands. The mononuclear phenanthroline complex in solution showed very good antimicrobial activity, which is comparable to the activity of the standard antibiotic amikacin against all tested bacterial strains. The same complex has better antifungal activity than fluconazole, which was used as a standard. Results of the brine shrimp test indicate that both complexes have good toxicity against Artemia nauplii.

Helichrysum plicatum DC. is widely used in folk medicine in treating a variety of health disorders. The aim of this study was to examine the influence of different extraction solvents on the chemical composition, antioxidant potential, and antimicrobial activities of H. plicatum. Aerial parts were separately extracted with ethanol, dichloromethane, and sunflower oil. The oil extract (OE) was re-extracted with acetonitrile. A total of 142 compounds were tentatively identified in ethanolic (EE), dichloromethane (DCME), and acetonitrile (ACNE) extracts using HPLC-DAD/ESI-ToF-MS. The dominant compound class in all extracts were α-pyrones, alongside flavonoids in EE, terpenoids in DCME and ACNE, and phloroglucinols in DCME. The antioxidant potential of the extracts was assessed by the 2,2-diphenyl-1-picrylhydrazyl radical (DPPH) assay. EE and DCME possessed the most potent radical scavenging capacity. Antimicrobial activity was investigated on eight bacterial, two yeast, and one fungal species. All extracts exhibited high antifungal and notable antibacterial activities compared to control substances, with DCME being the most potent. DCME exhibited stronger antimicrobial activity against P. aeruginosa than the standard chloramphenicol.

Tert-butylquinone (TBQ) and its alkylamino and aralkylamino derivatives are of high interest as a potential antitumor agent. Therefore, it was necessary to investigate if the compounds exert undesirable activities such as interaction with DNA molecule which could result in negative side effects in the case of their use in the diseases treatment. The major aim of this study was to investigate genotoxic potential of TBQ and selected derivatives in an acellular model by using plasmid DNA, in the prokaryotic model by the SOS/umuC assay in Salmonella typhimurium TA1535/pSK1002 and in eukaryotic models by using comet assay in human fetal lung cell line (MRC-5) and human liver cancer cell line (HepG2). Results indicated that in the acellular model TBQ and its derivatives do not interact with plasmid pUC19. In the prokaryotic model, only TBQ exerted weak genotoxic potential and only at highly cytotoxic concentrations. In eukaryotic models, genotoxic potential was detected mainly at the highest concentrations of the tested substances but the effect was lower in both cell lines in comparison with benzo[a]pyrene and etoposide which were used as positive controls. Weak genotoxic potential of tested compounds recommends them as good candidates for further testing in development of new antitumor agents. © 2018, © 2018 Informa UK Limited, trading as Taylor & Francis Group.

Tert-butylquinone (TBQ) and its alkylamino and aralkylamino derivatives are of high interest as a potential antitumor agent. Therefore, it was necessary to investigate if the compounds exert undesirable activities such as interaction with DNA molecule which could result in negative side effects in the case of their use in the diseases treatment. The major aim of this study was to investigate genotoxic potential of TBQ and selected derivatives in an acellular model by using plasmid DNA, in the prokaryotic model by the SOS/umuC assay in Salmonella typhimurium TA1535/pSK1002 and in eukaryotic models by using comet assay in human fetal lung cell line (MRC-5) and human liver cancer cell line (HepG2). Results indicated that in the acellular model TBQ and its derivatives do not interact with plasmid pUC19. In the prokaryotic model, only TBQ exerted weak genotoxic potential and only at highly cytotoxic concentrations. In eukaryotic models, genotoxic potential was detected mainly at the highest concentrations of the tested substances but the effect was lower in both cell lines in comparison with benzo[a]pyrene and etoposide which were used as positive controls. Weak genotoxic potential of tested compounds recommends them as good candidates for further testing in development of new antitumor agents. © 2018, © 2018 Informa UK Limited, trading as Taylor & Francis Group.

Eleven new steroidal mono- and bis(semicarbazones)2a–e, 4d and 3a–e have been prepared starting from various 3-oxo-α,β-unsaturated steroids. Mono-semicarbazones 2a–e were further subjected to ethyl chloroacetate in boiling absolute ethanol but, instead of expected intramolecular cyclocondensation reaction products, the new carbazate esters 5a-e were obtained. The structures of all synthesized compounds and identification of each E/Z isomer were deduced by elemental analysis, HRMS, NMR, and IR spectroscopy. Preliminary screening for the cytotoxic activity in vitro of the new compounds has been conducted against three cancer cell lines, K562, Jurkat and HeLa cells. HeLa cells were the most sensitive while K562 cells were the least sensitive to the cytotoxic action of the novel steroid derivatives. Compounds 2e, 3c and 5e were found to have the best but still moderate cytotoxic effects. All tested compounds showed very weak antimicrobial activities. These results demonstrate that the replacement of thioxo group with carbonyl group in steroidal hydrazone derivatives resulted in decrease in their biological activity.

U potrazi za biološki aktivnim jedinjenjima, počev od progesterona i 3-okso-α,β-nezasićenih androstenskih steroida, u okviru ove disertacije sintetisano je i potpunookarakterisano pedeset novih derivata steroidnih hidrazona, od kojih po jedanaesttiosemikarbazona, tijadiazolina i semikarbazona, dvanaest tiazolidin-4-ona i petkarbazatnih estara.Po prvi put je urađena detaljna analiza stereohemije steroidnih hidrazona u položajimaC-3/17 androstenskih, odnosno C-3/20 progesteronskih derivata. Struktura istereohemija potvrđene su rezultatima rendgenske strukturne analize za tijadiazolin 7a,prvo okarakterisano steroidno jedinjenje koje sadrži šestočlani ugljenični prstenkondenzovan sa spiro-tijadiazolinskim prstenom, i tiazolidinon 9b-E, prvi steroidniderivat sa poznatom konfiguracijom dvostruke veze u položaju C-3 hidrazonotiazolidin-4-onskog fragmenta.Sintetisana jedinjenja su ispoljila najjaču citotoksičnost prema HeLa ćelijamaadenokarcinoma cerviksa i prema K562 ćelijama hronične mijeloidne leukemije, a posvojoj aktivnosti istakli su se tiosemikarbazoni 2a, 2b, 2c i 2f, tijadiazolini 8a i 8e itiazolidin-4-oni 9a i 10a. Pritom su koeficijenti selektivnosti u antikancerskom dejstvuprema malignim ćelijama u odnosu na normalne humane PBMC, kako na nestimulisanetako i na mitogenom stimulisane, bili daleko veći od vrednosti 2,5 što ova jedinjenjasvrstava u potencijalne kandidate za in vivo ispitivanja. Sumporni derivati bili su dalekoaktivniji od kiseoničnih. Najaktivniji derivati indukovali su apoptozu posredstvomkaspaza-3, -8 i -9 i inhibirali angiogezu in vitro zbog čega se smatra da posedujuznačajan antikancerski potencijal., Searching for biologically active compounds, within this doctoraldissertation fifty new steroidal hydrazone derivatives, of which 11 thiosemicarbazones,11 thiadiazolines, 12 thiazolidin-4-ones, 11 semicarbazones and 5 carbazate esters, weresynthesized starting with progesterone and 3-oxo-α,β-unsaturated androstene steroids,and fully characterized.For the first time, detailed stereochemistry analyses of steroidal hydrazones in the C-3/17 positions of androstene derivatives, or C-3/20 positions of progesterone derivativeswas done. Structure and stereochemistry were confirmed by the results of X-rayanalyses for thiadiazoline 7a, the first characterized steroid compound that contains sixmemberedcarbon ring condensed with the spiro-thiadiazoline ring, and thiazolidinone9b-E, the first steroidal derivative with known configuration of double bond in C-3position of the hydrazono-thiazolidin-4-one fragment.Synthesised compounds manifested the best cytotoxicity towards HeLa cervixadenocarcinoma cells, and K562 cells of chronic myeloide leukemia, the best activitybeing showed by thiosemicarbazones 2a, 2b, 2c and 2f, thiadiazolines 8a and 8e, andthiazolidin-4-ones 9a and 10a. All of these compounds exhibited considerably higherintensities of cytotoxic action against malignant cells when compared with normalhuman PBMC, both resting and mitogen-stimulated, with coefficient of selectivityhigher than 2.5, which makes these compounds potential candidates for in vivoexperiments. Sulfur derivatives were much more active than oxygen derivatives. Themost active derivatives induced apoptosis mediated by caspase-3, -8 and -9, and theyinhibited angiogenesis in vitro, because of what they are considered to have significantanticancer potential.

This paper discusses antioxidative and biological activities of 25 novel amidino substituted benzamides with a variety of heteroaromatic nuclei attached to the benzamide moiety and with a variable number of methoxy or hydroxy substituents. Targeted compounds, bearing either amidino or 2-imidazolinyl substituent, were obtained in the Pinner reaction from cyano precursors. 3D-QSAR models were generated to predict antioxidative activity of the 25 novel aromatic and heteroaromatic benzamide derivatives. The compounds were tested for antioxidative activity using in vitro spectrophotometric assays. Direct validation of 3D-QSAR approach for predicting activities of novel benzamide derivatives was carried out by comparing experimental and computationally predicted antioxidative activity. Experimentally determined activities for all novel compounds were found to be within a standard deviation of error of the models. Following this, structure–activity relationships among the synthesized compounds are discussed. Furthermore, antiproliferative activity in vitro against HeLa cells as well as antibacterial and antifungal activity was tested to confirm the other biological activities of the prepared compounds.

Thymoquinone (TQ), a natural compound with antimicrobial and antitumor activity, was used as the starting molecule for the preparation of 3-aminothymoquinone (ATQ) from which ten novel benzoxazole derivatives were prepared and characterized by elemental analysis, IR spectroscopy, mass spectrometry and NMR (1H,13C) spectroscopy in solution. The crystal structure of 4-methyl-2-phenyl-7-isopropyl-1,3-benzoxazole-5-ol (1a) has been determined by X-ray diffraction. All compounds were tested for their antibacterial, antifungal and antitumor activities. TQ and ATQ showed better antibacterial activity against tested Gram-positive and Gram-negative bacterial strains than benzoxazoles. ATQ had the most potent antifungal effect against Candida albicans, Saccharomyces cerevisiae and Aspergillus brasiliensis. Three benzoxazole derivatives and ATQ showed the highest antitumor activities. The most potent was 2-(4-fluorophenyl)-4-methyl-7-isopropyl-1,3-benzoxazole-5-ol (1f). Western blot analyses have shown that this compound inhibited phosphorylation of protein kinase B (Akt) and Insulin-like Growth Factor-1 Receptor (IGF1R β) in HeLa and HepG2 cells. The least toxic compound against normal fibroblast cells, which maintains similar antitumor activities as TQ, was 2-(4-chlorophenyl)-4-methyl-7-isopropyl-1,3-benzoxazole-5-ol (1e). Docking studies indicated that 1e and 1f have significant effects against selected receptors playing important roles in tumour survival.

U okviru ove doktorske disertacije sintetisana je serija alkilamino i aralkilamino derivata marinskog seskviterpenskog hinona avarona, izolovanog iz morskog sunĊera Dysidea avara, i njegovog model-jedinjenja terc-butilhinona.Za sintezu su odabrani derivati za koje se smatralo da će imati negativniji redoks potencijal od polaznih hinona, i samim tim pokazivati veću biološku aktivnost.OdreĊena je in vitro citotoksiĉna aktivnost derivata prema ćelijskoj liniji nesitnoćelijskog karcinoma pluća − NCI-H460, višestruko rezistentnoj ćelijskoj liniji nesitnoćelijskog karcinoma pluća – NCI-H460/R, kao i normalnim ćelijama humanih keratinocita – HaCaT.Pored inhibicije rasta ćelija, ispitivana je i sposobnost derivata za indukciju ćelijske smrti, u pomenutim ćelijskim linijama.Nekoliko derivata koji su pokazali visok stepen efikasnosti i selektivnosti ka tumorskim ćelijama, ušli su u dalja ispitivanja mehanizma dejstva i to prema sposobnosti generisanja superoksidnog anjona, kao i prema sposobnosti za narušavanje membranskog potencijala mitohondrija.UtvrĊena je i antibakterijska aktivnost novih derivata prema seriji Gram-pozitivnih, kao i Gram-negativnih bakterija. Pored toga, ispitana je i inhibitorna aktivnost prema odabranim sojevima gljivica., In this doctoral dissertation, a series of alkylamino and aralkylamino derivatives of marine sesquiterpene quinone avarone, isolated from marine sponge Dysidea avara, and its model compound tert-butylquinone was synthesized.Derivatives, for which it was anticipated to possess more negative redox potentials than the parent quinones, and therefore stronger activity were chosen for synthesis.In vitro cytotoxic activity of derivatives toward three cell lines, non-small cell lung carcinoma – NCI-H460, its resistant counterpart – NCI-H460/R, as well as normal human keratinocytes – HaCaT, was determined.Besides cell growth inhibition, ability of derivatives to induce cell death, was also investigated.Several derivatives with high efficacy and selectivity toward cancer cells have entered into further investigation of their mechanism according to the potential to generate superoxide radical anion, as well as the ability to change mitochondrial membrane potential.Antibacterial activity of novel derivatives towards Gram-positive and Gram-negative strains of bacteria, as well as antimicotic activity against few fungal strains, were determined.

Ten biologically active 2,2,5,5-tetramethy1-9-aryl-3,4,5,6,7,9-hexahydro-1H-xanthene-1,8(2H)-dione derivatives were synthesized and their structures were confirmed by IR, H-1 and C-13 NMR spectroscopy and mass spectrometry. Synthesized compounds were scanned for their antioxidant, antimicrobial and antiproliferative activity. Antibacterial activity was tested by the diffusion and dilution method against Bacillus subtilis, Staphylococcus aureus, Escherichia coli and Pseudomonas aeruginosa, while a ntifunga I activity was tested against Candida albicans and Saccharomyces cerevisiae. Antiproliferative activity was tested against HeLa (cervical carcinoma), SW620 (colorectal adenocarcinoma, metastatic), hepatocellular carcinoma (HEpG2), lung carcinoma cells (A549) and mouse embryo fibroblast cell line (3T3). The best antioxidant activity showed compound 2 with two hydroxy groups substituted on phenyl ring in positions 2' and 3'. The best antimicrobial activity of all synthesized compounds showed compound 8, while the best antiproliferative activity showed compound 6. Results signify the importance of xanthene-1,8-dione derivatives as potential antioxidant and antiproliferative agents.

Due to the rise of microbial strains resistant to conventional therapies, there is an urgent need for finding the new antimicrobial chemotypes. Heterocyclic compounds such as thiocarbohydrazones (TCHs) are able to interact with many metalloenzymes essential for microbes, while sulfur atom increases lipophilicity which is generally positively correlated with potency. In this paper, we report antibacterial and antifungal activity of twenty-two TCHs toward eight bacterial and three fungal strains. Furthermore, three alignment independent 3D QSAR models based on descriptors derived from molecular interaction fields (MIFs) are developed in order to rationalize structure-activity relationships for activities of TCHs toward S. aureus, P. aeruginosa and C. albicans. Several structural fragments important for biological activity are recognized in each model, and structural modifications which could lead to increased potency are suggested. Designed structures will be synthesized accordingly and tested toward the same microbial strains in order to obtain more potent derivatives.

Screens of antioxidant activity (AA) of various natural products have been a focus of the research community worldwide. This work aimed to differentiate selected samples of Merlot wines originated from Montenegro, with regard to phenolic profile and antioxidant capacity studied by survival rate, total sulfhydryl groups and activities of glutathione peroxidase (GPx), glutathione reductase and catalase in H2O2-stressed Saccharomyces cerevisiae cells. In this study, DPPH assay was also performed. Higher total phenolic content leads to an enhanced AA under both conditions. The same trend was observed for catechin and gallic acid, the most abundant phenolics in the examined wine samples. Finally, the findings of an Artificial Neural Network (ANN) model were in a good agreement (r(2) = 0.978) with the experimental data. All tested samples exhibited a protective effect in H2O2-stressed yeast cells. Pre-treatment with examined wines increased survival in H2O2-stressed cells and shifted antioxidative defense towards GPx-mediated defense. Finally, sensitivity analysis of obtained ANN model highlights the complexity of the impact that variations in the concentrations of specific phenolic components have on the antioxidant defense system.

The synthesis and cytotoxic activities determination of new steroidal mono- and bis(thiazolidin-4-ones) 4a-f and 5a-f have been performed. Their anticancer action was also evaluated in comparison to previously synthesized and reported corresponding steroidal thiosemicarbazones. All compounds were obtained as stereoisomeric mixtures with different configuration (E or Z) in the hydrazone moiety at the C-3 position. After several consecutive crystallizations diastereomerically pure major (5)-isomers of mono-thiazolidin-4-ones were isolated. The structure and stereochemistry of 2,4-thiazolidinedione,2-[(17-oxoandrost-4-en-3-ylidene)hydrazone] were confirmed by X-ray analysis. A pathway for the formation of thiazolidin-4-one ring was proposed. The steroid thiazolidinone derivatives examined in this study exerted selective concentration-dependent cytotoxic activities on six tested malignant cell lines. Ten out of twelve examined compounds exhibited strong cytotoxic effects on K562 cells (IC50 values from 8.5 mu M to 14.9 mu M), eight on HeLa cells (IC50 values ranging from 8.9 mu M to 15.1 mu M) while against MDA-MB-361 cells six compouds exerted similar or even higher cytotoxic action (IC50 values from 12.7 mu M to 25.6 mu M) than cisplatin (21.5 mu M) which served as a positive control. Eight of these ten compounds showed high selectivity in the cytotoxic action against HeLa and K562 cancer cell lines when compared with normal human fibroblasts MRC-5 and normal human PBMC. The study of mechanisms of the anticancer activity of the two selected compounds, mono- and bis(thiazolidin-4-one) derivatives of 19-norandrost-4-ene-3,17-dione 4a and 5a, revealed that both of these compounds induced apoptosis in HeLa cells through extrinsic and intrinsic signalling pathways. Treatment of EA.hy926 cells with sub-toxic concentrations of these compounds led to the inhibition of cell connecting and sprouting, and tube formation. The synthesized compounds exhibited poor antioxidant activ

The first Co(III) complexes with (1,3-selenazol-2-yl)hydrazones as an unexplored class of ligands were prepared and characterized by NMR spectroscopy and X-ray diffraction analysis. The novel ligands act as NNN tridentate chelators forming octahedral Co(III) complexes. The impact of structural changes on ligands' periphery as well as that of isosteric replacement of sulphur with selenium on the electrochemical and electronic absorption features of complexes are explored. To support the experimental data, density functional theory (DFT) calculations were also conducted. Theoretical NMR chemical shifts, the relative energies and natural bond orbital (NBO) analysis are calculated within the DFT approach, while the singlet excited state energies and HOMO-LUMO energy gap were calculated with time-dependent density functional theory (TD-DFT). The electrophilic f(-) and nucleophilic f(+) Fukui functions are well adapted to find the electrophile and nucleophile centres in the molecules. Both (1,3-selenazol-2-yl)- and (1,3-thiazol-2-yl) hydrazone Co(III) complexes showed potent antimicrobial and antioxidant activity. A significant difference among them was a smaller cytotoxicity of selenium compounds.

U okviru ove doktorske disertacije je sintetisana serija aminokiselinskihderivata seskviterpenskog hinona avarona, izolovanog iz morskog sunđera Dysideaavara, kao i model jedinjenja tert-butilhinona.Određena je in vitro antitumorska aktivnost svih jedinjenja prema humanimtumorskim ćelijskim linijama (HeLa, A549, Fem-X, K562, MDA-MB-453) i zdravojMRC-5 ćelijskoj liniji. Utvrđeno je da aminokiselinski derivati avarona pokazuju jačedejstvo nego odgovarajući aminokiselinski derivati tert-butilhinona, sa IC50 vrednostimapojedinih derivata nižim od 10 μM. Rezultati analize ćelijskog ciklusa na HeLa ćelijamaukazuju da je apoptoza jedan od mogućih mehanizama dejstva derivata. Ispitan je uticajkaspaza 3, 8 i 9 na ćelijsku smrt korišćenjem specifičnih kaspaznih inhibitora.Ispitano je i antimikrobno dejstvo derivata prema nizu Gram-pozitivnih i Gramnegativnihbakterija, kao i na tri soja gljivica, pri čemu je zabeležena vrlo dobraaktivnost derivata avarona.Ispitane su interakcije derivata sa biomakromolekulima. SDS gel-ektroforezom imasenom spektrometrijom je potvrđeno da sintetisana jedinjenja ne modifikuju lizozim.Spektrofotometrijskim ispitivanjima je zabeležena pojava hiperhromizma kao posledicainterakcija između hinona i CT-DNA. Utvrđeno je da dolazi do smanjenja intenzitetafluorescencije interkalatora etidijum-bromida i boje Hoechst 33258 koja se vezuje umalu brazdu u kompleksu derivata sa CT-DNA. Spektri cirkularnog dihroizma suukazali na izostanak interkalacije hinona u CT-DNA. Rezultati molekulskogmodelovanja su sugerisali da se derivati smeštaju u malu brazdu DNA. Elektroforetskaispitivanja su potvrdila da ne dolazi do cepanja plazmida pUC19 u prisustvu derivata.Na kraju je utvrđen stepen antioksidativne aktivnosti dobijenih aminokiselinskihderivata hinona., In this doctoral dissertation, a series of amino acid derivatives of thesesquiterpene quinone avarone, isolated from the marine sponge Dysidea avara, as wellas the model compund tert-butylquinone has been synthesized.In vitro cytotoxic activity of all compounds toward human cancer cell lines(HeLa, A549, Fem-X, K562, MDA-MB-453) and normal MRC-5 cell line wasdetermined. It was found that the amino acid derivatives of avarone exhibit a strongeractivity than the corresponding amino acid derivatives of tert-butylquinone, with IC50values of some derivatives less than 10 μM. The results of the cell cycle analysis ofHeLa cells indicate that apoptosis is one of the possible mechanisms of action ofderivatives. The effect of caspases 3, 8, and 9 on cell death by using specific caspaseinhibitors was examined.The antimicrobial effect of the derivatives on the panel of Gram-positive andGram-negative bacteria, as well as on three fungal species, were investigated, wherebyvery good activity of avarone derivatives was observed.Interactions of the derivatives with biomacromolecules were studied. SDS gelelectrophoresisand mass spectrometry confirmed the absence of modifications oflysozyme by any of the synthesized compounds. Spectrophotometric studies haverecorded the occurrence of hyperchromism as a result of interactions between thequinone and CT-DNA. The quenching of the fluorescence of the intercalator ethidiumbromide and of the minor groove binder Hoechst 33258 in the complex with CT-DNAby the derivatives was determined. Circular dichroism spectra demonstrated a nonintercalativebinding mode of the quinone derivatives to CT-DNA. The results ofmolecular modeling suggested that the derivatives bind to the minor groove. Theelectrophoretic pattern showed no cleavage of the pUC19 plasmid in the presence ofany derivatives.Finally, the degree of antioxidant activity of the obtained amino acid derivativesof the quinones was determined.

In this study, mutagenic and genotoxic potential of anti-tumor compounds avarol, avarone, and its derivatives 3′-methoxyavarone, 4′-(methylamino)avarone and 3′-(methylamino)avarone was evaluated and compared to cytostatics commonly used in chemotherapy (5-fluorouracil, etoposid, and cisplatin). Mutagenic potential of selected hydroquinone and quinones was assessed in prokaryotic model by the SOS/umuC assay in Salmonella typhimurium TA1535/pSK1002. Genotoxic potential was also assessed in eukaryotic models using comet assay in human fetal lung cell line (MRC-5), human adenocarcinoma epithelial cell line (A549), and in human peripheral blood cells (HPBC). The results indicated that avarol and avarone do not exert mutagenic/genotoxic potential. Among the studied avarone derivatives, mutagenic potential was detected by SOS/umuC test for 3′-(methylamino)avarone, but only after metabolic activation. The results of comet assay indicated that 3′-methoxyavarone and 3′-(methylamino)avarone have a significant impact on the level of DNA damage in the MRC-5 cell line. Genotoxic potential was not observed in A549 cells or HPBC probably due to a different uptake rate for the compounds and lower in metabolism rate within these cells.

The interactions of nine amino acid derivatives of tert-butylquinone with biomacromolecules were studied. Sodium dodecyl sulphate (SDS) gel electrophoresis and mass spectrometry confirmed the absence of modifications of lysozyme by any of the synthesized compounds. Spectrophotometric studies demonstrated hyperchromism, i.e., the existence of interactions between the quinones and calf thymus DNA (CT-DNA). Determination of the binding constants by absorption titration indicated weak interactions between the quinone derivatives and CT-DNA. The quenching of fluorescence of the intercalator ethidium bromide (EB) from the EB-CT-DNA system and of the minor groove binder Hoechst 33258 (H) from the H-CT-DNA system by the synthesized derivatives indicated interactions of the compounds and CT-DNA. Circular dichroism (CD) spectra demonstrated a non-intercalative binding mode of the quinone derivatives to CT-DNA. Molecular docking results confirmed binding to the minor groove. The electrophoretic pattern showed no cleavage of the pUC19 plasmid in the presence of any of the synthesized compounds. The ability of the derivatives to scavenge radicals was confirmed by the 2,2-diphenyl-1-picrylhydrazyl (DPPH) test. All the presented results suggest that the DNA minor groove binding is the principal mechanism of action of the examined amino acid derivatives.

A comparative study of antitumor activity of mono- and bis-quinoline based (thio) carbohydrazones was investigated by a series of tests on two human malignant cell lines: acute monocytic leukemia (THP-1) and pancreatic adenocarcinoma cancer stem cells (AsPC-1). Thiocarbohydrazones (TCHs) revealed superior pro-apoptotic activity over carbohydrazones (CHs) on both tested cell phenotypes, also displaying multi-target profile activities. Programmed cell death triggered by TCHs was partially caspase-dependent, mainly caspase-8 related. Activity against cancer stem cells (CSCs) was evaluated on 2D monolayers and 3D spheroidal models, where two out of three tested bis-TCHs successfully stimulated apoptosis accompanied by a reduction in size of treated spheres. Additionally, all bis-TCHs induced significant decrease in percentage of CD44-expressing AsPC-1 cells that indicate on their ability to induce reprogramming of CSC phenotype. Current results highly support further assessment of bis-TCHs in order to specify their specific targets in cancer cells and particularly in the CSCs subpopulation.