Laura Gabriela Sarbu

Antibacterial structure–activity relationship studies of several tricyclic sulfur-containing flavonoids

Summary A structure–activity relationship study concerning the antibacterial properties of several halogen-substituted tricyclic sulfur-containing flavonoids has been performed. The compounds have been synthesized by cyclocondensation of the corresponding 3-dithiocarbamic flavanones under acidic conditions. The influence of different halogen substituents on the antibacterial properties has been tested against Staphylococcus aureus and Escherichia coli. Amongst the N,N-dialkylamino-substituted flavonoids, those having an N,N-diethylamino moiety exhibited good to excellent antimicrobial properties against both pathogens. Fluorine-substituted flavonoids were found to be less active than those bearing other halogen atoms.

[2.2]Paracyclophane derivatives containing tetrathiafulvalene moieties

Summary The synthesis of [2.2]paracyclophane derivatives containing tetrathiafulvalene units has been accomplished by the coupling reaction of 4-([2.2]paracyclophan-4-yl)-1,3-dithiol-2-thione in the presence of trimethylphosphite. The 1,3-dithiol-2-thione derivative was in turn synthesized by the regioselective bromination of 4-acetyl[2.2]paracyclophane, then through the corresponding dithiocarbamates and 1,3-dithiolium salts.

Click reactions with pseudo-geminal bis(azido-methylene)[2.2]paracyclophane

The regioselective copper-catalyzed cycloaddition reactions of pseudo-geminal bis(azido-methylene)[2.2]paracyclophane with terminal alkynes have provided the corresponding pseudo-geminal bis(1,2,3-triazoles). The precursor bis(azide) was synthesized from the corresponding pseudo-geminal bis(bromide) and sodium azide by a solvent-dependent reaction. X-ray structural analyses of the addition products demonstrate that the corresponding click reactions proceed regioselectively.Graphical abstract

The influence of halogen substituents on the biological properties of sulfur-containing flavonoids

A series of halogen-substituted tricyclic flavonoids containing a 1,3-dithiol-2-ylium moiety has been synthesized from the corresponding 3-dithiocarbamic flavanones. The influence of halogen substituents on the antibacterial properties of the tricyclic flavonoids has been investigated against Staphylococcus aureus and Escherichia coli. On going from fluorine to iodine, these compounds exhibit good to excellent inhibitory properties against both Gram-positive and Gram-negative pathogens. These results suggest that size is the main factor for the change in potency rather than polarity/electronics.

Selenium halide-induced bridge formation in [2.2]paracyclophanes.

Summary An addition/elimination sequence of selenium halides to pseudo-geminally bis(acetylene) substituted [2.2]paracyclophanes leads to new bridges with an endo-exo-diene substructure. The reactions have been found to be sensitive to the substitution of the ethynyl group. The formation of dienes with a zig-zag configuration is related to that observed for non-conjugated cyclic diynes of medium ring size.

New Bridges in [2.2]Paracyclophanes: The Interaction of Chalcogenide Halides with Pseudo-Geminal Triple Bonds

Abstract Novel heteroatom containing bridges have been introduced in [2.2]paracyclophanes by the interaction of chalcogenide halides with pseudo-geminal triple bonds. The anti-addition with Markovnikov orientation of selenium halides to 4,15-bisethynyl[2.2]paracyclophane leads to the corresponding E-adducts. The interaction of pseudo-geminally substituted bispropargylic alcohols with disulfur dichloride and sulfur dichloride leads to a mixture of cyclic ethers. These compounds are formed under mild acidic conditions provided by the organic ammonium chlorides or silica gel. The corresponding dipropargyloxy sulfides have been identified as reaction intermediates. Supplemental materials are available for this article. Go to the publishers online edition of Phosphorus, Sulfur, and Silicon and the Related Elements to view the free supplemental file.

Hybrid systems tetrathiafulvalenes - [2.2]paracyclophanes

Donor-acceptor cyclopropanes have been extensively used in synthetic chemistry in [3+2] and [3+3] cycloaddition reactions for the preparation of highly substituted carbo- and heterocyclic products. This methodology is further extended to donor-acceptor cyclobutane in [4+2] and [4+3] cycloaddition reactions for the synthesis of highly substituted carbo- and heterocyclic products. Initial work carried out makes use of cyclobutanes substituted with a metal-alkyne complex towards the synthesis of tetrahydropyrans in good yields and with acceptable diastereoselectivity. The initial aim of the project was to improve and expand the scope of the previous work carried out within the group on [4+2] cycloaddition reaction. For example, [4+2] and [4+3] cycloaddition reaction were carried out by using diester cyclobutanes having an alkene and phenyl π-donors. The [4+3] cycloaddition reaction of cyclobutane with nitrone did not work but [4+2] cycloaddition was successful when aldehydes were used as trapping reagents. Lower yields of the cycloadducts were observed due to formation of (±)-dimethyl-2-methyl-6-phenylcyclohex-3-ene-1,1-dicarboxylate and 2,6-diphenyl-4,8-dipropenylcyclooctane-1,1,5,5-tetracarboxylic acid tetramethyl ester. During the synthesis of a precursor cyclobutane a novel cycloisomerisation of malonyl epoxide under Lewis acidic conditions to 6,8-dioxabicyclo[3.2.1]octane derivatives was developed. This reaction has opened a new pathway for the synthesis of 6,8-dioxabicyclo[3.2.1]octanes in a diastereoselective fashion using malonyl epoxides as precursors. A wide range of malonyl epoxides were cycloisomerised under Lewis acidic conditions and the cycloisomerisation of syn and anti malonyl epoxides were stereospecific. The diastereoselectivity of the process was proven by nOe and X-ray analysis. The cycloisomerisation of malonyl diepoxide has also been investigated towards the formation of 5,5-dimethoxy-6,6,8,8-tetraoxa4,4-spirobi[bicyclo[3.2.1]octane].D mild and efficient conditions for C-O bond formation would be of significant interest for synthesis of organic compounds including natural products, pharmaceuticals, and various material compounds. Classical Ullmann and Buchwald coupling for C-O bond formation are well known and subsequent research on C-O bond coupling is still on going. Previously, aryl halides were important starting materials for C-O coupling. Recently, many groups reported that symmetric and asymmetric diaryliodonium salts have better reactivity than aryl halides in organic solvent and they are often used in C-O coupling reaction in place of aryl halides. When C-O alkyl bond is generated from diaryliodonium salts and aliphatic alcohols, either strongly basic alkoxide in the absence of metal catalyst is used at room temperature or aliphatic alcohols in the presence of transition metal catalysts at high temperature are used. A Non-basic and room temperature condition for C-O alkyl bond formation seems difficult to combine. Here, we report very mild, yet efficient reaction conditions for C-O-alkyl bond formation. Diaryliodonium triflate and diverse aliphatic diols were coupled under neutral and copper catalytic conditions. The reaction does not require any base and needs very low loading amount of copper (0.5-2 mol %). Still, the reaction can proceed even at room temperature within 10-15 min. Finally, we demonstrated that a variety of alkane diols cross-coupled with diaryliodonium triflate.O the past decades, azaheterocyclic derivatives were reported as valuable scaffolds in medicinal chemistry, showing variously biological activities such as anticancer, antibacterial, antituberculosis, anti-leishmania and other antimicrobials, etc. Leishmaniasis is a growing health problem worldwide. Current treatments for leishmaniasis are involving drugs such as imidazoquinolines, pentamidine, miltefosine, etc. Imidazoquinolines, especially imiquimod, resiquimod and gardiquimod, represent a class of drugs largely used in cutaneous leishmaniasis. Pentamidine is a second-line drug largely used in treatment against cutaneous leishmaniasis caused by Leishmania major infection, after miltefosine. Oxoisoaporphine class emerges as a new drug candidate for leishmaniasis, being from 2-4 times more active than Miltefosine (against ptomastigotes). However, their use is limited by their toxicity, side effects, relatively high cost, discomfort and the emergence of drug resistance. This is why new approaches are urgently needed. The emphasis of this work is on the design, synthesis and characterization of some new class of anti-leishmania derivatives with azaheterocycles skeleton, analogous with imidazoquinolines, pentamidine, miltefosine and oxoisoaporphine. In this respect several new classes of nitrogen heterocycles derivatives were designed, synthesized, characterized and tested in vitro for their antileishmania activity: polifused nitrogen heterocycles derived from benzo[f]quinoline, imidazo -isoquinolines and -phthalazine, PyrroloBenzoQuinone -pyridazine and -phthalazine (I-V), substitutedbis-pyridazinone VI, and amido-pyridiland amido-quinolyl derivatives, VII, VIII. Some of the compounds were also tested for antimalarial activity. The structures of the compounds were proved by elemental and spectral analysis [IR, 1H-NMR, 13C-NMR, two-dimensional experiments 2D-COSY, HMQC, HMBC and MS]. The antileishmanial assay against Leishmania donovani intramacrophage amastigotes revealed a very good and promising activity, some of the compounds being at least 10 times more active comparative with the witness, miltefosine. The results against Plasmodium faliciparum are modest.F constitute a family of anticancer natural products that relieve the resistance to cancer chemotherapies and display a strong cytotoxicity that is specific to cancer cells. These natural cyclopenta[b]benzofurans are characterized by a densely functionalized tricyclic framework, as exemplified by the structures of rocaglamide. In this presentation, we will describe our own recent endeavor toward the synthesis of new flavagline derivative that display enhanced in vivo anticancer activities, due to their actions on scaffold proteins, prohibitins, and the translation initiation factor eIF4a. Our in vivo studies indicate that flavaglines could greatly improve the treatment of chemoresistant metastatic melanoma. These compounds are also able to inhibit KRAS, a considered undruggable oncogene. Considering that clinically effective KRAS inhibitors have remained elusive for more than three decades of intensive research, flavaglines thus appear to hold great promise for the treatment of chemoresistant cancers.I of adulterants from liquid fuels by synthetic membrane ZSM-22 was studied. Crystallization for synthesis of ZSM-22 membrane was carried out at a static condition under autogenous high pressure and temperature of 200°C.The synthesized membranes were characterized by x-ray diffraction, scanning electron microscopy, energy dispersive spectroscopy and Fourier transformed infra-red techniques. Characterization of the material suggested that the synthesized membrane was highly crystalline in nature possessing hollow rod like structure (elongated rods ~200 nm long and 20-50 nm in diameter) and having crystals in the range ~ 5-10 μm. Effect of various parameters such as separation time, temperature, molar concentration, degree of swelling, zeolite loading for petrol-kerosene mixtures has been studied. The effect of time on separation of kerosene was studied by varying the time between 1 to 7 hours. The swelling percentage increases with increase in temperature till 170 and thereafter no considerable change in swelling with increase in temperature was observed. Swelling was also found to increase with increase in amount of zeolite membrane. It is observed that the degree of swelling increased almost linearly with increasing mass % of kerosene. The membrane thus used for isolation of adulterant from liquid fuel is found to be selective and cost effective.

Intramolecular interactions in [2.2]paracyclophanes

C organic sulfoxides are important synthons and chiral auxiliaries in synthetic organic chemistry. Therefore synthesis of chiral sulfoxide is an active area of continuing research interest. The most common method for the preparation of sulfoxide is by the oxidation of their corresponding sulfides. Both the chemical and biological catalysts have been developed for this purpose. Though the reaction conditions for the preparation of chiral organic sulfoxides. With hope that some of them will produce the desired sulfoxidation in a good enantiomeric excess. Being involving in biological catalysts are milder and ecofriendly in comparison to those involving in chemical catalysts, they are of limited practical use. This communication reports a crude preparation of ascorbate peroxidase from Musa paradisiaca which can be conveniently prepared and used for the transformation of methyl phenyl sulfide to its sulfoxide. This is the report of sulfoxide formation using a plant enzyme. The method for the preparation of enzyme from Musa paradisiaca has been developed. The enzymatic characteristics like Km for the substrates sulfide and H2O2, pH and temperature optima of the enzyme have been determined. The enzymatic transformation of sulfide to its sulfoxide has been demonstrated. The results of the above studies will be presented in the conference.M reactions (MCRs) are important processes from atom and step economy point of view. 1,3-Dipolar cycloadditions (1,3-DC) involving azomethine ylides and electrophilic alkenes are good examples for this type of transformation but are not so frequently described. In this lecture, the thermal and silver mediated multicomponent 1,3DC between α-amino esters, dipolarophiles and aldehydes will be considered. This 1,3-DC allows the synthesis of highly substituted pyrrolidines under conventional or MW heating. In general, 4,5-endo diastereoselectivity was mainly observed and 2,5-cis-cycloadducts are formed according to a W-shaped dipole. When this MCR was performed with 2-oxoaldehydes, the 1,3-DC takes place under silver acetate catalysis at rt [3b]. On the other hand, the multicomponent 1,3-dipolar cycloaddition between different proline esters, aldehydes and dipolarophiles afford highly substituted pyrrolizidines will also be described. The corresponding highly substituted pyrrolizidines are obtained in all cases with 2,5-trans-relative configuration between two electron-withdrawing groups and major endo-selectivity with 2,4-cis-relative configuration. The use of (2S,4R)-4hydroxyproline methyl ester hydrochloride allowed the synthesis of enantiomerically enriched pyrrolizidines. When pipecolic acid alkyl esters are used the corresponding indolizidines can be prepared under thermal reaction conditions.Background: The hypervalent iodine (III) compounds, (diacetoxyiodo)benzene (DIB) possess numerous applications as oxidizing reagent. A particularly useful methodology for the oxidative α-functionalization of enolizable carbonyl compounds involves DIB in methanolic potassium hydroxide resulting in the synthesis of α-hydroxydimethylacetals. The reaction is also applicable to enones which cannot form anion by α-hydrogen abstraction such as chromone, chalcone, flavones and flavanone.H compounds are the most valuable sources of diverse biologically active molecules. The utility of heterocyclic structures is the ability to synthesize one library based on one core scaffold and to screen it against a variety of different receptors, yielding several active compounds. Of these, particularly the indolic scaffolds are the important substances of a large number of important compounds that occur in nature. Therefore, the invention of new synthetic routes to functionalize the indolic scaffolds continues to command wide interest due to the numerous natural products and biologically significant compounds whose structures incorporate these heterocyclic systems. In contrast, few existing methods provide efficient and regiocontrolled access to functionalize the indolic molecules. In this context, the transition metal-catalyzed C-H bond activation strategy provides a powerful vehicle for the direct assembly and functionalization of the bioactive heterocyclic molecules. This approach is highly modular and is especially well-suited for the preparation of carbon-carbon and carbonheteroatom bond due to the minimization of stoichiometric metallic waste and of the costs associated with substrate preactivation. These considerations led us to investigate the possibility of functionalization of indolic scaffolds at the C7–position which is highly challenging in C-H activation events. Moreover, the constructed C7–functionalized indolic compounds were tested for in vitro cytotoxicity against various human cancer cell lines and some of them were found to display most potent anticancer activity, compared to that of anticancer doxorubicin a positive control.Since its discovery in 1949 by Brown and Farthing [1], [2.2]para-cyclophane has been intensely studied by chemists. Consisting of two benzene rings bound together by two ethano bridges, the [2.2]paracyclophane core can undergo chemical transformations specific to both aliphatic and aromatic compounds, resulting in a wide variety of functionalized [2.2]paracyclophanes. Thus, cyclophanes are ideal model systems to investigate whether and how functionalized groups can interact and react with each other. Because of the rigid molecular framework provided by the paracyclophane moiety and its short interannular distance, functional groups in pseudo-geminally substituted [2.2]paracyclophanes are often held in such a position as to allow highly specific reactions to take place between them. Both the parent hydrocarbon and its derivatives have been used in asymmetric catalysis, optoelectronics and polymer synthesis.T development of protocols for the construction of C-C bond following the principles of green chemistry is one of the most challenging tasks in organic synthesis. Since more and more organic solvents are blacklisted due to their damaging effect on human health and environment, organic reactions under solvent-free reaction conditions (SFRC), mainly fulfill these principles. C-C bond forming reactions display one of the most important implements for the synthesis of complex organic products, many of them developed bioactivity as drugs or agrochemicals. C-C bond formation by direct coupling of alcohols with other partners could be a very attractive strategy from practical, atom-efficient and environmental point of view, producing water as only a by-product of the reaction. Because of their lower leaving group ability, hydroxyl moieties are rarely substituted under mild conditions and must often be activated before treatment with nucleophiles. Numerous related methodologies have been elaborated using a substoichiometric amount of Brønsted acids, metals ions, Lewis/Brønsted acid combination or other promoters which have been touched on by several excellent reviews and recent advanced related reports. Silver hexafluoroantimonate (V) (AgSbF6) has been used as a catalyst for direct α-alkylation of unactivated ketones using benzylic alcohols. While a new method for direct benzylation/allylation of malonates with alcohols via a palladium catalyzed Tsuji-Trost type reaction was developed. Accordingly, the development of an efficient and environmentally benign catalytic methodology for C-C bond formation remains an attractive research subject. We report new, efficient and selective methodology for the direct C-C bond formation through the direct coupling of various benzyl alcohols with a different type of electron rich compounds including 1,3-dicarbonyl compounds, heteroatom benzo-cyclenes, phenyl substituted alkenes, or tertiary benzyl alcohols, bearing a vicinal hydrogen atom as alkene precursors, catalyzed by N-halo organic compound as a metaland acid-free catalyst under SFRC, enhancing the green chemical profiles of these transformations.Z have the chemical formula Mx/n[(AlO2)x(SiO2)y].wH2O, where the charge-balancing nonframework cation M has valence n, x is 2.0 or more, and y is the moles of water in the voids. The Al and Si tetrahedral atoms, or T-atoms, form a threedimensional (3D) framework of AlO4 and SiO4 tetrahedra linked together by shared oxygen ions. Although SiO4 tetrahedra are charge balanced, AlO4 tetrahedra has a negative charge balanced by a positive charge on M while water molecules lie within the pores of zeolites. The water can be expelled upon by heating and evacuation and may be replaced by a number of small inorganic and organic guests. We are developing novel nanoporous zeolite materials for the treatment of waste including radioactive, toxic gas/chemicals separation, pesticide/herbicide management, sewage treatment etc. Zeolite acts as auxiliary as well as functional support in gas sensing. Zeolites has been modified dually i.e. both surface modified and ion exchanged present inside in the pore cavity. Also several polymer based composites has been synthesized for gas sensing purposes. This modification in zeolite structure increases its sorption capacity, sensitivity and recyclability. The parent sodium form was also modified to proton form to increase their catalytic activity and further applying for organic drug synthesis.T vascular endothelial growth factor receptor-2 (VEGFR-2) is considered as the most important transducer of VEGFdependent angiogenesis. VEGFR-2 is highly up-regulated in several solid tumors and plays a critical role in the process of tumor angiogenesis; therefore, VEGFR-2 inhibition emerged as a prime approach for discovering new therapies for many human angiogenesis-dependent malignancies. A novel series of indole derivatives was synthesized and tested for their cytotoxic activities against a panel of 60 cancer cell lines. A molecular docking study was also carried out to determine their binding modes and binding affinities in the VEGFR-2 active site using a reference VEGFR-2 inhibitor, sorafenib (Figure 1). The synthesized compounds exhibited a broad spectrum antiproliferative activity on 60 cell lines with growth inhibition percent (GI)% ranging from 31 to 82.5%. An indoloimidazolone derivative was found the most potent VEGFR-2 inhibitor with IC50 of 0.07 μM more potent than that of sorafenib (0.09 μM). The molecular docking study attributed the promising inhibitory activity on VEGFR-2 of this series to their hydrophobic interaction with the VEGFR-2 binding site hydrophobic side chains and their hydrogen bonding interaction with the key amino acids Glu885 and Asp1046.

Tetrathiafulvalene-[2.2]paracyclophanes: Synthesis, crystal structures, and chiroptical properties

Two racemic tetrathiafulvalene-[2.2]paracyclophane electron donors EDT-TTF-[2.2]paracyclophane 1 and (COOMe)2 -TTF-[2.2]paracyclophane 2 have been synthesized via the phosphite mediated cross coupling strategy. Chiral HPLC allowed the optical resolution of the (RP ) and (SP ) enantiomers for both compounds. Solid-state structures of (RP )-1 and (rac)-2 have been determined by single crystal X-ray analysis. Intermolecular π-π and S•••S interactions are disclosed in the packing. Single crystal X-ray analysis of (RP )-1 combined with experimental and theoretical circular dichroism spectra allowed the assignment of the absolute configuration of the enantiomers of 1 and 2.

rac-1-(5-Bromo-2-hy-droxy-phen-yl)-1-oxopropan-2-yl morpholine-4-carbo-dithio-ate.

In the racemic title compound, C14H16BrNO3S2, synthesized from the corresponding ω-bromopropiophenone, the dihedral angle between the plane of the phenol group and that of the planar section [maximum deviation = 0.040 (2) Å] of the morpholine-4-carbodithiolate moiety is 76.36 (10)°. A strong intramolecular phenol O—H⋯O hydrogen bond if present in the molecule. In the crystal, only weak C—H⋯S and C—H⋯O interactions are found.