Lucian M. Birsa

Antibacterial activity and proposed action mechanism of a new class of synthetic tricyclic flavonoids.

This study reports on the inhibitory and bactericidal properties of a new synthetized flavonoid.

The antibacterial properties of sulfur containing flavonoids.

Some dithiocarbamic esters bearing a flavanone backbone, as well as their corresponding 1,3-dithiolium salts were tested against Staphylococcus aureus and Escherichia coli. The 1,3-dithiolium tricyclic flavonoids display good inhibitory properties against both Gram-positive and Gram-negative pathogens.

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

A novel synthetic flavonoid with potent antibacterial properties: In vitro activity and proposed mode of action

The emergence of pathogenic multidrug-resistant bacteria demands new approaches in finding effective antibacterial agents. Synthetic flavonoids could be a reliable solution due to their important antimicrobial activity. We report here the potent in vitro antibacterial activity of ClCl-flav—a novel synthetic tricyclic flavonoid. The antimicrobial effects were tested using the minimum inhibitory concentration (MIC), time kill and biofilm formation assays. Fluorescence microscopy and scanning electron microscopy were employed to study the mechanism of action. MTT test was used to assess the cytotoxicity of ClCl-flav. Our results showed that Gram positive bacteria were more sensitive (MIC = 0.24 μg/mL) to ClCl-flav compared to the Gram negative ones (MIC = 3.9 μg/mL). We found that our compound showed significantly enhanced antibacterial activities, 32 to 72-fold more active than other synthetic flavonoids. ClCl-flav showed bactericidal activity at concentrations ranging from 0.48 to 15.62 μg/mL. At twice the MIC, all Escherichia coli and Klebsiella pneumoniae cells were killed within 1 h. Also ClCl-flav presented good anti-biofilm activity. The mechanism of action is related to the impairment of the cell membrane integrity. No or very low cytotoxicity was evidenced at effective concentrations against Vero cells. Based on the strong antibacterial activity and cytotoxicity assessment, ClCl-flav has a good potential for the design of new antimicrobial agents.

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.

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.

4-Bromo-2-[5-methyl-2-(morpholin-4-yl)-1,3-thia­zol-4-yl]phenol

In the title compound, C14H15BrN2O2S, synthesized by the reaction of the corresponding phenacyl thiocyanate with morpholine, the dihedral angle between the 1,3-thiazole ring and the phenolic substituent ring is 23.46 (10)° as a result of the steric influence of the ortho-methyl group on the thiazole ring. A strong intramolecular phenolic O—H⋯N hydrogen bond is present in the molecule. In the crystal, a weak C—H⋯Ophenol hydrogen bond gives rise to chains lying parallel to [20-1]. A short intermolecular Br⋯Omorpholine interaction is also present [3.1338 (19) Å].