First triclosan-based macrocyclic inhibitors of InhA enzyme.

Two macrocyclic derivatives based on the triclosan frame were designed and synthesized as inhibitors of Mycobacterium tuberculosis InhA enzyme. One of the two molecules M02 displayed promising inhibitory activity against InhA enzyme with an IC50 of 4.7 µM. Molecular docking studies of these two compounds were performed and confirmed that M02 was more efficient as inhibitor of InhA activity. These molecules are the first macrocyclic direct inhibitors of InhA enzyme able to bind into the substrate pocket. Furthermore, these biaryl ether compounds exhibited antitubercular activities comparable to that of triclosan against M. tuberculosis H37Rv strain.

Structural Characterization and Anti-infective Activity of 9,10-Seco-29-norcycloartane Glycosides Isolated from the Flowers of the Peruvian Medicinal Plant Cordia lutea.

Six new secocycloartane glycosides (1-6) were isolated from the ethanol extract of the flowers of Cordia lutea Lam. on the basis of bioassay-guided fractionation. Their structures were determined by the application of NMR and MS data analyses together with X-ray crystallographic analyses for compounds 1 and 2. Compounds 1-6 represent the first examples of 9,10-seco-29-norcycloartane glycosides. These compounds showed significant in vitro anti-Helicobacter pylori activity, and no activity against either Escherichia coli or Pseudomonas aeruginosa. Significant activity was observed for 5 and 6 against Staphylococcus aureus. All compounds displayed weak cytotoxicity against RAW 264.7 cells. The in vitro antileishmanial and antiplasmodial activities of 1-6 were also evaluated.

Novel Re(I) tricarbonyl coordination compounds based on 2-pyridyl-1,2,3-triazole derivatives bearing a 4-amino-substituted benzenesulfonamide arm: synthesis, crystal structure, computational studies and inhibitory activity against carbonic anhydrase I, II, and IX isoforms†.

In this work, two bidentate 2-pyridyl-1,2,3-triazole ligands (3a and 3b) containing a 4-substituted benzenesulfonamide pharmacophore prepared by classical click chemistry procedures, as well as their corresponding rhenium complexes, 4a and 4b of general formula [ReCl(CO)3(L)] (L = 3a or 3b) were prepared and fully characterised by spectroscopic methods (IR, NMR, MS, UV-Vis), elemental analysis, X-ray diffraction, and theoretical studies using DFT and TD-DFT methods. In particular, we showed that, in the solid state, the pyridine and the triazole rings of 3b adopted an uncommon cis configuration which stems from intermolecular hydrogen bonds. Preliminary assays demonstrated a promising nanomolar inhibitory activity against carbonic anhydrase isoform IX for both ligands and complexes with a strong affinity Ki of 2.8 nM for ligand 3a. More interestingly, complex 4b exhibited a pronounced selectivity against hCA IX over the off-targets hCA I and hCA II which makes this compound a promising potential anticancer drug candidate.

Conjugates of Benzoxazole and GFP Chromophore with Aggregation-Induced Enhanced Emission: Influence of the Chain Length on the Formation of Particles and on the Dye Uptake by Living Cells.

Six conjugates of benzoxazole and green fluorescent protein chromophore that differ by the length of their alkyl chain (from C1 to C16) are investigated. They exhibit rigidofluorochromism and clear aggregation-induced emission enhancement (AIEE) behavior with emission in the orange-red that is specific to the solid state. A preparation method based on solvent exchange is used to prepare particles. The self-association properties of these molecules depend on the length of the alkyl chain. Microfibers, platelets, and rounded microparticles are successively obtained by increasing the chain length. The same method is used to prepare nanoparticles (NPs) that are fully characterized. In particular, homogeneous populations of stable NPs measuring around 70 nm are obtained with the analogs whose chains contain four to eight carbon atoms. The behavior with respect to living cells is also influenced by the nature of the compounds. Only the dyes with intermediate hydrophobicity are efficiently uptaken by both normal and tumor cells, and fluorescence only originates from dispersed dye molecules. There is no evidence for incorporation of NPs into cells. This work shows that small variations of the chemical structure must be taken into account for making the best use of AIEE compounds in view of precise applications.

A comparative study of nine berberine salts in the solid state: optimization of the photoluminescence and self-association properties through the choice of the anion.

The arrangement of an ionic fluorophore in the crystalline state was regulated by the presence of various counter-ions and the effect on spectroscopic and self-association properties was studied. To do so, nine salts of berberine (i.e. a fluorescent natural alkaloid) were investigated. Most of them contained organic anions and were prepared using an ion-exchange process. Berberine chloride and hemisulfate were also used for the sake of comparison. The diffuse reflectance and photoluminescence spectra were recorded on powder compounds. All salts were emissive in the solid state and the emission efficiency was increased seven-fold with the nature of the anion. The optical properties were tentatively discussed on the basis of the crystal-packing mode. The possibility of implementing a bottom-up approach to generate microparticles was investigated using the reprecipitation method. Salts that contain the most hydrophobic anions gave a large number of homogeneous, elongated microparticles. This study showed that most of the berberine salts could be used as fluorescent materials, but proper choice of the anion allows using the self-association properties to best advantage.

Surprising unreactivity of cholesterol-5,6-epoxides towards nucleophiles.

We recently established that drugs used for the treatment and the prophylaxis of breast cancers, such as tamoxifen, were potent inhibitors of cholesterol-5,6-epoxide hydrolase (ChEH), which led to the accumulation of 5,6α-epoxy-cholesterol (5,6α-EC) and 5,6ß-epoxy-cholesterol (5,6ß-EC). This could be considered a paradox because epoxides are known as alkylating agents with putative carcinogenic properties. We report here that, as opposed to the carcinogen styrene-oxide, neither of the ECs reacted spontaneously with nucleophiles. Under catalytic conditions, 5,6ß-EC remains unreactive whereas 5,6α-EC gives cholestan-3ß,5α-diol-6ß-substituted compounds. These data showed that 5,6-ECs are stable epoxides and unreactive toward nucleophiles in the absence of a catalyst, which contrasts with the well-known reactivity of aromatic and aliphatic epoxides. These data rule out 5,6-EC acting as spontaneous alkylating agents. In addition, these data support the existence of a stereoselective metabolism of 5,6α-EC.

Facile access to highly fluorescent nanofibers and microcrystals via reprecipitation of 2-phenyl-benzoxazole derivatives.

2-Phenyl-benzoxazole and five derivatives bearing an alkyl or alkoxy substituent on the phenyl ring were used to prepare aqueous suspensions of particles via a solvent-exchange method. In these conditions, the methyl and methoxy derivatives spontaneously gave nanofibers, while the other compounds led to microcrystals. This shows that minor chemical changes are enough to direct the formation of a given type of particle. From a spectroscopic viewpoint, all compounds strongly emit blue light in the solid state, with spectra much broader than those registered in n-heptane and ethanol solutions. The photoluminescence quantum yields reached 38% and were slightly affected in aqueous suspension by the polarity of the environment. The molecular arrangement, deduced from X-ray analysis for the methyl and methoxy derivatives, was used to explain the fluorescence properties in the solid state. This work shows that 2-phenyl-benzoxazole derivatives are interesting candidates for applications as fluorescent nanomaterials, including in aqueous and biological media.

Bis(amidinato)germylenerhodium complexes: synthesis, structure, and density functional theory calculations.

The first monogermylenerhodium complexes stabilized by bulky amidinato ligands on the divalent germanium center have been synthesized and characterized by NMR spectroscopy and X-ray crystallography. Their stability strongly depends on the steric hindrance of the amidinato ligand. With trimethysilyl groups on the nitrogen atoms of the amidinato ligand, only the germylene oxide rhodium complex could be obtained; by contrast, with t-Bu groups, the germylenerhodium complex was isolated. In both cases, the formation of amidinatorhodium complexes was observed. The donating ability of the germylene ligand has been assessed from the CO stretching frequency of the corresponding dicarbonylrhodium complex and was confirmed by density functional theory calculations.

Chalcogeno[bis(phosphaalkenyl)] germanium and tin compounds.

The first diphosphaalkenylstannylene stabilized through complexation with a carbene NHC-Sn[C(Cl)═PMes*](2)1 (Mes* = 2,4,6-tri-tert-butylphenyl; NHC = :C{N(iPr)C(Me)}(2)) was isolated and fully characterized including single crystal X-ray diffraction analysis. Its reaction with elemental sulfur rapidly gives the cyclic Sn(2)S(2) (dithiadistannetanne) derivative 3, presumably formed by dimerization of a stannathione intermediate. By contrast, its germanium analogue NHC-Ge[C(Cl)═PMes*](2)7 leads to the corresponding monomeric germathione 4 and germaselenone 5. The germaselenone was more stable than the germathione and could be structurally characterized. An unusual thermal cyclization reaction of the last one occurs with an excess of selenium to give the Ge(2)Se(3) (triselenadigermolane) ring derivative 6.

Tris(η(5)-cyclo-penta-dien-yl)-tris-[η(6)-[9,10-dihydro-anthracene-9,10-endo-3',4'-(N-benz-yl)pyrrolidine]]triruthenium(II) tris-(hexa-fluoro-phosphate) acetone disolvate.

In the title compound, [Ru(3)(C(25)H(23)N)(C(5)H(5))(3)]·3PF(6)·2C(3)H(6)O], the cation is a triruthenium complex of a 9,10-dihydro-anthracene derivative. Three RuCp(+) (Cp is cyclo-penta-dien-yl) groups are bonded to the three aromatic rings of the ligand. Surprisingly, the pyramidalized N atom of the heterocycle (Σ C-N-C = 329.0°) points towards the anthracenyl group, so losing its coordinative ability. There is an inter-molecular C-H⋯π inter-action involving an acetone mol-ecule and the adjacent benzyl ring of the ligand. In the crystal, mol-ecules are linked via a number of C-H⋯O and C-H⋯F inter-actions and a C-H⋯π inter-action, leading to the formation of a three-dimensional supra-molecular structure. One of the Cp groups is disordered over two positions, with refined occupancies of 0.695 (14):0.305 (14). Two of the three hexa-fluoro-phospate anions are disordered, with refined occupancies of 0.630 (6):0.370 (6) and 0.771 (8):0.229 (8). One of the two solvent acetone mol-ecules is also disordered, with refined occupancies of 0.82 (2):0.18 (2).

(1S,8R,15S,19R)-17-Benzyl-17-aza-penta-cyclo-[6.6.5.0(2,7).0(9,14).0(15,19)]nona-deca-2(7),3,5,9(14),10,12-hexa-ene chloro-form monosolvate.

In the title compound, C(25)H(23)N·CHCl(3), the dihydro-anthracene unit is bent with a dihedral angle between the benzene rings of 57.82 (8)°. The N atom of the pyrrolidine heterocycle, which has an envelope conformation with the N atom as the flap, exhibits a pronounced pyramidalization [Σ(C-N-C) = 328.07°], indicating an accentuated N-donor character. In the crystal, this behaviour is evident by the C-H⋯N hydrogen bond involving a solvent mol-ecule and the N atom. The absolute configuration at the C-atom fused positions of the pyrrolidine group were crystallographically confirmed to be S and R.

1-arsa-3-germaallene Tip(t-Bu)Ge═C═AsMes*: the heaviest mixed group 14 and 15 heteroallenic compound.

The 1-arsa-3-germaallene Tip(t-Bu)Ge═C═AsMes* (1, Tip = 2,4,6-triisopropylphenyl, Mes* = 2,4,6-tri-tert-butylphenyl), a stable heavier group 14 and 15 congener of allenes, has been synthesized by debromofluorination of Tip(t-Bu)Ge(F)-C(Br)═AsMes*. It reacts with methanol and 2,3-dimethyl-1,3-butadiene by the Ge═C double bond. The allenic-type structure of 1, featuring cumulated Ge═C and C═As double bonds, has been evidenced by means of spectroscopic and single-crystal X-ray determination. The electronic properties involved in this new system were obtained from DFT calculations. The mechanism of the reaction between 1 and the dimethylbutadiene is also described to understand the observed regio- and chemoselectivity.

Versatile stereoselective cycloadditions between heterocumulenes and phosphagermaallene Tip(tBu)Ge=C=PMes*: experimental and theoretical investigations.

Phosphagermaallene Tip(tBu)Ge=C=PMes* 1 (Tip=2,4,6-triisopropylphenyl, Mes*=2,4,6-tri-tert-butylphenyl) reacts with phenyl isocyanate and tert-butyl isocyanate by a [2+2] cycloaddition that involves the Ge=C and C=O double bonds to afford 1-oxa-2-germacyclobutanes 2 and 3. With N,N'-dicyclohexylcarbodiimide, a [2+2] cycloaddition is observed between the Ge=C and C=N unsaturations to lead to 1-aza-2-germacyclobutane 6 with exocyclic P=C and C=N double bonds. In sharp contrast, 1 reacts with phenyl isothiocyanate, ethyl isothiocyanate, and carbon disulfide according to a [3+2] cycloaddition that involves the whole Ge=C=P unit and the C=S double bond to give transient phosphagermacarbenes (PGeHCs) 11, 12, and 13. These new PGeHCs undergo C-H insertions into one o-tBu group of Mes* (in the case of 11 and 12) or one o-iPr group of Tip (in the case of 13) with formation of tricyclic compounds 8, 9, and 10, respectively. The reaction mechanisms that involve 1 and the phenyl isocyanate and the phenyl isothiocyanate are described and their regioselectivity is explained by theoretical calculations.

Spontaneous formation of fluorescent nanofibers and reticulated solid from berberine palmitate: a new example of aggregation-induced emission enhancement in organic ion pairs.

The salt formed between the large aromatic berberine cation and the long-chain palmitate anion was synthesized and used to prepare aqueous suspensions of particles owing to a solvent-exchange method. Under these conditions, elongated particles were readily obtained. They were studied by transmission microscopy with polarized light, as well as by fluorescence and electron microscopy. They were shown to be probably crystallized nanofibers, which were stable in suspension. Unexpectedly, upon filtration and drying, these fibers evolved to give a reticulated solid. The fluorescence properties of the compound were analyzed in solution, in aqueous suspension and in the powder crystalline state. Interestingly, berberine palmitate is virtually not fluorescent in aqueous solution because of the quenching effect of water, but transition to the solid state was accompanied by a strong increase in fluorescence intensity. This phenomenon was explained by the original molecular arrangement in the solid state. Actually, in the crystal, the anions form a distinct layer, which limits parallel-stacking of the fluorescent cations. Moreover, the berberine cations are protected from the access of water molecules, and so no quenching effect can take place. This example confirms that the newly introduced concept of ion-pair aggregation-induced fluorescence enhancement can be extended to a variety of structures. It also shows the interest of ion pairs for preparing fluorescent nanofibers and reticulated solids using a solvent-exchange method that is particularly easy to implement.

1,3-Bis(thiophosphinoyl)indene: a unique and versatile scaffold for original polymetallic complexes.

The coordination of tridentate ligands featuring lateral coordination sites prone to acting as bridging ligands was explored with the aim of obtaining original polymetallic species in a straightforward and controlled manner. Accordingly, the 2-indenylidene chloropalladate [{Ind(Ph(2)P═S)(2)}PdCl](-) was found to behave as a κ(2)-C,S bidentate ligand toward metal fragments, giving access to homo- and heteropolymetallic complexes. X-ray diffraction analyses reveal the presence of short metal-metal contacts in all of these complexes. Density functional theory calculations unambiguously substantiate that the metals engage in unusual d(8)···d(8) interactions with a quasi-perpendicular arrangement of their coordination planes.

Asymmetric synthesis and cytotoxic activity of isomeric phytosphingosine derivatives.

New phytosphingosine analogues have been conceived, synthesised and their cytotoxicity in B16 murine melanoma cells tested. These compounds embed an isomeric substitution pattern resulting from a formal permutation of the C-2 and C-4 substituents along the aliphatic skeleton of the original sphingoid base. Five different stereoisomers have been accessed through regio- and stereocontrolled opening of the oxirane of long chain epoxyamine precursors. The corresponding N-hexyl and N-octanoyl derivatives have also been prepared. In cell viability experiments all the primary amines were found to be more active than the natural phytosphingosine with IC(50) in the low µM range for the most potent compounds.

Aggregation-induced emission enhancement in organic ion pairs.

We present here a new example of aggregation-induced emission enhancement (AIEE), which involves an original mechanism based on the formation of organic ion pairs. The phenol 4-hydroxy-7-nitrobenzoxadiazole (NBDOH) is dissociated in water at pH 5.0 to give the corresponding phenolate, which is poorly fluorescent in this medium. We bring evidence that fluorescence quenching is due to an interaction with water molecules. In the presence of a relatively bulky ammonium salt, specifically tetrabutylammonium bromide (TBAB), NBDOH forms a hydrophobic salt, TBA(+)NBDO(-). This has no influence on the fluorescence of the anion as long as the salt is dissolved. However, the salt readily crystallizes in the medium and transition to the solid state is accompanied by a strong increase in fluorescence intensity. This effect can be explained by two reasons. The anions are protected from water molecules, and above all, the presence of the bulky cations prevents parallel-stacking of the anions, thus leading to an original molecular arrangement that is favorable to fluorescence. As the nature of the organic cation may be easily changed, the versatility of the system is very interesting for the design of new organic micro- and nanoparticles that must be fluorescent in the solid state, possibly in an aqueous environment.

Organo-catalyzed ring opening polymerization of a 1,4-dioxane-2,5-dione deriving from glutamic acid.

The (3S)-[(benzyloxycarbonyl)ethyl]-1,4-dioxan-2,5-dione (BED) was prepared in four steps starting from glutamic acid and bromoacetyl bromide. According to X-ray diffraction analysis, the pendant functional group is located in equatorial position and points away from the six-membered ring. The organo-catalyzed ring-opening polymerization of BED was promoted with 4-dimethylaminopyridine (DMAP) and the combination of thiourea TU(Cy) and (-)-sparteine. PolyBED samples of number-average molar mass M(n) up to 36000 and narrow polydispersity (M(w)/M(n) < 1.25) were thereby prepared in a controlled manner under mild conditions (dichloromethane solution, 30 degrees C), as substantiated by size-exclusion chromatography, matrix-assisted laser desorption ionization time-of-flight-mass spectrometry (MALDI-TOF-MS) and nuclear magnetic resonance (NMR) spectroscopy. The pendant functional group does not interfere with the polymerization and BED was even found to be slightly more reactive than lactide. Despite the strongly dissymmetric substitution pattern of the 1,4-dioxan-2,5-dione core, the ensuing polyBED polymers present a random distribution of glycolic-[(benzyloxycarbonyl)ethyl]glycolic (gly glu) units, as supported by a (1)H-(13)C HMBC 2D NMR experiment. The preparation of 1:1 adducts with n-pentanol confirmed that ring-opening of BED occurs almost indifferently on either of the endocyclic ester groups. Poly(alpha-hydroxyacids) featuring pendant carboxylic acids were finally obtained by acetylation of the terminal OH groups followed by hydrogenolysis.

Synthesis and anticancer activity evaluation of 2(4-alkoxyphenyl)cyclopropyl hydrazides and triazolo phthalazines.

A series of new 2(4-alkoxyphenyl)cyclopropyl hydrazide- and triazolo-derivatives were synthesized starting from 4-hydroxycinnamic acid (1) in a clean, mild, efficient and straightforward synthetic protocol. These compounds consisting of different alkoxy substitution, phenylcyclopropyl backbone and different heterocyclic groups were evaluated for in vitro anticancer activity against 4 cell lines displaying certain levels of resistance to pro-apoptotic stimuli and 2 cell lines sensitive to pro-apoptotic compounds. Compounds 7f and 8e were most active and displaying moderate in vitro cytostatic effect through different mechanisms. Significantly, chemically modified derivatives could be obtained in order to develop novel types of compounds aiming to combat apoptosis-resistant cancers, for example, those cancers associated with dismal prognoses.

1,5-Dimethyl-3-[(3-phenyl-4,5-dihydro-1,2-oxazol-5-yl)meth-yl]-1H-1,5-benzodiazepine-2,4(3H,5H)-dione.

The reaction of 3-allyl-1,5-dimethyl-1,5-benzodiazepine-2,4-dione and benzaldoxime leads to the title compound, C(21)H(21)N(3)O(3). The mol-ecular structure is built up from two fused six- and seven-membered rings linked to a chain including a five- and six-membered ring (isoxazoline and phen-yl) via a methyl-ene group. The seven-membered ring displays a boat conformation. The dihedral angle between the two six-membered rings is 74.3 (1)°.