Synthesis and Study of Multifunctional Cyclodextrin–Deferasirox Hybrids

Metal dyshomeostasis is central to a number of disorders that result from, inter alia, oxidative stress, protein misfolding, and cholesterol dyshomeostasis. In this respect, metal deficiencies are usually readily corrected by treatment with supplements, whereas metal overload can be overcome by the use of metal-selective chelation therapy. Deferasirox, 4-[(3Z,5E)-3,5-bis(6-oxo-1-cyclohexa-2,4-dienylidene)-1,2,4-triazolidin-1-yl]benzoic acid, Exjade, or ICL670, is used clinically to treat hemosiderosis (iron overload), which often results from multiple blood transfusions. Cyclodextrins are cyclic glucose units that are extensively used in the pharmaceutical industry as formulating agents as well as for encapsulating hydrophobic molecules such as in the treatment of Niemann–Pick type C or for hypervitaminosis. We conjugated deferasirox, via an amide coupling reaction, to both 6^A-amino-6^A-deoxy-β-cyclodextrin and 3^A-amino-3^A-deoxy-2^A(S),3^A(S)-β-cyclodextrin, at the upper and lower rim, respectively, creating hybrid molecules with dual properties, capable of both metal chelation and cholesterol encapsulation. Our findings emphasize the importance of the conjugation of β-cyclodextrin with deferasirox to significantly improve the biological properties and to decrease the cytotoxicity of this drug.     

Synthesis and Structure-Activity Relationship of Xenocoumacin 1 and Analogues as Inhibitors of Ribosomal Protein Synthesis

Ribosomal protein synthesis is an important target in antibacterial drug discovery. Numerous natural products have served as starting points for the development of antibiotics. We report here the total synthesis of xenocoumacin 1, a natural product that binds to 16S ribosomal RNA at a highly conserved region, as well as analogues thereof. Preliminary structure–activity relationship studies were aimed at understanding and modulating the selectivity between eukaryotic and prokaryotic ribosomes. Modifications were mainly tolerated in the aromatic region. Whole-cell activity against Gram-negative bacteria is limited by efflux and penetration, as demonstrated in genetically modified strains of E. coli. Analogues with high selectivity for eukaryotic ribosomes were identified, but it was not possible to obtain inhibitors selective for bacterial protein synthesis. Achieving high selectivity (albeit not the desired one) was thus possible despite the high homology between eukaryotic and prokaryotic ribosomes in the binding region.     

Divergent Synthesis and Evaluation of the in vitro Cytotoxicity Profiles of 3,4-Ethylenedioxythiophenyl-2-propen-1-one Analogues

A new series of 3,4-ethylenedioxythiophene (EDOT)-appended propenones were prepared by condensation reaction and their in vitro cytotoxicity effects were evaluated against five human cancer cell lines. Preliminary structure–activity relationships of EDOT-incorporated 2-propenone derivatives were also established. The EDOT-appended enones demonstrated significant cytotoxicity against human cancer cell lines. The most active analogue, (E)-3-(2,3-dihydrothieno[3,4-b][1,4]dioxin-5-yl)-1-(3,4,5-trimethoxyphenyl)prop-2-en-1-one ( 3 p , GI₅₀=110 nm ), severely inhibited the clonogenic potential of cancer cells, and induced cell-cycle arrest in the G2/M phase and caused an accumulation of HCT116 colon cancer cells with >4 N DNA content. Also, 3 p exhibited weak inhibition of the enzymatic activity of human topoisomerase I. Molecular docking studies indicated preferential binding of the compounds to the ATP-binding pocket of the human checkpoint 2 kinase (Chk2) catalytic domain, thus, identifying a novel diaryl 2-propenone chemotype for the development of potent inhibitors of Chk2.     

One-Pot Synthesis of Coumarin–Indomethacin Hybrids as COX-2 Targeting Probes for Cancer Imaging

Facile synthesis of 6- or 7-substituted coumarin-indomathacin hybrids (Coum-IDM) has been developed for specific cyclooxygenase-2 (COX-2) binding along with their intrinsic fluorescent properties. A mild and rapid condensation/dehydrative cyclization of 2-hydroxy benzaldehyde with activated indomethacin was carried out in one step under ultrasound irradiation. Coum-IDM₄ was found to be the best of this series as it presented significant binding to COX-2 and exhibited higher fluorescent intensity in cancer cells than in normal cells. Therefore, in the light of drug development tools, this new hybrid system could be a potential targeted probe for COX-2-overexpressed inflammation and cancer-cell tracking.     

Synthesis and Biological Evaluation of (−) and (+)-Spiroleucettadine and Analogues

A second-generation enantiospecific synthesis of spiroleucettadine is described. The original reported antibacterial activity was not observed when the experiment was repeated on the synthetic samples; however, significant anti-proliferative activity was uncovered for both enantiomers of spiroleucettadine. Comparison of the optical rotational data and ORD-CD spectra of both enantiomers and the reported spectrum from the natural source have not provided a definitive answer regarding the absolute stereochemistry of naturally occurring spiroleucettadine. Efforts then focussed on alteration at the C-4 and C-5 positions of the slightly more active (−)-spiroleucettadine. Ten analogues were synthesised, with three analogues found to possess similar anti-proliferative profiles to spiroleucettadine against the H522 lung cancer cell line.     

Structural Consequences of the 1,2,3-Triazole as an Amide Bioisostere in Analogues of the Cystic Fibrosis Drugs VX-809 and VX-770

Although the 1,2,3-triazole is a commonly used amide bioisostere in medicinal chemistry, the structural implications of this replacement have not been fully studied. Employing X-ray crystallography and computational studies, we report the spatial and electronic consequences of replacing an amide with the triazole in analogues of cystic fibrosis drugs in the VX-770 and VX-809 series. Crystallographic analyses quantify subtle differences in the relative positions and conformational preferences of the R¹ and R² substituents attached to the amide and triazole bioisosteres. Computational studies derived from the X-ray data highlight the improved hydrogen bonding donor and acceptor capabilities of the amide in comparison to the triazole. This analysis of the spatial and electronic differences between the amide and 1,2,3-triazole will inform medicinal chemists as they consider using the triazole as an amide bioisostere.     

Synthesis and characterization of new Mg–O–F system and its application as catalytic support

The Mg–O–F system (MgF₂–MgO) with different contents of MgF₂ (100–0%) and MgO is tested as support of iridium catalysts in the hydrogenation of toluene as a function of the MgF₂/MgO ratio. Mg–O–F samples have been prepared by the reaction of magnesium carbonate with hydrofluoric acid. The MgF₂–MgO supports, after calcination at 500 °C, are classified as mesoporous of surface area (34–135 m²·g^− 1) depending on the amount of MgO introduced. The Ir/Mg–O–F catalysts have been tested in the hydrogenation of toluene. The highest activity, expressed as TOF, min^− 1, was obtained for the catalyst supported on Mg–O–F containing 75 mol%MgF₂.     

Synthesis and Characterization of Carbazole–Fluorene–Silole Copolymers as Efficient Green Light Emitting Diodes

A novel series of soluble polyfluorene–carbazole–silole-containing polymers (PF–Cz–S) were prepared through the Suzuki coupling reaction; and, the chemical structures were characterized by elemental analysis and NMR. Optoelectronic properties including UV absorption, electrochemistry, photoluminescence (PL), and electroluminescence (EL) of the copolymers were investigated. The copolymers exhibit main absorption peaks at 359?nm for solutions and 354?nm for films with combined contributions from the carbazole and fluorene units. Compared with the solution PL, complete PL excitation energy transfer from the wide band gap segment to a narrow band gap silole unit was achieved by film PL even at a lower silole content. The optical band gaps for PF–Cz–S are between 2.68 and 2.78?eV and the HOMO levels are ?5.65?eV, which are contributed by 3,6-carbazole and fluorene blocks. Light-emitting devices fabricated from these polymers display a maximum external quantum efficiency of 0.44?% with an indium–tin oxide (ITO)/poly(3,4-ethylenedioxythiophene) (PEDOT)/PF–Cz–S/CsF/Al configuration whereas an ITO/PEDOT/PCz–F–S/1,3,5-tris(N-phenylbenzimidizol-2-yl)benzene (TPBI)/CsF/Al with TPBI hole-blocking layer device configuration boosts the efficiency to 2.43?%. The TPBI hole-blocking layer largely improved the efficiency of exciton formation from which the highly efficient green EL from the silole units could be displayed.     

Synthesis,in vitro Antileishmanial Efficacy and Hit/Lead Identification of Nitrofurantoin-Triazole Hybrids

Leishmaniasis is a vector-borne neglected parasitic infection affecting thousands of individuals, mostly among populations in low- to moderate-income developing countries. In the absence of protective vaccines, the management of the disease banks solely on chemotherapy. However, the clinical usefulness of current antileishmanial drugs is threatened by their toxicity and the emergence of multidrug-resistant strains of the causative pathogens. This emphasizes the imperative for the development of new and effective antileishmanial agents. In this regard, we synthesized and evaluated in vitro the antileishmanial activity and cytotoxicity profile of a series of nitrofurantoin-triazole hybrids. The nitrofurantoin derivative 1 featuring propargyl moiety was distinctively the most active of all, was nontoxic to human cells and possessed submicromolar cellular activity selectively directed towards the pathogens of the life threatening visceral leishmaniasis. Hence it was identified as potential antileishmanial lead for further investigation into its prospective to act as alternative to therapies.     

Synthesis and Structure–Activity Relationship Studies of Benzo[b][1,4]oxazin-3(4H)-one Analogues as Inhibitors of Mycobacterial Thymidylate Synthase X

Since the discovery of a flavin-dependent thymidylate synthase (ThyX or FDTS) that is absent in humans but crucial for DNA biosynthesis in a diverse group of pathogens, the enzyme has been pursued for the development of new antibacterial agents against Mycobacterium tuberculosis, the causative agent of the widespread infectious disease tuberculosis (TB). In response to a growing need for more effective anti-TB drugs, we have built upon our previous screening efforts and report herein an optimization campaign of a novel series of inhibitors with a unique inhibition profile. The inhibitors display competitive inhibition toward the methylene tetrahydrofolate cofactor of ThyX, enabling us to generate a model of the compounds bound to their target, thus offering insight into their structure–activity relationships.     

Synthesis and characterization of new poly(ether–ester–imide)s as a generation of soluble and thermally stable polymers

A new-type of dicarboxylic acid 6 was synthesized from the reaction of 1,4-bis[4-aminophenoxy]butane 4 with trimellitic anhydride 5 in a solution of glacial acetic acid/pyridine (Py) at refluxing temperature. 1,4-Bis[4-nitrophenoxy]butane 3 was prepared by reaction of 4-nitrophenol 1 with 1,4-dibromo butane 2 in N,N-dimethylformamide (DMF) solution. Then dinitro 3 was reduced to 1,4-bis[4-aminophenoxy]butane 4 by using 10% Pd–C, ethanol, and hydrazine monohydrate. So six new thermally stable and organosoluble poly(ether–ester–imide)s (PEEIs) 8a–f with good inherent viscosities were synthesized by the direct polycondensation reaction of new 1,4-bis[4-(trimellitimido)phenoxy]butane 6 with several aromatic diols 7a–f through direct polycondensation using tosyl chloride (TsCl)/pyridine (Py)/DMF system as condensing agent. The resulted polymers were fully characterized by means of FTIR and ¹H NMR spectroscopy, elemental analyses, inherent viscosity, solubility tests, differential scanning calorimeter (DSC), thermogravimetric analysis (TGA), and derivative of thermogravimetric (DTG).     

Development of Therapeutic Gramicidin S Analogues Bearing Plastic β,γ-Diamino Acids

Gramicidin S (GS), one of the most widely investigated antimicrobial peptides (AMPs), is known for its robust antimicrobial activity. However, it is restricted to topical application due to undesired hemolytic activity. With the aim of obtaining nontoxic GS analogues, we describe herein a molecular approach in which the native GS β-turn region is replaced by synthetic β,γ-diamino acids (β,γ-DiAAs). Four β,γ-DiAA diastereomers were employed to mimic the β-turn structure to afford GS analogues GS 3 – 6 , which exhibit diminished hemolytic activity. A comparative structural study demonstrates that the (βR,γS)-DiAA is the most-stable β-turn mimic. To further improve the therapeutic index (e. g., high antibacterial activity and low hemolytic activity) and to extend the molecular diversity, GS 5 and GS 6 were used as structural scaffolds to introduce additional hydrophobic or hydrophilic groups. We show that GS 6K , GS 6F and GS display comparable antibacterial activity, and GS 6K and GS 6F have significantly decreased toxicity. Moreover, antibacterial mechanism studies suggest that GS 6K kills bacteria mainly through the disruption of the membrane.     

Synthesis and Characterization of Linear and Tri-Block PLLA–PEG–PLLA Blends

This study was conducted to synthesize poly(L-lactide)–poly(ethylene glycol)–poly(L-lactide) triblock copolymer (PEGLA) with different poly(L-lactide) block length, and explore its applicability in a blend with linear poly(L-lactide) (3051D NatureWorks) with the intention of improving heat seal and adhesion properties at extrusion coating on paperboard. Poly(L-lactide)–poly(ethylene glycol)–poly(L-lactide) was obtained by ring opening polymerization of L-lactide using poly(ethylene glycol) (molecular weight 6000 g mol^?1) as an initiator and stannous octoate as catalyst. The structures of the PEGLAs were characterized by proton nuclear magnetic resonance spectroscopy. The melt flow and thermal properties of all PEGLAs and their blends were evaluated using dynamic rheology and differential scanning calorimeter. All blends containing 10 wt% of PEGLAs displayed similar zero shear viscosities to neat poly(L-lactide), while blends containing 30 wt% of PEGLAs showed slightly higher zero shear viscosity. However, all blends displayed higher shear thinning and increased melt elasticity (based on tan δ). No major changes in thermal properties were distinguished from differential scanning calorimetric studies. High molecular weight PEGLAs could be used in extrusion coating with 3051D without problems.     

Synthesis of Co–Ni and Cu–Ni based-catalysts for dry reforming of methane as potential components for SOFC anodes

In this work, we report a comparative study of Ni-based anode compositions, made of Cu and Co (40 and 80 mol%) and gadolinia-doped ceria (CGO) matrices, for application the dry reforming of methane (DRM) reaction using Solid Oxide Fuel Cells (SOFCs). The new compositions are synthesized by a one-step synthesis route, using citric acid as chelating agent, and characterized at three different stages: i) after synthesis, ii) after reduction, and iii) after DRM. X-ray diffraction (XRD) analysis combined with thermodynamic calculations is used to understand phase evolution along the different stages, revealing that complete solid solutions of NiCo- and NiCu-based alloys are formed after DRM reaction. Transmission Electron Microscopy (TEM) shows the formation of nanocrystalline powders, while surface area (S_BET) measurements show higher values in the case of the NiCo-based samples. Moreover, the Co-containing compositions exhibit higher reducibility and stronger metal-ceramic interactions than the Cu-containing samples, according to the Temperature Programmed Reduction (TPR) results. Finally, DRM results demonstrate higher CO₂ and CH₄ conversions in the case of the Co-containing samples, as well as increased resistance towards carbon deposition, as confirmed by Thermogravimetric and Differential Scanning Calorimetry analyses (TG-DSC). Overall, the Co-based compositions are highly beneficial for their use as anodes for the CO₂ reforming of methane in SOFCs.     

Study of Ribavirin–Nucleic Acids Interaction

The UV–Vis absorption spectra of ribavirin in the absence and presence of calf thymus DNA are presented and discussed in this paper. The molecular structure of ribavirin was investigated by the semiempirical AM1 method, which triggered two polymorphic modifications of the antiviral drug also reported in the literature. Our experimental results point out two types of the binding. The first type involves a non-electrostatic (internal) binding, consisting of the intercalation of drug between the nitrogenous bases of nucleic acid. The second type (an external binding) involves the drug binding to the nucleic acid grooves. In addition, the binding constant of the second process has an order of magnitude greater than the binding constant for the first process, calculated by the Benesi–Hildebrand, Scott, and Scatchard methods, which supposes a 1:1 binding ratio. Also, the interactions of two polymorphic modifications of ribavirin (V₁ and V₂) with nucleic acids by the molecular mechanic and semiempirical AM1 methods were analyzed. The experimental data pointed out that in the ribavirin–nucleic acid complexes, the 1,2,4-triazole-3-carboxamide chromophore is intercalated between the bases of the nucleic acid sequences, the carboxamidic group is set outside of the nucleic acid sequence toward the major groove, and the 2-hydroxymethyl-tetrahydrofuran-3,4-diol fragment is located in the minor groove. In order to stress the sequence specificity of ribavirin, different models of the nucleic acid sequences containing adenine (A), thymine (T), cytosine (C), and guanine (G) in AAAAAA, TTTTTT, CCCCCC, GGGGGG, ATATAT, CGCGCG, ATCGAT, and CGATCG were used. The theoretical results outline the differences in the contributions of the electrostatic and van der Waals interactions to the total binding energy and the preference of ribavirin for the binding at the sequences of nucleic acids containing adenine and thymine bases.