Synthesis of potent inhibitors of β-ketoacyl-acyl carrier protein synthase III as potential antimicrobial agents

Mycobacterium tuberculosis FabH, an essential enzyme in the mycolic acid biosynthetic pathway, is an attractive target for novel anti-tubercolosis agents. Structure-based design and synthesis of 1-(4-carboxybutyl)-4-(4-(substituted benzyloxy)phenyl)-1H-pyrrole-2-carboxylic acid derivatives 7a-h, a subset of eight potential FabH inhibitors, is described in this paper. The Vilsmeier-Haack reaction was employed as a key step. The structures of all the newly synthesized compounds were identified by IR, 1H-NMR, 13C-NMR, ESI-MS and HRMS. The alamarBlue? microassay was employed to evaluate the compounds 7a-h against Mycobacterium tuberculosis H??Rv. The results demonstrate that the compound 7d possesses good in vitro antimycobacterial activity against Mycobacterium tuberculosis H??Rv (Minimum Inhibitory Concentration value [MIC], 12.5 μg/mL).These compounds may prove useful in the discovery and development of new anti-tuberculosis drugs.     

Molecular and quantum mechanical studies on the monomer recognition of a highly-regular β-helical antifreeze protein

The possible interaction models for an antifreeze protein from Tenebrio molitar (TmAFP) have been systematically studied using the methods of molecular mechanics, molecular dynamics and quantum chemistry. It is hoped that these approaches would provide insights into the nature of interaction between protein monomers through sampling a number of interaction possibilities and evaluating their interaction energies between two monomers in the course of recognition. The results derived from the molecular mechanics indicate that monomerś β-sheets would be involved in interaction area and the side chains on two p-faces can match each other at the two-dimensional level. The results from molecular mechanics and ONIOM methods show that the strongest interaction energy could be gained through the formation of H-bonds when the twoβ-sheets are involved in the interaction model. Furthermore, the calculation of DFT and analysis of van der Waals bond charge density confirm further that recognition between the two TCTs mainly depends on inter-molecular hydroxyls. Therefore, our results demonstrate that during the course of interaction the most favorable association of TmAFPs is via their β-sheets.     

Molecular and quantum mechanical studies on the monomer recognition of a highly-regular β-helical antifreeze protein

The possible interaction models for an antifreeze protein from Tenebrio molitar (TmAFP) have been systematically studied using the methods of molecular mechanics, molecular dynamics and quantum chemistry. It is hoped that these approaches would provide insights into the nature of interaction between protein monomers through sampling a number of interaction possibilities and evaluating their interaction energies between two monomers in the course of recognition. The results derived from the molecular mechanics indicate that monomer's β-sheets would be involved in interaction area and the side chains on two β-faces can match each other at the two-dimensional level. The results from molecular mechanics and ONIOM methods show that the strongest interaction energy could be gained through the formation of H-bonds when the two β-sheets are involved in the interaction model. Furthermore, the calculation of DFT and analysis of van der Waals bond charge density confirm further that recognition between the two     

Molecular recognition of a self-assembled monolayer of a polydithiocarbamate derivative of β-cyclodextrin on silver

The synthesis and molecular recognition properties of a new sulfur containing β-cyclodextrin (β-CD) derivative chemisorbed on a silver surface are described. Hepta-6-amino-6-deoxy-β-CD was allowed to react with CS₂ in the presence of ammonia to give a mixture of partially substituted dithiocarbamate derivatives with an average degree of substitution of 4.5. A modified silver electrode with this derivative is capable of discriminating between the three positional isomers of nitrobenzoate ion and nitrophenol, as determined by cyclic voltammetry. Only the meta- and para-isomers give a signal corresponding to the reduction of the nitro group. This is attributed to the different orientations of the nitro group with respect to the silver surface after inclusion in the CD cavity. Experiments in the presence of cyclohexanol showed a decrease in signal intensity of the meta- and para-isomers which is associated with the competitive complexation of this guest, suggesting that the electroactive probe is complexed to the cavity.     

Molecular Inclusion Properties of Hydrophobic Organic Compounds by a Modified β-Cyclodextrin Intercalated within a Layered Double Hydroxide

A study was conducted to evaluate the inclusion properties of various nonionic hydrophobic organic compounds by a novel intercalate derived from magnesium-aluminum layered double hydroxide (Mg/Al LDH) and carboxymethyl--cyclodextrin with a degree of substitution of 3 [CMCD(3)]. The isotherm sorption results at 25 °C showed that the CMCD(3)-Mg/Al LDH intercalate could retain all the organic compounds (trichloroethylene, tetrachloroethylene, benzene, toluene, p-, o-, m-xylene, ethylbenzene, 1,2,3-trichlorobenzene, naphthalene) studied and its sorption affinity for organic compounds was positively related to their hydrophobicities. The host-guest interaction was attributed to a partition process of the organic compounds into cyclodextrin cavities as well as intermolecular pores. A stereoselective interaction might also be involved due to the intercalation of CMCD(3) within Mg/Al LDH interlayers.     

Molecular recognition of naphthalenediamine by polyamine modified β-cyclodextrin:yttrium metal complexes

The 6-OH group of β-cyclodextrin was modified by diethylene triamine and triethylene tetramine, respectively, mono[6-diethylenetriamino]-6-deoxy-β-cyclodextrin (DTCD) and mono[6-triethylenetetraamino]-6-deoxy-β-cyclodextrin (TTCD) were synthesized, which included 1,5-naphthalenediamine and 1,8-naphthalenediamine, respectively, in the presence of rare earth metal yttrium chloride. As a result, four ternary inclusion complexes (host–guest-metal) formed, which were characterized via ¹HNMR spectroscopy. The chemical shift variations of host and guest molecules were studied. The stoichiometric proportion of host and guest molecules is 2:1 for all the complexes. Signal degeneration still exists for the guest molecules after the inclusion process, which verifies the symmetrical conformation of guest molecules inside the cavities of two host molecules. All the four complexes exhibit “sandwich”-typed structure.     

Molecular recognition and biological application of modified β-cyclodextrins

The molecular recognition based on cyclodextrins(CDs) has become a focus of interest in modern supramolecular chemistry.CDs are known to encapsulate various ions and organic/inorganic molecules in their hydrophobic cavities and form stable inclusion complexes through cooperative noncovalent interactions. During the past few decades, a large variety of modified CDs have been elaborately designed and synthesized, which significantly promotes our molecular-level understanding of the structure–function relationship in many supramolecular systems. Through the accurate analysis on the molecular binding behaviors, one can create a library of CD-based nanoassemblies with controlled physicochemical properties. In this review, we will focus on the stability constant-directed molecular recognition and the biological activities of β-CDs toward some representative bioactive substrates, including metal ions, steroids, porphyrins, amino acids and oligopeptides, as well as drug molecules, with the final goal of promoting their practical applications in the biomedical field.     

One-Pot Synthesis of β-Phosphonomalonates Catalyzed by Molecular Iodine

A one-pot procedure has been developed for the synthesis of β-phosphonomalonates via P-C bond formation through tandem Knoevenagel–phospha–Michael reaction catalyzed by iodine as a new, inexpensive, nonmetallic, and commercially available catalyst.

[Supplementary materials are available for this article. Go to the publisher's online edition of Synthetic Communications® for the following free supplemental resource(s): Full experimental and spectral details.]     

Molecular recognition of endocrine disruptors by synthetic and natural 17β-estradiol receptors: a comparative study

A β-estradiol receptor binding mimic was synthesised using molecular imprinting. Bulk polymers and spherical polymer nanoparticles based on methacrylic acid and ethylene glycol dimethacrylate as the functional monomer and crosslinker, respectively, were prepared in acetonitrile. The selectivity was evaluated by radioligand binding assays. The imprinted polymers were very specific to β-estradiol since the control polymers bound virtually none of the radioligand. The bulk polymer was then employed to screen endocrine disrupting chemicals. Structurally related steroids like α-estradiol, estrone and ethynylestradiol showed, respectively, 14.0, 5.0 and 0.7% of relative binding to the β-estradiol polymer, whereas most unrelated chemicals did not bind at all. These results are compared to those obtained with a bioassay using stably transfected yeast cells in culture bearing the human estrogen receptor. The receptor was activated by several estrogen-like chemicals and to a lesser extent by some structurally related chemicals. Figure A molecularly imprinted polymer that was a synthetic receptor for beta-estradiol was used for the screening of endocrine disrupting chemicals that are structurally related or unrelated to beta-estradiol. The results were compared with the recognition of the compounds by the biological estrogen receptor expressed in yeast cells. Related steroids like alpha-estradiol, estrone and ethynylestradiol showed significant binding to the beta-estradiol imprinted polymer, whereas most unrelated chemicals did not bind. The biological receptor was activated by several estrogen-like chemicals, and to a lesser extent by some structurally related chemicals     

Molecular recognition by indoleacetic acid-imprinted polymers – effects of 2-hydroxyethyl methacrylate content

Molecularly imprinted polymers for indole-acetic acid were prepared by co-polymerizing N,N-dimethylaminoethyl methacrylate, 2-hydroxyethyl methacrylate (HEMA), and ethylene glycol dimethacrylate. The dependence of the affinity and selectivity of the imprinted polymers on HEMA content was evaluated chromatographically. The affinity was improved by increasing the HEMA content; the selectivity of the imprinted polymer was best when the HEMA content was approximately 30%, irrespective of monomer content.     

β-Biguanidinium-cyclodextrin: a supramolecular mimic of mitochondrial ADP/ATP carrier protein

We reported a novel mono-β-cyclodextrin derivative, mono-6-deoxy-6-biguanidino-β-cyclodextrin (β-biGCD), which was investigated as a mimic of ADP/ATP carrier (AAC). Its affinity toward AMP, ADP, and ATP was evaluated by means of isothermal titration calorimetry (ITC). The association constants (K_a) of β-biGCD binding to AMP, ADP, and ATP were determined to be (1.07±0.04)×10⁶, (5.86±0.02)×10⁶, and (4.33±0.06)×10⁶ L mol⁻¹, respectively, which were 100-fold higher than mono-guanidino-β-cyclodextrin (ca. 10⁴ L mol⁻¹). UV spectroscopic titrations further confirmed the above results. The interaction between β-biGCD and nucleotides was probed by docking simulation. These results reveal that the biguanidinium moiety mimics the arginine residues of mitochondrial AAC protein.     

Relative reactivities of bromine-substituted substrates toward bromophilic attack by a carbanion

Halophilic attack on carbon-halogen bond by nucleophiles has recently become a sub-ject of interest and intensive study.A wide variety of substrates and nucleophiles has beenexamined.But no quantitative measurements on the reactivities of substrates have ever beenreported.The present work is a first attempt to evaluate the relative reactivities of perfluoro-bromoalkanes(R-Br)and some bromo organic compounds(R-Br)by intermolecular compe-tition kinetics.A large excess of Cl_3CCF_2CF_2Cl(1),a chlorine-containing substrate withconvenient reactivity toward halophilic attack,and R-Br is used to compete for a small amountof the enolate anion of mesityl isopropyl ketone(E-)in dimethyl formamide(DMF)at 20℃in their reactions to form α-chloroisopropyl mesityl ketone(A)and α-bromoisopropylmesityl ketone(B)as products(eq 1)     

Dynamical Aspects of TEM-1 β-Lactamase Probed by Molecular Dynamics

The dynamical aspects of the fully hydrated TEM-1 β-lactamase have been determined by a 5 ns Molecular Dynamics simulation. Starting from the crystallographic coordinates, the protein shows a relaxation in water with an overall root mean square deviation from the crystal structure increasing up to 0.17 nm, within the first nanosecond. Then a plateau is reached and the molecule fluctuates around an equilibrium conformation. The results obtained in the first nanosecond are in agreement with those of a previous simulation (Diaz et al., J. Am. Chem. Soc., (2003) 125, 672–684). The successive equilibrium conformation in solution shows an increased mobility characterized by the following aspects. A flap-like translational motion anchores the Ω-loop to the body of the enzyme. A relevant part of the backbone dynamics implies a rotational motion of one domain relative to the other. The water molecules in the active site can exchange with different residence times. The H-bonding networks formed by the catalytic residues are frequently interrupted by water molecules that could favour proton transfer reactions. An additional simulation, where the aspartyl dyad D214–D233 was considered fully deprotonated, shows that the active site is destabilized.     

An Improved Synthesis of Vinyl- and β-Iodovinyl Sulfones by a Molecular Iodine-Mediated One-Pot Iodosulfonation-Dehydroiodination Reaction

An improved one-pot method to synthesize vinyl sulfones from unsaturated systems by using molecular iodine/sodium arenesulfinate/sodium acetate as reagents was described. Vinyl sulfones derived from styrene derivatives were generally obtained in good to excellent yields except for those bearing strong electron releasing substituent. Aliphatic alkenes and activated alkenes gave the corresponding vinyl sulfone products in moderate to good yields. Arylacetylenes yielded the respective β-iodovinyl sulfones in good yields while low yield was observed with aliphatic terminal alkyne. The potentials of the method entail simplicity, short reaction time, non-anhydrous reaction conditions, employing inexpensive, non-metallic reagent and integrating two reactions that are commonly accomplished separately into a single operation.

Supplemental materials are available for this article. Go to the publisher's online edition of Synthetic Communications® to view the free supplemental file.     

Is there a scaffolding domain within the structure of the immunosuppressive agent cyclosporin a (CsA)? Studies of the cyclophilin binding domain of CsA

The synthesis of a peptide that approximates the critical binding/immunosuppressive domain within CsA but which is lacking any form of molecular scaffolding is described. The analysis of the conformation and cyclophilin binding properties of this synthetic analogue provides further evidence for the existence of a scaffolding domain within the natural product.     

Enhancement of sortase A-mediated protein ligation by inducing a β-hairpin structure around the ligation site

A Staphylococcus aureus transpeptidase, sortase A (SrtA), catalyzes selective peptide/protein ligations that have been applied to cell imaging and protein engineering, while the ligations do not proceed to completion due to their reversibility. We successfully enhanced SrtA-mediated protein ligation through the formation of a β-hairpin around the ligation site.     

Synthesis of a β-cyclodextrin derivate and its molecular recognition behavior on modified glassy carbon electrode by diazotization

A novel β-cyclodextrin (β-CD) derivative containing mono-phenylamino (MPA-β-CD) was newly synthesized by classical Mitsunobu reaction in good yield, and its structure has been confirmed by ¹H NMR, ¹³C NMR and electrospray ionization mass spectra. The compound MPA-β-CD was immobilized onto glassy carbon electrode (GCE) by diazotization, and with this modified electrode the binding behavior of MPA-β-CD for ferrocene (Fc) was investigated qualitatively, and the comparison of differential pulse voltammetry before and after immersion in ferrocene solution indicated that the MPA-β-CD immobilized GCE exhibited the molecular recognition behavior between β-CD and ferrocene.