Solvent effect on the synthesis of clarithromycin: A molecular dynamics study

Clarithromycin (6-O-methylerythromycin A) is a 14-membered macrolide antibiotic which is active in vitro against clinically important gram-positive and gram-negative bacteria. The selectivity of the methylation of the C-6 OH group is studied on erythromycin A derivatives. To understand the effect of the solvent on the methylation process, detailed molecular dynamics (MD) simulations are performed in pure DMSO, pure THF and DMSO:THF (1:1) mixture by using the anions at the C-6, C-11 and C-12 positions of 2',4"-[O-bis(TMS)]erythromycin A 9-[O-(dimethylthexylsilyl)oxime] under the assumption that the anions are stable on the sub-nanosecond time scale. The conformations of the anions are not affected by the presence of the solvent mixture. The radial distribution functions are computed for the distribution of different solvent molecules around the 'O-' of the anions. At distances shorter than 5 A, DMSO molecules are found to cluster around the C-11 anion, whereas the anion at the C-12 position is surrounded by the THF molecules. The anion at the C-6 position is not blocked by the solvent molecules. The results are consistent with the experimental finding that the methylation yield at the latter position is increased in the presence of a DMSO:THF (1:1) solvent mixture. Thus, the effect of the solvent in enhancing the yield during the synthesis is not by changing the conformational properties of the anions, but rather by creating a suitable environment for methylation at the C-6 position.     

Rational or statistical routes from 1-acyldipyrromethanes to meso-substituted porphyrins. Distinct patterns, multiple pyridyl substituents, and amphipathic architectures

New methodology is described for the synthesis of porphyrins bearing four (A 4, cis-A 2B 2, cis-ABC 2, trans-A 2B 2) or fewer (A, cis-AB, cis-A 2, trans-A 2) meso substituents. The method entails condensation of two 1-acyldipyrromethanes in the presence of a metal salt (MgBr 2, 3 mol equiv) and a noncoordinating base (DBU, 10 mol equiv) in a noncoordinating solvent (toluene) with heating (conventional or microwave irradiation) and exposure to air. The rational synthesis of trans-A 2B 2- or trans-A 2-porphyrins was achieved via condensation of two identical 1-acyldipyrromethanes. The statistical synthesis of various meso-substituted porphyrins was achieved via condensation of two nonidentical 1-acyldipyrromethanes. Both routes possess attractive features including (1) no scrambling, (2) good yield (up to 60%) at high concentration (100 mM) for the macrocycle-forming step, (3) reasonable scope (aryl, heteroaryl, alkyl, or no substituent), (4) short reaction time ( approximately 2 h) via microwave irradiation, (5) magnesium porphyrins as the products, which easily undergo demetalation, and (6) facile chromatographic purification. A key advantage of the statistical route is to obtain a cis-substituted porphyrin without the corresponding trans isomer. For example, reaction of an A/B-substituted 1-acyldipyrromethane and the fully unsubstituted 1-formyldipyrromethane gave the magnesium chelates of three porphyrins: the trans-A 2B 2-porphyrin, the "hybrid" cis-AB-porphyrin, and porphine (no trans-AB-porphyrin can form), which were readily demetalated and separated as the free base species. Altogether 26 1-acyldipyrromethanes and 26 target porphyrins have been prepared, including many with two different pyridyl substituents. One set of amphipathic porphyrins includes cis-A 2B 2- or cis-A 2BC-porphyrins wherein A = pentyl and B/C = pyridyl ( o-, m-, p-). Taken together, the rational and statistical routes enable facile conversion of readily available 1-acyldipyrromethanes to diverse porphyrins bearing 1-4 meso substituents for which access is limited via other methods.     

Xanthene-modified and hangman iron corroles

Iron corroles modified with a xanthene scaffold are delivered from easily available starting materials in abbreviated reaction times. These new iron corroles have been spectroscopically examined with particular emphasis on defining the oxidation state of the metal center. Investigation of their electronic structure using (57)Fe Mo?ssbauer spectroscopy in conjunction with density functional theory (DFT) calculations reveals the non-innocence of the corrole ligand. Although these iron corroles contain a formal Fe(IV) center, the deprotonated corrole macrocycle ligand is one electron oxidized. The electronic ground state of these complexes is best described as an intermediate spin S = 3/2 Fe(III) site strongly antiferromagnetically coupled to the S = 1/2 of the monoradical dianion corrole [Fe(III)Cl-corrole(+?)]. We show here that iron corroles as well as xanthene-modified and hangman xanthene iron corroles are redox active and catalyze the disproportionation of hydrogen peroxide via the catalase reaction, and that this activity scales with the oxidation potential. The meso position of corrole macrocycle is susceptible toward nucleophilic attack during catalase turnover. The reactivity of peroxide within the hangman cleft reported here adds to the emerging theme that corroles are good at catalyzing two-electron activation of the oxygen-oxygen bond in a variety of substrates.     

Modification of polysulfones by click chemistry: Amphiphilic graft copolymers and their protein adsorption and cell adhesion properties

Well‐defined amphiphilic graft copolymer with hydrophobic polysulfone (PSU) backbone and hydrophilic poly(acrylic acid) (PAA) side chains were synthesized and characterized. For this purpose, commercially available PSU was converted to azido‐functionalized polymer (PSU‐N₃) by successive chloromethylation and azidation processes. Independently, poly(tert‐butyl acrylate) (PtBA) with an alkyne‐end‐group is obtained by using suitable initiator in atom transfer radical polymerization (ATRP). Then, this polymer was successfully grafted onto PSU‐N₃ by click chemistry to yield polysulfone‐graft‐poly(tert‐butyl acrylate), (PSU‐g‐PtBA). Finally, amphiphilic polysulfone‐graft‐poly(acrylic acid), (PSU‐g‐PAA), membranes were obtained by hydrolyzing precursor the PSU‐g‐PtBA membranes in trifluoroacetic acid. The final polymer and intermediates at various stages were characterized by ¹H NMR, FTIR, GPC, and SEM analyses. Protein adsorption and eukaryotic and prokaryotic cell adhesion on PSU‐g‐PAA were studied and compared to those of PSU‐g‐PtBA and unmodified PSU. © 2010 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2010     

Biosensing approach for glutathione detection using glutathione reductase and sulfhydryl oxidase bienzymatic system

Chitosan membrane with glutathione reductase and sulfhydryl oxidase (SOX) was subsequently integrated onto the surface of spectrographic graphite rods for obtaining a glutathione biosensor. The working principle was based on the monitoring of O₂ consumption that correlates the concentration of glutathione during the enzymatic reaction. A linear relationship between sensor response and concentration was obtained between 0.5 and 2.0 mM for oxidized glutathione (GSSG), and 0.2–1.0 mM for reduced glutathione (GSH) in the presence of 2 μM nicotinamide adenine dinucleotide phosphate (NADPH) under the optimum working conditions. Also, reduced/oxidized glutathione were separated by HPLC and utility of bienzymatic system was investigated as an electrochemical detector for the analysis of these compounds. All data were given as a comparison of two systems: biosensor and diode array detector (DAD).     

Simple model for the growth behaviour of mixed lecithin-bile salt micelles

Mixed lecithin-bile salt micelles are known to have a cylindrical or worm-like structure. We investigated their shape, length, flexibility and cross-sectional structure using small-angle neutron scattering (SANS). A broad range of sample compositions was studied varying both the total amphiphile concentration and the molar ratio of bile salt (sodium taurochenodeoxycholate, NaTCDC) to lecithin (egg yolk phosphatidylcholine, EYL). The length of the micelles was quantitatively linked to the micellar composition by introducing a simple model. The model takes into account the partitioning of lecithin and bile salt between the bulk, cylindrical parts and the end caps of the micelles. The model also sheds light on the organization of the micelles, both in their cylindrical regions and end caps.     

FT-IR, FT-Raman vibrational spectra and molecular structure investigation of 2-chloro-4-methylaniline: A combined experimental and theoretical study

In this work, the experimental and theoretical vibrational spectra of 2-chloro-4-methylaniline (2Cl4MA, C₇H₈NCl) were studied. FT-IR and FT-Raman spectra of 2Cl4MA in the liquid phase have been recorded in the region 4000–400 cm⁻¹ and 3500–50 cm⁻¹, respectively. The structural and spectroscopic data of the molecule in the ground state have been calculated by using Hartree-Fock (HF) and density functional method (B3LYP) with the 6-31G(d), 6-31G(d,p), 6-31+G(d,p), 6-31++G(d,p) and 6-311G(d), 6-311G(d,p), 6-311+G(d,p), 6-311++G(d,p) basis sets. The vibrational frequencies have been calculated and scaled values have been compared with experimental FT-IR and FT-Raman spectra. The observed and calculated frequencies are found to be in good agreement. The complete assignments were performed on the basis of the total energy distribution (TED) of the vibrational modes, calculated with scaled quantum mechanics (SQM) method. The DFT-B3LYP/6-311++G(d,p) calculations have been found more reliable than the ab initio HF/6-311++G(d,p) calculations for the vibrational study of 2Cl4MA. The optimized geometric parameters (bond lengths and bond angles) were compared with experimental values of aniline and p-methylaniline molecules.     

New Amperometric Cholesterol Biosensors Using Poly(ethyleneoxide) Conducting Polymers

Accumulation of cholesterol in human blood can cause several health problems such as heart disease, coronary artery disease, arteriosclerosis, hypertension, cerebral thrombosis, etc. Therefore, simple and fast cholesterol determination in blood is clinically important. In this study, two types of amperometric cholesterol biosensors were designed by physically entrapping cholesterol oxidase in conducting polymers; thiophene capped poly(ethyleneoxide)/polypyrrole (PEO-co-PPy) and 3-methylthienyl methacrylate-co-p-vinyl benzyloxy poly(ethyleneoxide)/polypyrrole (CP-co-PPy). PEO-co-PPy and CP-co-PPy were synthesized electrochemically and cholesterol oxidase was immobilized by entrapment during electropolymerization. The amperometric responses of the enzyme electrodes were measured by monitoring oxidation current of H₂O₂ at +0.7 V in the absence of a mediator. Kinetic parameters, such as Km and Imax, operational and storage stabilities, effects of pH and temperature were determined for both entrapment supports. Km values were found as 1.47 and 5.16 mM for PEO-co-PPy and CP-co-PPy enzyme electrodes, respectively. By using these Km values, it can be observed that ChOx immobilized in PEO-co-PPy shows higher affinity towards the substrate.     

A new dinuclear copper (II) complex of 2,5–Furandicarboxyclic acid with 4(5)‐Methylimidazole as a high potential α‐glucosidase inhibitor: Synthesis,Crystal structure,Cytotoxicity study,and TD/DFT calculations

A new dinuclear copper (II) complex of 2,5–furandicarboxyclic acid with 4(5)‐methylimidazole, [Cu (FDCA)((4(5)MeI)₂]₂·2H₂O, was synthesized, and its structure characterized by XRD, FT–IR and UV–Vis spectroscopic techniques. The α‐glucosidase inhibition and cytotoxicity study of the synthesized Cu (II) complex were determined by IC₅₀ values. The optimized geometry and vibrational harmonic frequencies for the Cu (II) complex were obtained by using Density Functional Theory (DFT) of HSEh1PBE/6–311++G(d,p)/LanL2DZ level. TD‐DFT/HSEh1PBE/6–311++G(d,p)/LanL2DZ level with CPCM model was applied to examine the electronic spectral properties and major contributions were determined via Swizard program. To investigate linear and nonlinear optical behavior of the synthesized Cu (II) complex, the α, Δα and χ⁽¹⁾/β, γ and χ⁽³⁾ parameters called linear/nonlinear optical parameters in gas phase and ethanol solvent were computed at the same level and basis set. Furthermore, molecular electrostatic potential (MEP) surface was determined by using the same level. The docking study of the Cu (II) complex to the binding site of the target protein (the template structure S. cerevisiae isomaltase) is fulfilled. Natural bond orbital (NBO) analysis was used to investigate the hyperconjugative interactions, inter‐ and intra‐molecular bonding and to determine coordination around Cu (II) ion. Finally, present work is the first remarkable scientific report of mixed‐ligand (H₂FDCA and 4(5)MeI) Cu (II) complex as novel drug candidate for DM II. It is also determined that microscopic third?NLO parameters for the Cu (II) complex is remarkable.     

Improving the Antibacterial Property of Polyethylene Terephthalate by Cold Plasma Treatment

Many studies suggest strong hydrophilicity of plasma treated polyester surfaces. However, no studies have been reported on the influence of plasma on the antibacterial activity of polyethylene terephthalate. First samples were padded with triclosan as antibacterial agent with different concentrations. Second samples were treated by oxygen plasma with different operating frequency and treating time, respectively. Afterwards, plasma treated samples were padded with triclosan in same conditions. The results revealed that the antibacterial activity slighlty increased after treating with triclosan. SEM images and FTIR spectra showed that horizontal channels were brought about on the fiber surface and then better surface roughness and wettability were obtained by plasma. Fibers were fully coated with triclosan after plasma and the antibacterial activity increased with increasing operating frequency and reaction time. Finally, the samples treated with triclosan after plasma gave acceptable results and showed the best antibacterial activity for Staphylococcus aureus and Escherichia coli.