Molecular structure of 2-Amino-5-(1-methyl-5-nitro-2-imidazolyl)-1,3,4-thiadiazol (Megazol) and related compounds: A concerted study using X-ray crystallography,molecular mechanics,and semiempirical methods

A structural study of three nitroimidazoles was carried out using molecular mechanics, semiempirical methods, and X-ray crystallography. Structural features which might account for the high efficiency of1 (Megazol) as an antiparasitic drug and its opposite, the inactivity of its regiomers2 and3 were examined, i.e., coplanarity of the two rings, preferred conformations, and rotational barriers around the pivot bond between the two rings. For the three compounds an antiperiplanar conformation is preferred for the N(CH₃) and C-S bonds. For compounds1 and3, the rings are coplanar, with2 being somewhat twisted. The geometry obtained by molecular mechanics for compound1 is in excellent agreement with the X-ray structure, and greater confidence can be placed in this method than in semiempirical ones. Similarities observed on the LUMO positions, as well as rotational barriers lead to the conclusion that the differences in biological activity of these compounds do not rely on their ground state properties but rather on their subsequent reactions with oxygen. In addition, the calculations revealed significant structural information of a family of biological importance (nitroimidazoles) and constitute a comparative test for the MM2, AM1, and PM3 methods.     

Hydrogen bonding or deprotonation: on fluoride ion fluorescence sensing with 1,1′-bi-2-naphthol derivatives

The isolation and structural characterisation of two ionic complexes (S)-3 and(S)-4 based on fluoride ion-mediated deprotonation of 1,1′-bi-2-naphthol (BINOL) derivatives (S)-1 and (S)-2 have been carried out for the first time. X-ray crystallographic study showed that the deprotonated forms (S)-3 and (S)-4 adopt remarkably different molecular geometries, bond parameters as well as molecular packing modes from their neutral analogs, in agreement with their significant fluorescence changes upon the addition of fluoride ion, giving insights into the actual mechanism of fluoride ion fluorescence sensing. The deprotonation–protonation processes in two BINOL derivatives were also investigated by both fluorescence measurements and X-ray structural analyses. Such chiral basic compounds can be promising organocatalysts for asymmetric reactions.     

CHEMO-ENZYMATIC SYNTHESIS AND CHARACTERIZATION OF NOVEL FUNCTIONALIZED AMPHIPHILIC POLYMERS

ABSTRACT

The condensation copolymerization of Dimethyl 5-hydroxyisophthalate (1) with Polyethylene glycols (PEGs) (2a–2d) of varying molecular weights, catalyzed by Novozyme-435 (immobilized Candida antarctica lipase B) in bulk is reported. The structures of the resulting polymers, Poly[(poly(oxyethylene)-oxy-5-hydroxyisophthaloyl] (3a–3c) were characterized by ¹H (1D and 2D) and ¹³C-NMR spectroscopic experiments. Further, these polymers have been derivatized by attaching decanyl and 12-hydroxydodecanyl chains to the phenolic hydroxyl group. The resulting amphiphilic polymeric systems were characterized by detailed spectroscopic analysis. Light Scattering Photometry as well as Gel Per meation Chromatography were used to evaluate the particle size and molecular weights of the polymers. In principle, the method developed is flexible so that it can be used to generate a wide array of functionalized amphiphilic polymers. In the absence of biocatalytic transformation, such structural control would be extremely difficult or currently impossible to obtain.     

Supramolecular complexes based on cyclodextrins

A summary of the application of cyclodextrins (CDs) in the field of supramolecular chemistry has been given. Unique structural features of CDs, namely the separation of hydrophilic and hydrophobic groups, cause unusual physical and chemical properties of these molecules. The most important property of natural or chemically modified CDs is the ability to reversibly and selectively bind organic, inorganic, and biological molecules, forming inclusion complexes (ICs) of the “guest-host” type or nanostructured supramolecular assemblies. The most interesting examples of the application of ICs with CDs in pharmaceutical, food, and chemical industry, spectrometric analysis, separation technologies, of the use of CDs as models for molecular recognition in biology, as well as the cyclical component in the construction of supramolecular architectures (rotaxanes, pseudorotaxanes) are given in the review. The mechanism and methods of the formation of ICs, their properties and the methods of analysis have been described. Particular attention has been paid to molecular necklaces. One of the new promising directions of the application of CDs, namely, the preparation of nanosized materials, has been considered.     

Studies on molecular mechanism between SHP2 and pyridine derivatives by 3D-QSAR,molecular docking and MD simulations

BackgroundSrc homology 2 (SH2)-containing protein tyrosine phosphatase 2 (SHP2) as a major phosphatase would affect the development of tumors by regulating several cellular processes, and is a significant potential target for cancer treatment.MethodsIn the present work, a series of pyridine derivatives possessing a wide range of inhibitory activity was employed to investigate the structural requirements by developing three dimensional quantitative structure–activity relationship (3D-QSAR) models using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) methods. The results show that CoMFA (R²_cv = 0.646, R²_pred = 0.5587) and CoMSIA (R²_cv = 0.777, R²_pred = 0.7131) have excellent stability and predictability. The relationship between the inhibitory activity and structure of the inhibitors was analyzed by the derived contour maps. Furthermore, the QSAR models were validated by molecular docking and molecular dynamics simulations, which were also applied to reveal the potential molecular mechanism of these inhibitors.FindingsIt was found that Arg110, Asn216, Thr218, Thr252 and Pro490 play a crucial role in stabilizing the inhibitors. Additionally, MM/PBSA calculations provided the binding free energy were also conducted to explain the discrepancy of binding activities. Overall, the outcomes of this work could provide useful information and theoretical guidance for the development of novel and potent SHP2 inhibitors.     

In silico study directed towards identification of the key structural features of GyrB inhibitors targeting MTB DNA gyrase: HQSAR,CoMSIA and molecular dynamics simulations

ABSTRACT

Mycobacterium tuberculosis DNA gyrase subunit B (GyrB) has been identified as a promising target for rational drug design against fluoroquinolone drug-resistant tuberculosis. In this study, we attempted to identify the key structural feature for highly potent GyrB inhibitors through 2D-QSAR using HQSAR, 3D-QSAR using CoMSIA and molecular dynamics (MD) simulations approaches on a series of thiazole urea core derivatives. The best HQSAR and CoMSIA models based on IC₅₀ and MIC displayed the structural basis required for good activity against both GyrB enzyme and mycobacterial cell. MD simulations and binding free energy analysis using MM-GBSA and waterswap calculations revealed that the urea core of inhibitors has the strongest interaction with Asp79 via hydrogen bond interactions. In addition, cation-pi interaction and hydrophobic interactions of the R₂ substituent with Arg82 and Arg141 help to enhance the binding affinity in the GyrB ATPase binding site. Thus, the present study provides crucial structural features and a structural concept for rational design of novel DNA gyrase inhibitors with improved biological activities against both enzyme and mycobacterial cell, and with good pharmacokinetic properties and drug safety profiles.     

Analysis of Ah receptor binding affinities of polybrominated diphenyl ethers via in silico molecular docking and 3D-QSAR

Polybrominated diphenyl ethers (PBDEs) have become ubiquitous contaminations due to their use as flame retardants. The structural similarity of PBDE to some dioxin-like compounds suggested that they may share similar toxicological effects: they might activate the aryl hydrocarbon receptor (AhR) signal transduction pathway and thus might have adverse effects on wildlife and humans. In this study, in silico computational workflow combining molecular docking and three-dimensional quantitative structure–activity relationship (3D-QSAR) was performed to investigate the binding interactions between PBDEs and AhR and the structural features affecting the AhR binding affinity of PBDE. The molecular docking showed that hydrogen-bond and hydrophobic interactions were the major driving forces for the binding of ligands to AhR, and several key amino acid residues were also identified. The CoMSIA model was developed from the conformations obtained from molecular docking and exhibited satisfactory results as q ² of 0.605 and r ² of 0.996. Furthermore, the derived model had good robustness and statistical significance in both internal and external validations. The 3D contour maps generated from CoMSIA provided important structural features influence the binding affinity. The obtained results were beneficial to better understand the toxicological mechanism of PBDEs.     

Structural Relationships and Theoretical Study of Electron Transfer Properties of 1,3,2-Dithiazolyl Radicals with Fullerenes in Nanostructure [1,3,2-DTA(s)]@Cn Supramolecular Complexes

Various empty carbon fullerenes with different carbon atoms have been obtained and investigated. The dithiazolyl radicals have shown important electron-transfer properties. Topological indices are digital values that are assigned based on chemical composition. These values are purported to correlate chemical structures with various chemical and physical properties. They have been successfully used to construct effective and useful mathematical methods to establish clear relationships between structural data and the physical properties of these materials. In this study, the number of carbon atoms in the fullerenes was used as an index to establish a relationship between the structures of 2,3-naphthalene-1,3,2-dithiazolyl (NDTA), 2,3-quinoxaline-1,3,2-dithiazolyl (QDTA), and 1,2,5-thiazolo[3,4-b]-1,3,2-dithiazolo[3,4-b]pyridazin-2-yl (TDP-DTA), radicals, 1–3 as molecular conductor radicals and fullerenes C_n (n = 60, 70, 76, 82, and 86), which create [1,3,2-DTA(s)]@C_n, A-1 to A-5 (NDTA]@C_n), B-1 to B-5 ([QDTA]@C_n), and C-1 to C-5 ([TDP-DTA]@C_n). The relationship between the number of carbon atoms and the free energies of electron transfer (ΔG_et(1) to ΔG_et(4) ) are assessed using the Rehm–Weller equation for A-1 to A-5, B1 to B-5, and C-1 to C-5 supramolecular [1,3,2-DTA(s)]@C_n complexes. Calculations are presented for the four reduction potentials ( ^Red.E₁ to ^Red.E₄ ) of fullerenes C_n . The results were used to calculate the four free energies of electron transfer (ΔG_et(1) to ΔG_et(4) ) of supramolecular complexes A-1 to A-18, B-1 to B-18, and C-1 to C-18 (5–60) for fullerenes C₆₀ to C₃₀₀.     

Network pharmacology analysis of Chaihu Lizhong Tang treating non-alcoholic fatty liver disease

BackgroundIn this study, the network pharmacological methods were used to predict the target of active components of Chaihu Lizhong Tang (CHLZT) in the treatment of non-alcoholic fatty liver disease (NAFLD).MethodThe active components of "CHLZT", their targets, and NAFLD related targets were screened by multiple databases, and the potential targets of "CHLZT" in the treatment of NAFLD were predicted. The active component-target network of "CHLZT" was constructed by Cytoscape software. The potential target of "CHLZT" for the treatment of NAFLD constructed protein-protein interaction (PPI) network in the Search Tool for the Retrieval of Interacting Genes Database (STRING). The hub genes of “CHLZT” in the treatment of NAFLD were screened by network topological parameters, and the results were verified by molecular docking. "ClusterProfiler" in R was used for Gene Ontology (GO) analysis and KEGG pathway enrichment analysis.ResultsOB ≥ 30 % and DL ≥ 0.18 were selected as the screening criteria of active components. A total of 83 active components and 456 targets were selected. Based on the evaluation of topological parameters of degree network, five hub genes for interaction with "CHLZT" therapy for NAFLD were screened, that is, AKT1, ALB, IL6, EGFR, and CASP3. The results of molecular docking showed that the active components in "CHLZT" had a good binding ability with the key targets. The enrichment analysis results showed that the treatment of NAFLD with "CHLZT" mainly involved in cofactor binding, protease binding, AGE-RAGE signaling pathway in diabetic complications, and IL-17 signaling pathway, which mediated the potential mechanism of "CHLZT" intervention in NAFLD.ConclusionThe molecular mechanism of "CHLZT" in the treatment of NAFLD indicated the synergistic features of multi-component, multi-target, and multi-pathway of traditional Chinese medicine, which provided an important scientific basis for further elucidating the mechanism of "CHLZT" in the treatment of NAFLD.     

RADICAL POLYMERIZATION OF METHYL METHACRYLATE WITH DIPHENYL DISELENIDE UNDER THERMAL OR PHOTOIRRADIATIONAL CONDITIONS

Polymerization of methyl methacrylate (MMA) with diphenyl diselenide (DPDSE) in the presence of AIBN at 60°C was investigated. DPDSE was worked as a chain transfer agent (CTA). The chain transfer constant (C_tr) of DPDSE for MMA was estimated to be 1.43. On the other hand, DPDSE was functioned as a photoiniferter for the photopolymerization of MMA. In a limited range of conversion, both the polymer yield and number average of molecular weight ([Mbar]_n) increased with the reaction time, and the [Mbar]_n linearly increased with the yield. The terminal structure of poly(MMA) was investigated by the ⁷⁷Se NMR spectrum based on Methyl α-phenylseleno isobutylate (MSEPI) as model compound of the ω-chain end of poly(MMA). Further, photopolymerization of poly (MMA) containing phenylseleno group at ω-chain end as a polymeric photoiniferter with MMA effectively afforded a poly (MMA) having higher molecular weight.     

Identification of Chlorinated Phenyl and Phenoxy Substituted Dibenzodioxin,Dibenzofuran, and Diphenyl Ether Homologs in Commercial Grade Pentachlorophenol

Abstract

As part of a bioassay study by the National Toxicology Program, technical grade pentachlorophenol (PCP) was analyzed for chlorinated impurities using capillary gas chromatography/mass spectrometry (GC/MS). Several high molecular weight impurities eluting after octachlorodibenzodioxin were detected during the analysis of this material. These impurities were tentatively identified according to structural classes as chlorinated triphenyl ethers, dibenzodioxin phenyl ethers, phenyldibenzodioxins, and dibenzofuran phenyl ethers.     

Aliphatic Polyester Blends Based upon Poly(Lactic Acid) and Oligomeric Poly(Hexamethylene Succinate)

Abstract

In an attempt to gain a degree of control over the mechanical and degradation properties of poly(lactic acid) [PLA], large-scale efforts are underway to alter the phase morphology of PLA through chemical and physical modification. Consistent with this theme, our work aims to adjust the molecular architecture of highly amorphous PLA with an increasing concentration of hydroxy-terminated oligomeric poly(hexamethylene succinate) [PHS]. Gel-permeation chromatography (GPC) verifies the enhanced presence of PHS in the blends with a concomitant reduction in number-average molecular weight as the weight fraction of PHS is raised from 0.10 to 0.40. Differential scanning calorimetry (DSC) indicates amorphous phase compatibility between PHS and PLA at weight compositions of 10/90 and 20/80. However, as the amount of PHS approaches 30 and 40 wt%, the PHS exhibits the ability to crystallize independently from the induced PLA crystalline phase. Dynamic mechanical thermal analysis (DMTA) illustrates variable behavior of the materials under tension as a consequence of structural alterations generated by the oligoester. Finally, preliminary results suggest that these alterations may suppress the hydrolytic degradation of PLA.     

Self-Assembly of Alkylammonium Chains on Montmorillonite: Effect of Interlayer Cations,CEC, and Chain Length

Recently, polymeric materials have been filled with synthetic or natural inorganic compounds in order to improve their properties. Especially, polymer clay nanocomposites have attracted both academic and industrial attention. Currently, the structure and physical phenomena of organoclays at molecular level are difficultly explained by existing experimental techniques. In this work, molecular dynamics (MD) simulation was executed using the CLAYFF and CHARMM force fields to evaluate the structural properties of organoclay such as basal spacing, interlayer density, energy and the arrangement of alkyl chains in the interlayer spacing. Our results are in good agreement with available experimental or other simulation data. The effects of interlayer cations (Na⁺, K⁺, Ca²⁺), the cation exchange capacity, and the alkyl chain length on the basal spacing and the structural properties are estimated. These simulations are expected to presage the microstructure of organo-montmorillonite and lead relevant engineering applications.     

A reversible fluorescence “ON–OFF–ON” sensor for sequential detection of F− and Cu2+ ions and its application as a molecular-scale logic device and security keypad lock

A new azoimine receptor, R₁, was synthesized by Schiff base condensation of 4-(4-butylphenyl) azophenol and 2,6-diaminopyridine and acts as a colorimetric and fluorometric chemosensor for F^? and also toward Cu²⁺ ions in aqueous environment. UV–Vis absorption and fluorescent emission spectra were employed to study the sensing process. Emission study was performed to examine the dual sensing ability of the obtained probe with sequential addition of F^? followed by Cu²⁺ and vice versa. The receptor is an efficient “ON–OFF” fluorescent probe for the fluoride ion. Also, R₁ + F^? operated as an “OFF–ON” fluorescent sensor for Cu²⁺ ions. Considering emission intensity and absorption wavelength for F^? and Cu²⁺ ions, a molecular system was developed with the ability to mimic the functions of XNOR logic gating on the molecular level. In addition, R₁ behaved as a molecular security keypad lock with F^? and Cu²⁺ inputs. The keypad lock operation is particularly important, as the output of the system depends not only on the proper combination but also on the order of input signals, creating the correct password that can be used to “open” this molecular keypad lock through strong fluorescence emission at 460?nm.