Artificial polymeric flavonoids: synthesis and applications

Flavonoids, one of the most numerous and best studied groups of plant polyphenols, are well known to exhibit various biological and pharmacological effects. Functional artificial polymeric flavonoids, flavonoid polymers and amine containing polymer-flavonoid conjugates have been developed. The acid-catalyzed polymerization of catechin and aldehydes proceeds regioselectively to produce catechin-aldehyde polycondensates. Peroxidases and laccases catalyze the oxidative coupling of flavonoids and oxidative conjugation with polyamines. The resulting polymers show much higher antioxidant activities than the flavonoid monomers. In addition, these polymeric flavonoids efficiently inhibit disease related enzymes, such as xanthine oxidase, collagenase, elastase, hyaluronidase and tyrosinase. Based on these results, the molecular design for amplification of the biological and pharmacological properties of flavonoids is proposed.     

Molecular docking studies,structural and spectroscopic properties of monomeric and dimeric species of benzofuran-carboxylic acids derivatives: DFT calculations and biological activities

Structural optimization, molecular docking analysis, electronic and vibrational properties have been investigated for the 1-benzofuran-2-carboxylic acid (2BF) and 1-benzofuran-3-carboxylic acid (3BF) using DFT/B3LYP/6-311++G(d,p) level of theory. The theoretical parameters have a very good consistency with the experimental ones. The weak intermolecular interactions were analyzed by different tool such as: Hirshfeld surfaces, topological analysis and natural bond orbital studies. The nonlinear optical properties have been investigated. Molecular electrostatic potential and frontier molecular orbitals (FMOs) analysis have been carried out to understand the reactivity of the molecule. In addition, TD-DFT calculation is initiated to simulate the UV–vis absorption spectrum and to determine several important electronic properties like HOMO-LUMO gap energy and electronic transitions. The complete vibrational assignments and the force constants were reported for monomer and dimers of both acids. The biological activities of the tow acids have been studied via molecular docking analysis. The later calculations prove that the studied acids have an inhibitor effect against cancer and microbial diseases.     

Molecular structure–biological activity relationships on the basis of quantum-chemical calculations

Detailed quantum-chemical calculations by means of semiempirical all-valence electrons methods and a generalized (multivariable) rank correlation analysis are the fundamentals of a novel strategy of search for QSAR within homologous series of compounds. The set of molecular parameters (describing the electronic and conformational properties as well as potential interactions of the drugs) is calculated theoretically. Owing to the rank correlation method, no linear model (like LFER ) for the dependence of the biological activity upon the molecular parameters is presumed. The computed correlation coefficients are valued by carefully determined levels of statistical significance. Significant correlations are used to predict unknown activities in terms of ranks relative to the basic sample.     

Microwave-Assisted One Pot Three-Component Synthesis of Novel Bioactive Thiazolyl-Pyridazinediones as Potential Antimicrobial Agents against Antibiotic-Resistant Bacteria

Pyridazine and thiazole derivatives have various biological activities such as antimicrobial, analgesic, anticancer, anticonvulsant, antitubercular and other anticipated biological properties. Chitosan can be used as heterogeneous phase transfer basic biocatalyst in heterocyclic syntheses. Novel 1-thiazolyl-pyridazinedione derivatives were prepared via multicomponent synthesis under microwave irradiation as ecofriendly energy source and using the eco-friendly naturally occurring chitosan basic catalyst with high/efficient yields and short reaction time. All the prepared compounds were fully characterized by spectroscopic methods, and their in vitro biological activities were investigated. The obtained results were compared with those of standard antibacterial/antifungal agents. DFT calculations and molecular docking studies were used to investigate the electronic properties and molecular interactions with specific microbial receptors.     

A theoretical study on electronic structure and structure–activity properties of novel drug precursor 6‐acylbenzothiazolon derivatives

In this work, electronic properties and structure–activity relationship (SAR) parameters of 20 novel drug precursor 6‐acylbenzothiazolon derivatives with analgesic activity have been investigated theoretically by performing Austin Model‐1 (AM1) and DFT‐B3LYP/6‐31G (d) calculations with the aim to correlate the properties of each substance—particularly electronic properties and SAR parameters—with the biological interactions that are linked to their pharmacological effects. Their molecular properties were related to the biological activity of these drug precursor molecules. The relationship between octanol–water partition coefficient (log P) and each of the SAR parameters [E_LUMO–HOMO, molecular volume (V_m), ionization potential (IP), electron affinity, electronegativity (χ), chemical hardness (η), chemical softness (S), electrophilic index (ω), and molar refractivity] present linear correlation except for IP and χ. This result suggests that there are future prospects for designing or developing new drugs based on the correlation between the theoretically calculated parameters. According to AM1 calculation, the values of heat of formation of 6‐acylbenzothiazolon derivatives are negative (exothermic), which shows that these molecules are thermodynamically stable. E_LUMO–HOMO energy levels of the studied molecules are 4–5 eV, which also indicate that they are kinetically unstable. © 2011 Wiley Periodicals, Inc. Int J Quantum Chem, 2011     

Enhanced Detection and Structural Characterization of Flavonoids by Complexation with N,O-Bis(trimethysilyl)trifluoroacetamide Using Electrospray Ionization Mass Spectrometry

Many natural products contain flavonoids that display biological effects when ingested by humans and animals. Flavonoids have received a great deal of research interest, especially for possible cancer and heart disease-preventive properties. The content and the quality of each flavonoid may be a key to their biological effects. The recent development of electrospray ionization mass spectrometry (ESI-MS/MS) has made it possible to use it to study molecular interactions. In the present work, we investigated the derivatization procedures for three flavonoids (chrysin, genistein, and luteolin) by using ESI-MS/MS. Each flavonoid and the derivatization reagent, N,O-bis(trimethylsilyl)trifluoroacetamide (BSTFA), are mixed using acetonitrile and the mixture is introduced through an electrospray needle. The signal intensities for the derivative ions significantly increased, almost two or three orders of magnitude increased as compared to those for the protonated molecular ions of the flavonoids. Mass spectra of trimethylsilyl derivatives are fragmented at a fixed pattern by collision induced dissociation to obtain the structural relevance of the derivative flavonoids. Further fragmentation studies have been performed and results are discussed in detail. The results in the positive mode detection show that better high intensity data and more simplification of peaks appeared than that for the underivatized cases.     

Effect of green solvents physical,chemical, biological and bonding nature on 5-acetyl-thiophene-2-carboxylic acid by DFT and TD-DFT approach – An antiviral agent

The density functional theory (DFT) is applied to 5-acetyl-thiophene-2-carboxylic acid (5AT2CA). To determine the optimal structure and different physical, chemical, and biological characteristics, the B3LYP technique and 6–311++G(d,p) basis set are employed. The binding energies and ellipticity are determined using the atoms in molecules theory (AIM). NBO analysis is used to study the exchanges between the contributor and receiver by energies. By utilizing HOMO-LUMO values and important electronic parameters, stability is determined. The molecular electrostatic potential (MEP) and Fukui function from Mulliken charges are used to determine the reactive regions of the molecule. The TD-DFT technique obtains the electronic transition using UV–Vis spectrum with various solvents. NLO studies were carried out on this molecule. Studies of temperature effect on 5AT2CA are done by thermodynamic parameters. Drug-likeness and molecular docking tests are used to evaluate the bioactivity and antiviral properties.     

噻吩低聚物分子器件电输运特性的理论研究

Based on the first-principles computational method and the elastic scattering Green's func-tion theory, we have investigated the electronic transport properties of different oligothio-phene molecular junctions theoretically. The numerical results show that the difference of geometric symmetries of the oligothiophene molecules leads to the difference of the contact configurations between the molecule and the electrodes, which results in the difference of the coupling parameters between the molecules and electrodes as well as the delocalization properties of the molecular orbitals. Hence, the series of oligothiophene molecular junctions display unusual conductive properties on the length dependence.     

Structure-activity relationships in 3-isothiazolones

The biological activity of a series of structurally diverse 3-isothiazolones (1) has been assessed by evaluating the minimum inhibitory concentration required to inhibit the growth of E. Coli. The structure and electronic properties of these derivatives have been calculated using both semi-empirical and ab initio molecular orbital methods. Multi-linear regression analysis shows no correlation between the experimental activity of the 3-isothiazolones and either the calculated geometries, electronic properties, or the frontier orbital energies of these derivatives, but a reasonable relationship is found with other parameters including their calculated solvation energies, suggesting that diffusion may play an important role in their mode of action.     

Metabolic Engineering of Microbial Cell Factories for Biosynthesis of Flavonoids: A Review

Flavonoids belong to a class of plant secondary metabolites that have a polyphenol structure. Flavonoids show extensive biological activity, such as antioxidative, anti-inflammatory, anti-mutagenic, anti-cancer, and antibacterial properties, so they are widely used in the food, pharmaceutical, and nutraceutical industries. However, traditional sources of flavonoids are no longer sufficient to meet current demands. In recent years, with the clarification of the biosynthetic pathway of flavonoids and the development of synthetic biology, it has become possible to use synthetic metabolic engineering methods with microorganisms as hosts to produce flavonoids. This article mainly reviews the biosynthetic pathways of flavonoids and the development of microbial expression systems for the production of flavonoids in order to provide a useful reference for further research on synthetic metabolic engineering of flavonoids. Meanwhile, the application of co-culture systems in the biosynthesis of flavonoids is emphasized in this review.     

Analysis of flavonoids: tandem mass spectrometry, computational methods, and NMR

Due to the increasing understanding of the health benefits and chemopreventive properties of flavonoids, there continues to be significant effort dedicated to improved analytical methods for characterizing the structures of flavonoids and monitoring their levels in fruits and vegetables, as well as developing new approaches for mapping the interactions of flavonoids with biological molecules. Tandem mass spectrometry (MS/MS), particularly in conjunction with liquid chromatography (LC), is the dominant technique that has been pursued for elucidation of flavonoids. Metal complexation strategies have proven to be especially promising for enhancing the ionization of flavonoids and yielding key diagnostic product ions for differentiation of isomers. Of particular value is the addition of a chromophoric ligand to allow the application of infrared (IR) multiphoton dissociation as an alternative to collision-induced dissociation (CID) for the differentiation of isomers. CID, including energy-resolved methods, and nuclear magnetic resonance (NMR) have also been utilized widely for structural characterization of numerous classes of flavonoids and development of structure/activity relationships.The gas-phase ion chemistry of flavonoids is an active area of research particularly when combined with accurate mass measurement for distinguishing between isobaric ions. Applications of a variety of ab initio and chemical computation methods to the study of flavonoids have been reported, and the results of computations of ion and molecular structures have been shown together with computations of atomic charges and ion fragmentation. Unambiguous ion structures are obtained rarely using MS alone. Thus, it is necessary to combine MS with spectroscopic techniques such as ultraviolet (UV) and NMR to achieve this objective. The application of NMR data to the mass spectrometric examination of flavonoids is discussed.     

Quantum mechanical parametrization of a conformationally dependent hydrophobic index

An extension of our previous work on the development of a conformationally dependent hydrophobic index is presented. The parameter was computed in four alternative ways based on steric parameters, such as the total molecular surface area or the solvent accessible surface, and on quantum mechanically computed electronic properties, such as the molecular dipole moment, Mulliken charge densities, and a lone–pair index. The method was parametrized based on 110 rigid analogs and all properties required were calculated using the semiempirical methods PM 3, AM 1, and MNDO . Examples of the application of this method in calculating hydrophobic indices are presented.     

Polarizable empirical force field for sulfur‐containing compounds based on the classical Drude oscillator model

Condensed‐phase computational studies of molecules using molecular mechanics approaches require the use of force fields to describe the energetics of the systems as a function of structure. The advantage of polarizable force fields over nonpolarizable (or additive) models lies in their ability to vary their electronic distribution as a function of the environment. Toward development of a polarizable force field for biological molecules, parameters for a series of sulfur‐containing molecules are presented. Parameter optimization was performed to reproduce quantum mechanical and experimental data for gas phase properties including geometries, conformational energies, vibrational spectra, and dipole moments as well as for condensed phase properties such as heats of vaporization, molecular volumes, and free energies of hydration. Compounds in the training set include methanethiol, ethanethiol, propanethiol, ethyl methyl sulfide, and dimethyl disulfide. The molecular volumes and heats of vaporization are in good accordance with experimental values, with the polarizable model performing better than the CHARMM22 nonpolarizable force field. Improvements with the polarizable model were also obtained for molecular dipole moments and in the treatment of intermolecular interactions as a function of orientation, in part due to the presence of lone pairs and anisotropic atomic polarizability on the sulfur atoms. Significant advantage of the polarizable model was reflected in calculation of the dielectric constants, a property that CHARMM22 systematically underestimates. The ability of this polarizable model to accurately describe a range of gas and condensed phase properties paves the way for more accurate simulation studies of sulfur‐containing molecules including cysteine and methionine residues in proteins. © 2010 Wiley Periodicals, Inc. J Comput Chem, 2010     

2D-QSAR Studies on Triazolone Compounds Containing Benzenesulfonic Amide

The geometry structures of 6 triazolone compounds containing benzenesulfonic amide were fully optimized with DFT (Density Functional Theory) method at the B3LYP/6-31G level, and the structural and electronic parameters of the compounds were calculated. The hydrophobic and topological parameters of the title compounds were calculated by HyperChem software. The mono-and bi-parametric models between the parameters and biological activity of the compounds were analyzed by Multiple Linear Regression method based on Hansch-Fujita model. The results show that the activities of the title compounds were increased with higher hydrophobic property logP and molecular volume V, lower molecular energy ETOTAL and elec-tronegative of benzene ring Qph.     

Molecular and supramolecular control of the work function of an inorganic electrode with self-assembled monolayer of umbrella-shaped fullerene derivatives

The surface properties of inorganic substrates can be altered by coating with organic molecules, which may result in the improvement of the properties suitable for electronic or biological applications. This article reports a systematic experimental study on the influence of the molecular and supramolecular properties of umbrella-shaped penta(organo)[60]fullerene derivatives, and on the work function and the water contact angle of indium-tin oxide (ITO) and gold surfaces. We could relate these macroscopic characteristics to single-molecular level properties, such as ionization potential and molecular dipole. The results led us to conclude that the formation of a SAM of a polar compound generates an electronic field through intermolecular interaction of the molecular charges, and this field makes the overall dipole of the SAM much smaller than the one expected from the simple sum of the dipoles of all molecules in the SAM. This effect, which was called depolarization and previously discussed theoretically, is now quantitatively probed by experiments. The important physical properties in surface science such as work function, ionization potential, and water contact angles have been mutually correlated at the level of molecular structures and molecular orientations on the substrate surface. We also found that the SAMs on ITO and gold operate under the same principle except that the "push-back" effect operates specifically for gold. The study also illustrates the ability of the photoelectron yield spectroscopy technique to rapidly measure the work function of a SAM-covered substrate and the ionization potential value of a molecule on the surface.     

Ab initio assessment of the electronic structure of 5α-reduced progestins

Progesterone (P) yields to 5α-reduced progestins, namely 5α-pregnanedione (DHP), tetrahydroprogesterone (THP), and allopregnanolone (ALLO-P). The geometries and electronic structure of these steroids were assessed by ab initio calculations using the 6-31G* basis set. The parameters measured were bond distances, valence angles, and dihedral angles. Likewise, the following were calculated: total energy; frontier orbitals, i.e., highest occupied molecular orbital (HOMO); lowest unoccupied molecular orbital (LUMO); dipole moment; atomic charges; and electrostatic potentials. The frontier orbitals of P were located at the π-double bond. However, the HOMO of the 5α-progestins was extended into the molecule, while the LUMO was confined at the C20 carbonyl group. The atomic charges, electronic density surfaces and electrostatic potentials showed patterns according to the stereochemical arrangement of the C3 and C20 carbonyl and hydroxyl functional groups. Interestingly, P and THP showed the larger dipole moment and high electronic density at the A-ring because the double bond and the 3α-hydroxy group, respectively. The present results might explain to some extent the metabolism of the studied progestins. Similarly, some physicochemical properties, such as dipole moments and electrostatic potentials, seem related with important biological actions such as uterine contractility and control of gonadotropin secretion. © 1998 John Wiley & Sons, Inc. Int J Quant Chem 67: 329–338, 1998