Synthesis, spectroscopic characterization, DFT calculations, in silico-ADMET and molecular docking analysis of novel quinoline-substituted 5H-chromeno [2,3-b] pyridine derivatives as antibacterial agents.

A convenient, straightforward, and effective one-step reaction for the synthesis of a three-component compound of biologically relevant novel 2,4-diamino-5-(8-hydroxyquinolin-7-yl)-5H-chromeno[2,3-b] pyridine-3-carbonitrile derivatives was designed and synthesized. The synthesis was developed by the reaction between salicylaldehyde 1, 8-hydroxyquinoline 2, 2-aminopropene-1,1,3-tricarbonitrile 3, and the catalytic amount of triethylamine in ethanol at 78 °C. This methodology has many beneficial features, including the use of inexpensive and non-hazardous starting materials, single-flask reactions, optimized reaction conditions, the termination of intermediate isolation, easy workup, reducing organic waste products, being chromatography-free, and decreasing the reaction time along with quantitative yields with high functional group tolerance. A proposed mechanism with supporting experimental data is presented, including 1H NMR, 13C NMR, 2D NMR (HMBC, COSY, HSQC), mass, and IR spectroscopy, which are used to characterize the complete derivatives. All synthesized compounds were evaluated in vitro for their antibacterial activities against Bacillus subtilis, Staphylococcus aureus, Escherichia coli and Pseudomonas aeruginosa bacterial strains via the agar-well diffusion method compared with the reference drug gentamicin. The data indicated that compounds 4A, 4F, 4G, 4 J, and 4K consistently demonstrated strong antimicrobial activity against Gram-positive and Gram-negative bacteria. Furthermore, a molecular docking investigation was carried out to gain insight into the binding mode of the most promising compounds via the crystal structure of the S. aureus DNA gyrase complex with ciprofloxacin (PDB ID: 2XCT). Density functional theory (DFT) calculations were performed to determine the various molecular properties of the synthesized novel 2,4-diamino-5-(8-hydroxyquinolin-7-yl)-5H-chromeno [2,3-b] pyridine-3-carbonitrile derivatives (4A-4 M). On the basis of the reactive sites explored by the molecular electrostatic potential maps, the antibacterial activities of the compounds were screened.

Transition metals-doped g-C3N4 nanostructures as advanced photocatalysts for energy and environmental applications.

Graphitic carbon nitride (g-C3N4)-based heterostructured photocatalysts have received significant attention for its potential applications in the treatment of wastewater and hydrogen evolution. The utilization of semiconductor materials in heterogeneous photocatalysis has recently received great attention due to their potential and eco-friendly properties. Doping with metal ions plays a crucial role in altering the photochemical characteristics of g-C3N4, effectively enhancing photoabsorption into the visible range and thus improving the photocatalytic performance of doped photocatalysts. As an emerging nanomaterial, nanostructured g-C3N4 represents a visible light-active semiconducting photocatalyst that has attracted significant interest in the photocatalysis field, particularly for its practical water treatment applications. To the best of our knowledge, investigations of functionalized photocatalytic (PC) materials on 3d transition metal-doped g-C3N4 remain unexplored in the existing literature. g-C3N4 based heterohybrid photocatalysts have demonstrated excellent reusability, making them highly promising for wastewater treatment applications. This paper describes the overview of numerous studies conducted on the heterostructured g-C3N4 photocatalysts with various 3d metals. Research studies have revealed that the introduction of element doping with various 3d transition metals (e.g., Ti, Mn, Fe, Co, Ni, Cu, Zn, etc.) into g-C3N4 is an efficient approach to enhance degradation efficacy and boost photocatalytic activity (PCA) of doped g-C3N4 catalysts. Moreover, the significance of g-C3N4 heterostructured nanohybrids is highlighted, particularly in the context of wastewater treatment applications. The study concludes by providing insights into future perspectives in this developing area of research, with a specific focus on the degradation of various organic contaminants.

An overview of mechanism and chemical inhibitors of shikimate kinase.

Tuberculosis is a highly infectious disease other than HIV/AIDS and it is one of the top ten causes of death worldwide. Resistance development in the bacteria occurs because of genetic alterations, and the molecular insights suggest that the accumulation of mutation in the individual drug target genes is the primary mechanism of multi-drug resistant tuberculosis. Chorismate is an essential structural fragment for the synthesis of aromatic amino acids and synthesized biochemically by a number of bacteria, including Mycobacterium tuberculosis, utilizing the shikimate pathway. This shikimate kinase is the newer possible target for the generation of novel antitubercular drug because this pathway is expressed only in mycobacterium and not in Mammals. The discovery and development of shikimate kinase inhibitors provide an opportunity for the development of novel selective medications. Multiple shikimate kinase inhibitors have been identified via insilico virtual screening and related protein-ligand interactions along with their in-vitro studies. These inhibitors bind to the active site in a similar fashion to shikimate. In the current review, we present an overview of the biology and chemistry of the shikimate kinase protein and its inhibitors, with special emphasis on the various active scaffold against the enzyme. A variety of chemically diversified synthetic scaffolds including Benzothiazoles, Oxadiazoles, Thiobarbiturates, Naphthoquinones, Thiazoleacetonitriles, Hybridized Pyrazolone derivatives, Orthologous biological macromolecule derivatives, Manzamine Alkaloids derivatives, Dipeptide inhibitor, and Chalcones are discussed in detail. These derivatives bind to the specific target appropriately proving their potential ability through different binding interactions and effectively explored as an effective and selective Sk inhibitor.Communicated by Ramaswamy H. Sarma.

Identification of novel scaffold using ligand and structure based approach targeting shikimate kinase.

Tuberculosis (TB) remains a major global health problem. It causes ill-health among millions of people each year and rank as the second leading cause of death from an infectious disease worldwide, after the human immunodeficiency virus (HIV). Shikimate kinase is one of the major enzymes targeted for TB. Most approaches to overcome TB were based on synthesis and screening of a known compounds to obtain a few representatives with desired potency. In this study, we have applied a virtual screening approach which combines ligand- and structure-based approaches to screen a large library of compounds as a starting point for the identification of new scaffolds for the development of shikimate kinase inhibitors. The combined approach has identified 2 new scaffolds as potential inhibitors of shikimate kinase. To prove the approach, few of the molecules and their derivatives, a total of 17 compounds, were synthesized. The compounds were tested for biological activity and shows moderate activity against shikimate kinase. The shikimate kinase enzyme inhibition study reveals that the compounds showed inhibition (IC50) at concentrations of 50 µg/mL (Compounds 21, 22, 24, 25, 26, 27, 30, 32, 34) and 25 µg/mL (14, 19, 23, 31, 33).

Crystallography, in Silico Studies, and In Vitro Antifungal Studies of 2,4,5 Trisubstituted 1,2,3-Triazole Analogues.

A series of 2,4,5 trisubstituted-1,2,3-triazole analogues have been screened for their antifungal activity against five fungal strains, Candida parapsilosis, Candida albicans, Candida tropicalis, Aspergillus niger, and Trichophyton rubrum, via a 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) microdilution assay. Compounds GKV10, GKV11, and GKV15 emerged as promising antifungal agents against all the fungal strains used in the current study. One of the highly active antifungal compounds, GKV10, was selected for a single-crystal X-ray diffraction analysis to unequivocally establish its molecular structure, conformation, and to understand the presence of different intermolecular interactions in its crystal lattice. A cooperative synergy of the C-H···O, C-H···N, C-H···S, C-H···π, and π···π intermolecular interactions was present in the crystal structure, which contributed towards the overall stabilization of the lattice. A molecular docking study was conducted for all the test compounds against Candida albicans lanosterol-14α-demethylase (pdb = 5 tzl). The binding stability of the highly promising antifungal test compound, GKV15, from the series was then evaluated by molecular dynamics studies.

Syn vs Anti Carboxylic Acids in Hybrid Peptides: Experimental and Theoretical Charge Density and Chemical Bonding Analysis.

A comparative study of syn vs anti carboxylic acids in hybrid peptides based on experimental electron density studies and theoretical calculations shows that, in the anti form, all three bond angles surrounding Ccarboxyl of the -COOH group are close to ∼120°, as expected for a C-sp2 atom, whereas in the syn form, the ∠Cα-C(O)-Ohydroxyl angle is significantly smaller by 5-10°. The oxygen atom in the carboxyl group is more electronegative in the anti form, so the polarity of the acidic O-H bond is higher in the anti form compared to the syn form, as observed within the limitations of H atom treatment in X-ray diffraction. Consequently, the investigated anti carboxylic acid forms the strongest O-H···O hydrogen bond among all model compounds. Furthermore, according to natural bond orbital analysis, the oxygen lone pairs are clearly nonequivalent, as opposed to the general notion of hybridization of equivalent sp2 and sp3 lone pairs on carbonyl or hydroxyl oxygen atoms. The hybridization of the lone pairs is directly related to the directionality and strength of hydrogen bonds.

Synthesis of one-dimensional gold nanostructures and the electrochemical application of the nanohybrid containing functionalized graphene oxide for cholesterol biosensing.

This manuscript reports a new approach for the synthesis of one dimensional gold nanostructure (AuNs) and its application in the development of cholesterol biosensor. Au nanostructures have been synthesized by exploiting ß-diphenylalanine (ß-FF) as an sacrificial template, whereas the Au nanoparticles (AuNPs) were synthesized by ultrasound irradiation. X-ray diffractometer (XRD), scanning electron microscope (SEM) and energy dispersive analysis of X-rays (EDAX) have been employed to characterize the morphology and composition of the prepared samples. With the aim to develop a highly sensitive cholesterol biosensor, cholesterol oxidase (ChOx) was immobilized on AuNs which were appended on the graphite (Gr) electrode via chemisorption onto thiol-functionalized graphene oxide (GO-SH). This Gr/GO-SH/AuNs/ChOx biosensor has been characterized using cyclic voltammetry (CV), electrochemical impedance spectroscopy and chronoamperometry. CV results indicated a direct electron transfer between the enzyme and the electrode surface. A new potentiostat intermitant titration technique (PITT) has been studied to determine the diffusion coefficient and maxima potential value. The proposed biosensor showed rapid response, high sensitivity, wide linear range and low detection limit. Furthermore, our AuNs modified electrode showed excellent selectivity, repeatability, reproducibility and long term stability. The proposed electrode has also been used successfully to determine cholesterol in serum samples.

Directing peptide conformation with centrally positioned pre-organized dipeptide segments: studies of a 12-residue helix and ß-hairpin.

Secondary structure formation in oligopeptides can be induced by short nucleating segments with a high propensity to form hydrogen bonded turn conformations. Type I/III turns facilitate helical folding while type II'/I' turns favour hairpin formation. This principle is experimentally verified by studies of two designed dodecapeptides, Boc-Val-Phe-Leu-Phe-Val-Aib-Aib-Val-Phe-Leu-Phe-Val-OMe 1 and Boc-Val-Phe-Leu-Phe-Val-(D)Pro-(L)Pro-Val-Phe-Leu-Phe-Val-OMe 2. The N- and C-terminal flanking pentapeptide sequences in both cases are identical. Peptide 1 adopts a largely α-helical conformation in crystals, with a small 310 helical segment at the N-terminus. The overall helical fold is maintained in methanol solution as evidenced by NMR studies. Peptide 2 adopts an antiparallel ß-hairpin conformation stabilized by 6 interstrand hydrogen bonds. Key nuclear Overhauser effects (NOEs) provide evidence for the antiparallel ß-hairpin structure. Aromatic proton chemical shifts provide a clear distinction between the conformation of peptides 1 (helical) and 2 (ß-hairpin). The proximity of facing aromatic residues positioned at non-hydrogen bonding positions in the hairpin results in extensively ring current shifted proton resonances in peptide 2.

Temperature-induced reversible first-order single crystal to single crystal phase transition in Boc-γ(4)(R)Val-Val-OH: interplay of enthalpy and entropy.

Crystals of Boc-γ(4)(R)Val-Val-OH undergo a reversible first-order single crystal to single crystal phase transition at Tc ≈ 205 K from the orthorhombic space group P22121 (Z' = 1) to the monoclinic space group P21 (Z' = 2) with a hysteresis of ∼2.1 K. The low-temperature monoclinic form is best described as a nonmerohedral twin with ∼50% contributions from its two components. The thermal behavior of the dipeptide crystals was characterized by differential scanning calorimetry experiments. Visual changes in birefringence of the sample during heating and cooling cycles on a hot-stage microscope with polarized light supported the phase transition. Variable-temperature unit cell check measurements from 300 to 100 K showed discontinuity in the volume and cell parameters near the transition temperature, supporting the first-order behavior. A detailed comparison of the room-temperature orthorhombic form with the low-temperature (100 K) monoclinic form revealed that the strong hydrogen-bonding motif is retained in both crystal systems, whereas the non-covalent interactions involving side chains of the dipeptide differ significantly, leading to a small change in molecular conformation in the monoclinic form as well as a small reorientation of the molecules along the ac plane. A rigid-body thermal motion analysis (translation, libration, screw; correlation of translation and libration) was performed to study the crystal entropy. The reversible nature of the phase transition is probably the result of an interplay between enthalpy and entropy: the low-temperature monoclinic form is enthalpically favored, whereas the room-temperature orthorhombic form is entropically favored.

Unconstrained homooligomeric γ-peptides show high propensity for C14 helix formation.

Monosubstituted γ(4)-residues (γ(4)Leu, γ(4)Ile, and γ(4)Val) form helices even in short homooligomeric sequences. C14 helix formation is established by X-ray diffraction in homooligomeric (γ)n tetra-, hexa- and decapeptide sequences demonstrating the high propensity of γ residues, with proteinogenic side chains, to adopt locally folded conformations.

Does follistatin gene have any direct role in the manifestation of polycystic ovary syndrome in Indian women?

BACKGROUND: Out of a panel of 37 candidate genes tested for linkage with polycystic ovary syndrome (PCOS), the strongest evidence of linkage was reported in the follistatin (FST) gene region. Subsequently, a couple of studies outside India investigated the FST gene for the presence of any mutations and its association with PCOS and the results were found to be largely inconsistent probably due to differences in the ethnic backgrounds and small sample sizes. AIMS: To screen the FST gene for mutations and to establish their association pattern with PCOS among a large cohort of South Indian women. SETTINGS AND DESIGN: Case-control study. MATERIALS AND METHODS: PCOS cases were recruited according to the 2003 Rotterdam diagnostic criteria. All the exons of the FST gene were amplified and analyzed in all the cases and controls for the presence of mutations using polymerase chain reaction (PCR) and direct DNA sequencing. RESULTS: A total of 549 women consisting of 250 PCOS cases and 299 controls were recruited for the study. No mutations were found in any of the exons of the FST gene in our Indian sample which is consistent with an earlier finding among the Asian women from Singapore. Although three of the four cohorts of Caucasian background studied earlier reported variants, none of them could establish a strong association with PCOS. CONCLUSIONS: The occurrence of the exonic variants of FST gene seems to be dependent on the ethnic background of the subjects under study and its role in the PCOS pathophysiology cannot be established with hitherto available evidence.

Androidal fat dominates in predicting cardiometabolic risk in postmenopausal women.

We hypothesized that soy isoflavones would attenuate the anticipated increase in androidal fat mass in postmenopausal women during the 36-month treatment, and thereby favorably modify the circulating cardiometabolic risk factors: triacylglycerol, LDL-C, HDL-C, glucose, insulin, uric acid, C-reactive protein, fibrinogen, and homocysteine. We collected data on 224 healthy postmenopausal women at risk for osteoporosis (45.8-65 y, median BMI 24.5) who consumed placebo or soy isoflavones (80 or 120 mg/d) for 36 months and used longitudinal analysis to examine the contribution of isoflavone treatment, androidal fat mass, other biologic factors, and dietary quality to cardiometabolic outcomes. Except for homocysteine, each cardiometabolic outcome model was significant (overall P-values from ≤.0001 to .0028). Androidal fat mass was typically the strongest covariate in each model. Isoflavone treatment did not influence any of the outcomes. Thus, androidal fat mass, but not isoflavonetreatment, is likely to alter the cardiometabolic profile in healthy postmenopausal women.

Soy protein intake by perimenopausal women does not affect circulating lipids and lipoproteins or coagulation and fibrinolytic factors.

Soy protein favorably alters serum lipids and lipoproteins in hypercholesterolemic individuals, thereby reducing cardiovascular disease risk. The primary purpose was to determine the effect of soy protein (40 g/d) on circulating lipids and lipoproteins or coagulation and fibrinolytic factors in normocholesterolemic and mildly hypercholesterolemic perimenopausal women. We also determined the contribution of coagulation and fibrinolytic and other factors (e.g., body size and composition; serum estrogens, ferritin, iron; dietary intake) to lipid profiles. Subjects were randomly assigned to treatment: isoflavone-rich soy (n = 24), isoflavone-poor soy (n = 24), or whey control (n = 21) protein. We measured circulating lipids and lipoproteins at baseline, wk 12 and wk 24, and coagulation/fibrinolytic factors at baseline and wk 24. Coagulation and fibrinolytic factors were not adversely affected by treatment. Treatment did not alter lipid profiles in mildly hypercholesterolemic (n = 30) or in all subjects combined. Time significantly (P < 0.001) affected serum total cholesterol, triacylglycerol, LDL cholesterol and HDL cholesterol concentrations. We could not attribute changes over time to various factors, but at baseline accounted for 57% of the variability in HDL cholesterol (P < or = 0.0001) and for 50% in the total to HDL cholesterol ratio (P < or = 0.0001). Dietary vitamin E and % energy from fat had positive effects, whereas plasma plasminogen activator inhibitor-1, fibrinogen, body weight and serum ferritin had negative effects on HDL and total to HDL cholesterol. Isoflavone-rich or isoflavone-poor soy protein had no effect on lipid profiles or coagulation and fibrinolytic factors, whereas the effect of time suggested that the hormonal milieu during the menopausal transition may have overridden any detectable treatment effect on lipids. The relationship between coagulation factors and serum lipids should be examined further as indices of cardiovascular disease risk in midlife women.

Effect of ascorbic acid intake on nonheme-iron absorption from a complete diet.

BACKGROUND: Ascorbic acid has a pronounced enhancing effect on the absorption of dietary nonheme iron when assessed by feeding single meals to fasting subjects. This contrasts with the negligible effect on iron balance of long-term supplementation with vitamin C. OBJECTIVE: Our goal was to examine the effect of vitamin C on nonheme-iron absorption from a complete diet rather than from single meals. DESIGN: Iron absorption from a complete diet was measured during 3 separate dietary periods in 12 subjects by having the subjects ingest a labeled wheat roll with every meal for 5 d. The diet was freely chosen for the first dietary period and was then altered to maximally decrease or increase the dietary intake of vitamin C during the second and third periods. RESULTS: There was no significant difference in mean iron absorption among the 3 dietary periods despite a range of mean daily intakes of dietary vitamin C of 51-247 mg/d. When absorption values were adjusted for differences in iron status and the 3 absorption periods were pooled, multiple regression analysis indicated that iron absorption correlated negatively with dietary phosphate (P = 0.0005) and positively with ascorbic acid (P = 0.0069) and animal tissue (P = 0.0285). CONCLUSIONS: The facilitating effect of vitamin C on iron absorption from a complete diet is far less pronounced than that from single meals. These findings may explain why several prior studies did not show a significant effect on iron status of prolonged supplementation with vitamin C.

Caco-2 cells can be used to assess human iron bioavailability from a semipurified meal.

A Caco-2 cell model with extrinsic radioiron was used to evaluate the effect of dietary factors on nonheme iron bioavailability from a semipurified meal. Study 1 was conducted to evaluate the effect of enhancers (ascorbic acid) and inhibitors (bran, phytate and tea) on iron bioavailability when added to semipurified meal containing egg albumen as a protein source. The effect of various proteins [bovine serum albumin (BSA), casein, beef and soy] on iron bioavailability was evaluated in Study 2 by substituting the above protein sources for egg albumen. Protein solubilization following in vitro digestion for individual test meals was not significantly different from the control. On the other hand, nonheme iron solubilization (0.8+/-0.0 to 5.9+/-0.3 vs. 4.9+/-0.8 mg/L) varied significantly. The total iron uptake for each meal was calculated based on the percentage of radioiron taken up and transported by Caco-2 cells and the amount of nonheme iron present in uptake solutions. Iron uptake ratios represent test/control values. With the exception of BSA and ascorbic acid, the effect of dietary factors was similar to that found in humans reported in the literature. A significant correlation (r = 0.97; P<0.0001) was found between the published human absorption data and the iron uptake by the Caco-2 cells. The results of our study indicate the usefulness of Caco-2 cells in assessing human iron absorption and the feasibility of this cell model in studying iron bioavailability from various food combinations, otherwise not easily performed in humans.

Estimation of nonheme-iron bioavailability from meal composition.

BACKGROUND: Considerable data are available on the individual effects of dietary factors on nonheme-iron absorption, but their combined effect when they are present in the same meal is not known. OBJECTIVE: Our objective was to predict the bioavailability of iron from complex meals that are consumed commonly in the United States on the basis of the contents of factors that are known to promote or inhibit food iron absorption. DESIGN: Radioisotopic measurements of nonheme-iron absorption from 25 meals were made in 86 volunteer subjects by using extrinsic radioiron labeling. The meal contents of nonheme iron, calcium, ascorbic acid, polyphenols, and phytic acid were determined by biochemical analysis; energy and protein contents were estimated from food-composition tables. Animal tissue content was based on weight or was obtained from the manufacturer. RESULTS: After adjusting iron absorption for differences in iron status, the significant biochemical predictors of iron absorption as determined by multiple regression analysis were the contents of animal tissue (P = 0.0001), phytic acid (P = 0.0001), and ascorbic acid (P = 0. 0441). Collectively, these 3 variables accounted for 16.4% of the variation in absorption. On the basis of the multiple regression analysis, we developed the following equation to estimate iron absorption: Ln absorption, % (adjusted to serum ferritin concentration of 30 microg/L) = 1.9786 + (0.0123 x animal tissue in g) - (0.0034 x phytic acid in mg) + (0.0065 x ascorbic acid in mg). CONCLUSION: For the 25 meals evaluated, only the contents of animal tissue, phytic acid, and ascorbic acid were useful for estimating nonheme-iron absorption.

Does epidermal turnover reduce percutaneous penetration?

PURPOSE: After its removal from the skin surface, chemical remaining within the skin can become systemically available. The fraction of chemical in the skin that eventually enters the body depends on the relative rates of percutaneous transport and epidermal turnover (i.e., stratum corneum desquamation). Indeed, some investigators have claimed that desquamation is an efficient mechanism for eliminating dermally absorbed chemical from the skin. METHODS: The fate of chemical within the skin following chemical contact was examined using a mathematical model representing turnover of and absorption into the stratum corneum and viable epidermis. The effects of turnover rate, exposure duration, penetrant lipophilicity, and lag time for chemical diffusion were explored. RESULTS: These calculations show that significant amounts of chemical can be removed from skin by desquamation if epidermal turnover is fast relative to chemical diffusion through the stratum corneum. However, except for highly lipophilic and/or high molecular weight (>350 Da) chemicals, the normal epidermal turnover rate is not fast enough and most of the chemical in the skin at the end of an exposure will enter the body. CONCLUSIONS: Epidermal turnover can significantly reduce subsequent chemical absorption into the systemic circulation only for highly lipophilic or high molecular weight chemicals.