Aqueous phase synthesis, crystal structure and antimicrobial activity of 4-(substituted phenylazo)-3-methyl-4H-isoxazol-5-one azo dyes

3-Methyl-4H-isoxazol-5-one was synthesized at room temperature by simple stirring method from ethyl acetoacetate and hydroxylamine hydrochloride in aqueous medium and coupled with diazotized substituted amine to form series of 4-(substituted phenylazo)-3-methyl-4H-isoxazol-5-ones through green chemistry. All the compounds formed were characterized by IR, 1H and 13C NMR spectroscopy, MS and elemental analysis. Crystal structure of novel 4-(4-fluorophenylazo)-3-methyl-4H-isoxazol-5-one was determined by the X-ray diffraction. Antibacterial and antifungal activity was studied against Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, Staphylococcus pyogenus and Candida albicans, Aspergillus niger, Aspergillus clavatus, respectively. All synthesized compounds were found to be active against a gram-positive bacterium Staphylococcus aureus. Two compounds showed antifungal activity against Candida albicans close to standard greseofulvin.               KEY WORDS: Azo dyes, Substituted amines, Antibacterial and antifungal activity, X-ray diffraction, Spectroscopy, Green chemistry Bull. Chem. Soc. Ethiop. 2018, 32(2), 249-257.DOI: https://dx.doi.org/10.4314/bcse.v32i2.

In silico study of CYP450 inhibitor activity of (E)-1-(3-((4-chlorophenyl) diazenyl)-4-hydroxyphenyl)ethanone

Molecular docking and single crystal study of azo dye (E)-1-(3-((4-chlorophenyl)diazenyl)-4-hydroxyphenyl)ethanone (3) is reported here. It has been synthesized by diazotization of 4-chloroaniline followed by coupling with 4-hydroxyacetophenone. Molecule is almost planar with acetyl as well as azo groups only slightly deviating from the plane of C3–C8 phenyl ring as evident by C1–C2–C3–C8 and N2–N1–C7–C6 torsion angles of –3.6(3)° and –3.9(3)°, respectively. Torsion angle N1–N2–C9–C14 between azo group and chlorophenyl ring is somewhat larger being –13.1(3)° leading to torsion angle between phenyl C3–C8 and chlorophenyl C9–C14 ring of 17.26(11)°. Intramolecular O2–H2···N2 hydrogen-bonding is observed here. Pillars along b-axis are formed due to π∙∙∙π stacking interactions of parallel molecules in head-to-head fashion with centroid-to-centroid distance of 3.8829(14) Å and ring slippage of 1.416 Å. Title compound shows good binding affinity towards six enzymes of CYP450 family. Both nitrogens of the azo bond show significant involvement in bonding interactions with proteins in case of all the six enzymes

Structural Analysis of a Peptide Fragment of Transmembrane Transporter Protein Bilitranslocase

Using a combination of genomic and post-genomic approaches is rapidly altering the number of identified human influx carriers. A transmembrane protein bilitranslocase (TCDB 2.A.65) has long attracted attention because of its function as an organic anion carrier. It has also been identified as a potential membrane transporter for cellular uptake of several drugs and due to its implication in drug uptake, it is extremely important to advance the knowledge about its structure. However, at present, only the primary structure of bilitranslocase is known. In our work, transmembrane subunits of bilitranslocase were predicted by a previously developed chemometrics model and the stability of these polypeptide chains were studied by molecular dynamics (MD) simulation. Furthermore, sodium dodecyl sulfate (SDS) micelles were used as a model of cell membrane and herein we present a high-resolution 3D structure of an 18 amino acid residues long peptide corresponding to the third transmembrane part of bilitranslocase obtained by use of multidimensional NMR spectroscopy. It has been experimentally confirmed that one of the transmembrane segments of bilitranslocase has alpha helical structure with hydrophilic amino acid residues oriented towards one side, thus capable of forming a channel in the membrane

Structure activity relationships of αv integrin antagonists for pulmonary fibrosis by variation in aryl substituents

Antagonism of alphav beta6 is emerging as a potential treatment of idiopathic pulmonary fibrosis based on strong target validation. Starting from an alphav beta3 antagonist lead and through simple variation in the nature and position of aryl substituent, the discovery of compounds with improved alphav beta6 activity is described. The compounds also have physicochemical properties commensurate with oral bioavailability and are high quality starting points for a drug discovery programme. Compounds 33S and 43E1 are pan alphav antagonists having ca 100 nM potency against alphav beta3, alphav beta5, alphav beta6 and alphav beta8 in cell adhesion assays. Detailed structure activity relationships with these integrins are described which also reveal substituents providing partial selectivity (defined as at least a 0.7 log difference in pIC50 values between the integrins in question) for alphav beta3 and alphav beta5

Free energy of binding of coiled-coil complexes with different electrostatic environments: the influence of force field polarisation and capping

Coiled-coils are well known protein–protein interaction motifs, with the leucine zipper region of activator protein-1 (AP-1) consisting of the c-Jun and c-Fos proteins being a typical example. Molecular dynamics (MD) simulations using the MM/GBSA method have been used to predict the free energy of interaction of these proteins. The influence of force field polarisation and capping on the predicted free energy of binding of complexes with different electrostatic environments (net charge) were investigated. Although both force field polarisation and peptide capping are important for the prediction of the absolute free energy of binding, peptide capping has the largest influence on the predicted free energy of binding. Polarisable simulations appear better suited to determine structural properties of the complexes of these proteins while non-polarisable simulations seem to give better predictions of the associated free energies of bindin

Functional Rotation of the Transporter AcrB: Insights into Drug Extrusion from Simulations

The tripartite complex AcrAB-TolC is the major efflux system in Escherichia coli. It extrudes a wide spectrum of noxious compounds out of the bacterium, including many antibiotics. Its active part, the homotrimeric transporter AcrB, is responsible for the selective binding of substrates and energy transduction. Based on available crystal structures and biochemical data, the transport of substrates by AcrB has been proposed to take place via a functional rotation, in which each monomer assumes a particular conformation. However, there is no molecular-level description of the conformational changes associated with the rotation and their connection to drug extrusion. To obtain insights thereon, we have performed extensive targeted molecular dynamics simulations mimicking the functional rotation of AcrB containing doxorubicin, one of the two substrates that were co-crystallized so far. The simulations, including almost half a million atoms, have been used to test several hypotheses concerning the structure-dynamics-function relationship of this transporter. Our results indicate that, upon induction of conformational changes, the substrate detaches from the binding pocket and approaches the gate to the central funnel. Furthermore, we provide strong evidence for the proposed peristaltic transport involving a zipper-like closure of the binding pocket, responsible for the displacement of the drug. A concerted opening of the channel between the binding pocket and the gate further favors the displacement of the drug. This microscopically well-funded information allows one to identify the role of specific amino acids during the transitions and to shed light on the functioning of AcrB

Copper(II) ions mediated crystal formation of 3-(3-hydroxy phenyl)-1-phenyl-1h-pyrazole- 4-carbaldehyde

Schiff base obtained from 3-hydroxyacetophenone and phenylhydrazine was subjected to Vilsmeier-Haack reaction to obtain 3-(3-hydroxyphenyl)-1-phenyl-1H-pyrazole-4-carbaldehyde (2). Successful formation of crystals of 2 was achieved using copper ions (Cu2+) as template. Present paper reports study of spectroscopic characterization and single-crystal X-ray study of 2. Hydrogen bonding network between 2 and water molecules enable the formation of 2D layer along ab-plane supported also by π···π stacking interactions of parallel molecules in head-to-head fashion.                     KEY WORDS: Cu2+ assisted crystal growth, Pyrazole-4-carbaldehyde, X-ray crystal study, Hydrogen bonding study   Bull. Chem. Soc. Ethiop. 2020, 34(3), 589-596. DOI: https://dx.doi.org/10.4314/bcse.v34i3.1