(E)-3-((2-Fluorophenyl)(hydroxy)methylene)imidazo[1,2-a]pyri-din-2(3H)-one

Treatment of a N-2-pyridyl-β-ketoamide precursor with bromine afforded the first example of the 3-aryl(α-hydroxy)methylenelimidazo[1,2-a]pyridin-2(3H)-one framework. This transformation proceeded through a domino process comprising an initial bromination, cyclization via an intramolecular SN reaction, and a final keto-enol tautomerism, and allows generation of the fused heterocyclic system and installation of the acyl substituent in a single operation.

Synthesis and evaluation of analogues of the glycinocin family of calcium-dependent antibiotics

We describe the synthesis and calcium-dependent antimicrobial activity of a small library of glycinocin analogues that differ by variation in the exocyclic fatty acyl substituent.

Structural and Biological Characterization of a Capsular Polysaccharide Produced by Staphylococcus haemolyticus

ABSTRACT The DNA sequence of the genome of Staphylococcus haemolyticus JCSC1435 revealed a putative capsule operon composed of 13 genes in tandem. The first seven genes (capABCDEFGSh ) showed ≥57% similarity with the Staphylococcus aureus cap5 or cap8 locus. However, the capHIJKLMSh genes are unique to S. haemolyticus and include genes encoding a putative flippase, an aminotransferase, two glycosyltransferases, and a transcriptional regulator. Capsule-like material was readily apparent by immunoelectron microscopy on bacteria harvested in the postexponential phase of growth. Electron micrographs of a JCSC1435 mutant with a deleted cap region lacked the capsule-like material. Both strains produced small amounts of surface-associated material that reacted with antibodies to polyglutamic acid. S. haemolyticus cap genes were amplified from four of seven clinical isolates of S. haemolyticus from humans, and three of these strains produced a serologically cross-reactive capsular polysaccharide. In vitro assays demonstrated that the acapsular mutant strain showed greater biofilm formation but was more susceptible to complement-mediated opsonophagocytic killing than the parent strain. Structural characterization of capsule purified from S. haemolyticus strain JCSC1435 showed a trisaccharide repeating unit: −3-α-l-FucNAc-3-(2-NAc-4-N-Asp-2,4,6-trideoxy-β-d-Glc)-4-α-d-GlcNAc-. This structure is unique among staphylococcal polysaccharides in that its composition includes a trideoxy sugar residue with aspartic acid as an N-acyl substituent.

Tin-Carbon Cleavage of Organotin Compounds by Pyoverdine from Pseudomonas chlororaphis

ABSTRACT The triphenyltin (TPT)-degrading bacterium Pseudomonas chlororaphis CNR15 produces extracellular yellow substances to degrade TPT. Three substances (F-I, F-IIa, and F-IIb) were purified, and their structural and catalytic properties were characterized. The primary structure of F-I was established using two-dimensional nuclear magnetic resonance techniques; the structure was identical to that of suc-pyoverdine from P. chlororaphis ATCC 9446, which is a peptide siderophore produced by fluorescent pseudomonads. Spectral and isoelectric-focusing analyses revealed that F-IIa and F-IIb were also pyoverdines, differing only in the acyl substituent attached to the chromophore part of F-I. Furthermore, we found that the fluorescent pseudomonads producing pyoverdines structurally different from F-I showed TPT degradation activity in the solid extracts of their culture supernatants. F-I and F-IIa degraded TPT to monophenyltin via diphenyltin (DPT) and degraded DPT and dibutyltin to monophenyltin and monobutyltin, respectively. The total amount of organotin metabolites produced by TPT degradation was nearly equivalent to that of the F-I added to the reaction mixture, whereas DPT degradation was not influenced by monophenyltin production. The TPT degradation activity of F-I was remarkably inhibited by the addition of metal ions chelated with pyoverdine. On the other hand, the activity of DPT was increased 13- and 8-fold by the addition of Cu2+ and Sn4+, respectively. These results suggest that metal-chelating ligands common to pyoverdines may play important roles in the Sn-C cleavage of organotin compounds in both the metal-free and metal-complexed states.

Structure-reactivity correlations in the reaction of 2,4-dinitrophenyl X-substituted benzoates with alicyclic secondary amines

Apparent second-order rate constants (kapp) have been measured spectrophotometrically for the reaction of 2,4-dinitrophenyl X-substituted benzoates with a series of alicyclic secondary amines in H2O containing 20 mol% DMSO at 25°C. The microconstants involved in the reaction (k-1/k2, k1, and k1k2/k-1) have also been calculated. The magnitude of kapp, k1, and k1k2/k-1 values increases with increasing amine basicity and with increasing acid strengthening ability of the acyl substituent X. The k-1/k2 value decreases from ca. 6.5 to 0.3 with increasing the amine basicity, but remains almost constant upon changing the acyl substituent X for a given amine, indicating that the rate-determining step is governed by the basicity of amine but not by the electronic nature of the acyl substituent X. The Brønsted-type plots for kapp show a break at pKa = 9.1, supporting the assumption that a change in the rate-determining step occurs from rate-limiting breakdown to formation of the addition intermediate as amine basicity increases. The corresponding Brønsted-type plots for k-1/k2, k1, and k1k2/k-1 are linear but their β values are different. σ+ constants show better correlation with log kapp, log k1 and log k1k2/k-1 for the reaction with low basic amines (pKa < 9.1), while σ constants exhibit better correlation for the reaction with highly basic amines (pKa > 9.1). The magnitude of ρ1 is identical to that of ρapp and ρeq for a given amine.Key words: aminolysis, Brønsted-type plot, structure-reactivity correlations, rate-determining step.

Kukoamine A and other hydrophobic acylpolyamines: potent and selective inhibitors of Crithidia fasciculata trypanothione reductase

The enzyme trypanothione reductase (TR), together with its substrate, the glutathione-spermidine conjugate trypanothione, plays an essential role in protecting parasitic trypanosomatids against oxidative stress and is a target for drug design. Here we show that a naturally occurring spermine derivative, the antihypertensive agent kukoamine A [N1N12-bis(dihydrocaffeoyl)-spermine] inhibits TR as a mixed inhibitor (Ki = 1.8 microM, Kii = 13 microM). Kukoamine shows no significant inhibition of human glutathione reductase (Ki > 10 mM) and thus provides a novel selective drug lead. The corresponding N1N8-bis(dihydrocaffeoyl)spermidine derivative was synthesized and acted as a purely competitive inhibitor with Ki = 7.5 microM. A series of mono- and di-acylated spermines and spermidines were synthesized to gain an insight into the effect of polyamine chain length, the nature and position of the acyl substituent and the importance of conformational mobility. These compounds inhibited TR with Ki values ranging from 11 to 607 microM.