LpxC inhibition: Potential and opportunities with carbohydrate scaffolds.

Uridine diphosphate-3-O-(hydroxymyristoyl)-N-acetylglucosamine deacetylase (LpxC) is a key enzyme involved in the biosynthesis of lipid A, an essential building block, for the construction and assembly of the outer membrane (OM) of Gram-negative bacteria. The enzyme is highly conserved in almost all Gram-negative bacteria and hence has emerged as a promising target for drug discovery in the fight against multi-drug resistant Gram-negative infections. Since the first nanomolar LpxC inhibitor, L-161,240, an oxazoline-based hydroxamate, the two-decade-long ongoing search has provided valuable information regarding essential features necessary for inhibition. Although the design and structure optimization for arriving at the most efficacious inhibitor of this enzyme has made good use of different heterocyclic moieties, the use of carbohydrate scaffold is scant. This review briefly covers the advancement and progress made in LpxC inhibition. The field awaits the use of potential associated with carbohydrate-based scaffolds for LpxC inhibition and the discovery of anti-bacterial agents against Gram-negative infections.

Storage and Temperature Stability of Emulsified Biodiesel-Diesel Blends.

The scarcity of fossil fuel has led to the recent worldwide commercialization of biodiesel-blended diesel. The benefits associated with emulsion fuels have encouraged researchers to study the blended emulsified fuels in diesel engines. Recent results show the effectiveness of blended emulsified fuels in terms of better fuel economy and less harmful emissions. Investigation on the stability of these blended emulsified fuels during storage in the fuel tank is equally crucial for commercialization and practical application. A systematic study on the storage stability of water in biodiesel/diesel blend nanoemulsions (nEs) is presented in this work. A mixture of two biodegradable surfactants, Span 80 and Tween 80, is used to stabilize the nEs. The nEs are formulated by subjecting a mixture of 5 vol % of each surfactant, 5 vol % of water, and 85 vol % of pure or blended diesel to high shear homogenization at 5000 rpm for 2 min. Storage stability of the emulsified fuels is studied for 65 days at 25 °C with the help of dynamic light scattering and viscosity measurements. The mean droplet size increases, and the stability decreases with an increase in the biodiesel concentration. The smallest mean droplet size is 32 nm for emulsified fuel using pure diesel, and these emulsions remain stable for 65 days. No macroscopic phase separation is observed for any sample aged for 24 days. A moderate increment in droplet sizes is observed during this period. The droplet size increases significantly when more than 15 vol % biodiesel is used in the fuel blend. Those samples show stratification after 65 storage days. An increment in the zero-shear viscosity of the samples over aging helps hinder the rapid coalescence of the droplets, thus preventing phase separation. Furthermore, the thermal stability of the samples is also investigated at elevated temperatures up to 50 °C. The nEs are found to be highly stable within this temperature range and showed a moderate change in mean droplets size, especially when the concentration of biodiesel in the emulsified fuel blend is less than 15 vol %.

Novel Chemical Scaffolds to Inhibit the Neutral Amino Acid Transporter B0AT1 (SLC6A19), a Potential Target to Treat Metabolic Diseases.

Lack of B0AT1 (SLC6A19) partially protects mice against the onset of non-alcoholic steatohepatitis (NASH). To achieve a similar outcome through pharmacological treatment, we improved previously identified inhibitors of B0AT1 by medicinal chemistry and identified second generation inhibitors by high through-put screening. Modified diarylmethine compounds inhibited B0AT1 with IC50 values ranging from 8-90 µM. A second generation of inhibitors was derived from high-throughput screening and showed higher affinity (IC50 of 1-15 µM) and strong selectivity against amino acid transporters with similar substrate specificity, such as ASCT2 (SLC1A5) and LAT1 (SLC7A5). All compounds were unrelated to B0AT1 substrates, but were likely to bind in the vicinity of the substrate binding site.

Discovery of an isocoumarin analogue that modulates neuronal functions via neurotrophin receptor TrkB.

Isocoumarins are lactone ring-containing natural products, are quite abundant in microbes and higher plants, and have been shown to exhibit a broad range of pharmacological properties. However, the molecular mechanism or target of this class of molecules is not known. In this study, we have synthesized 14 isocoumarin derivatives and evaluated for their activity at TrkB receptor in transiently transfected HEK293T cells. We identified 8-hydroxy-3-aryl isocoumarin (1) as a high-affinity agonist at the TrkB receptor. We also demonstrated that isocoumarin 1 activated endogenously TrkB receptor in primary cortical neurons and modulated various markers of synaptic plasticity, and increased dendritic arborization. These results indicate therapeutic potential and molecular target of 8-hydroxy-3-aryl isocoumarin 1 for the treatment of various CNS disorders.

Stereoselective total synthesis of Oxylipin from open chain gluco-configured building block.

Total synthesis of naturally occurring Oxylipin has been achieved from open chain gluco-configured building block which is readily assembled from inexpensive and commercially available D-(+)-gluconolactone. Grignard reaction and Wittig olefination reactions are key steps for the requisite CC bond formation.

Inhibition of the enzymes in the leukotriene and prostaglandin pathways in inflammation by 3-aryl isocoumarins.

The biosynthesis of leukotrienes in one of the arachidonic acid pathways and PGE2 in the other by 5-LOX and mPGES1 respectively, play pivotal roles in augmenting inflammatory responses. PGE2 is known to participate in cancer pathological processes as well. Isocoumarins are natural compounds with a wide range of biological activities. In this study, 3-aryl isocoumarin derivatives are synthesized and tested against 5-LOX enzyme in vitro and PGE2 production in HeLa cells. Most of the compounds show high activity, and 1c is identified as a dual inhibitor with an IC50 of 4.6 ± 0.26 µM and 6.3 ± 0.13 µM against 5-LOX and PGE2 production respectively. Another compound 7f, exhibits an IC50 of 12.4 ± 0.14 µM against 5-LOX. Further investigations reveal that the mechanism of action of 1c and 7f against 5-LOX is mixed and competitive modes of action respectively. Thunberginol A (7c) exhibits IC50 of 15.8 ± 0.03 µM against PGE2 production. 1c and 7c inhibit the mRNA expression of mPGES1 and COX-2. The study has identified a novel scaffold, 1c with a dual inhibitory activity which can be further optimized to compete against Licofelone which is under clinical trials (with IC50 of 6.0 µM for mPGES1 & 0.2 µM for 5-LOX). To conclude, 3-aryl isocoumarin derivatives appears as promising tools to fight against inflammatory diseases as well as cancer.

Study of aqueous phase aggregation of FTY720 (fingolimod hydrochloride) and its effect on DMPC liposomes using fluorescent molecular probes.

This work focuses on the study of aqueous phase aggregation of the recently FDA approved oral drug molecule FTY720 (fingolimod hydrochloride) and its effect on dimyristoylphosphatidylcholine (DMPC) liposomes using different fluorescent molecular probes and fluorescence parameters. The variation of the steady state fluorescence intensity of 8-anilino-1-naphthalene sulfonic acid (ANS) with FTY720 in water shows an efficient micellar aggregation with the critical micellar concentration (CMC) at ~75 µM. The aggregation number calculation from steady state fluorescence quenching of pyrene shows the formation of small micellar aggregates in aqueous solution having an aggregation number of 42 ± 3 with the free energy of micellization ~-23 kJ mol(-1). Fluorescence intensity and lifetime decay analysis of the molecular probe 1-naphthol indicate that the interaction of FTY720 with the DMPC lipid bilayer membrane prevents partitioning of small molecules such as 1-naphthol to the membrane in both solid gel (SG) and liquid crystalline (LC) phases. Temperature dependent fluorescence intensity studies of 1-naphthol and fluorescence anisotropy measurements of 1,6-diphenyl-1,3,5-hexatriene (DPH) have shown that above the CMC of FTY720, the SG to LC main phase transition temperature (T(M)) of the lipid bilayer membrane decreases from 23 °C to 21 °C in the aqueous medium.

Convenient synthesis of D- and L-xylo-1,2,3,4-alkane tetrols from a D-gluco-configured common building block.

D-gluco-configured building block derived from D-(+)-gluconolactone has served as a common chiral template for the synthesis of enantiopure D- and L-xylo-configured 1,2,3,4-alkane tetrols. This has enabled synthesis of medicinally important guggultetrols and their enantiomers from a common starting point. Wittig and Grignard reactions are the key steps used for the incorporation of lipophilic chain.

Convenient strategies for the synthesis of 1,4-phenylene spaced sugars.

Two synthetic strategies have been developed for the synthesis of spaced sugars with lipophilic 1,4-phenylene core. A building block combining the usefulness of Weinreb amide functionality and modified Julia olefination reaction has been explored towards this objective. This building block offers complete flexibility in attaching any desired sugar derivative across phenylene spacer via C-C bond formation. The other strategy uses carbohydrate based building blocks for the synthesis of symmetrical as well as unsymmetrical 1,4-phenylene spaced sugars. This is the first report for the synthesis of 1,4-phenylene spaced sugars via C-C bond formation.

Propargyl bromide as an excellent alpha-bromoacetone equivalent: convenient and new route to alpha-aroylacetones.

[reaction: see text] A variety of alpha-aroylacetones 4a-g have been prepared in excellent yields following a new protocol wherein alpha-aminonitriles 1a-g as the aryl acyl anion equivalents readily react with propargyl bromide as the alpha-bromoacetone equivalent. The alkylated product undergoes one-pot unmasking of the keto functionality along with Markovnikov's hydration of the terminal alkyne with CuSO4 x 5H2O in aqueous methanol at 60 degrees C to furnish the desired target in excellent isolated yields.

Consequences of rigidity and conformational locking in a 4,4-dimethyl-1,3-dioxolane ring system during protection of internal diol.

The presence of an isopropylidene ketal protection of an internal diol in 3,4-O-isopropylidene-D-arabino-1-C-phenyl hexanone locks it in a conformation that prevents its cyclization to a pyranose ring.

Umpolung strategy for the synthesis of 2-deoxy-C-aryl glycosides: a serendipitous, efficient route for C-furanoside analogues.

[reaction: see text] 2-Deoxy-C-aryl glycosides are potential synthetic targets as they form a very vital moiety of several biologically active natural products. This paper describes a synthetic route using an umpolung strategy, which has not been explored till date. Our synthetic endeavor led to a versatile intermediate aryl ketone 10, which has paved the way for two important classes of C-glycosides, viz., C-alkyl furanosides 12 and methyl 2-deoxy-C-aryl pyranosides 14.