Blocking the Peroxisome Proliferator‐Activated Receptor (PPAR): An Overview

Peroxisome proliferator‐activated receptors (PPARs) have been studied extensively over the last few decades and have been assessed as molecular targets for the development of drugs against metabolic disorders. A rapid increase in understanding of the physiology and pharmacology of these receptors has occurred, together with the identification of novel chemical structures that are able to activate the various PPAR subtypes. More recent evidence suggests that moderate activation of these receptors could be favorable in pathological situations due to a decrease in the side effects brought about by PPAR agonists. PPAR partial agonists and antagonists are interesting tools that are currently used to better elucidate the biological processes modulated by this family of nuclear receptors. Herein we present an overview of the various molecular structures that are able to block each of the PPAR subtypes, with a focus on promising therapeutic applications.     

Synthesis and Pharmacological Evaluation of a series of the Agomelatine Analogues as Melatonin MT1/MT2 Agonist and 5‐HT2C Antagonist

Agomelatine is a naphthalenic analogue of melatonin that is in clinical use for the treatment of major depressive disorders. Interestingly, while agomelatine exhibits potent affinity for melatonin receptors, it binds with only moderate affinity to the serotonin 5‐HT_2C receptor. Optimization of agomelatine toward this target could further potentiate its clinical efficacy. To explore this hypothesis and to access derivatives in which a key point of agomelatine metabolism is blocked, a series of naphthalenic derivatives was designed and synthesized as novel analogues of agomelatine. Most of the prepared compounds exhibited good binding affinity at the melatonin MT₁ and MT₂ receptor subtypes. Two compounds, an acetamide and an acrylamide derivative, exhibited good binding affinities at both the human melatonin (MT) receptors and the serotonin 5‐HT_2C receptor subtype, with pK_i values of 7.96 and 7.95 against MT₁, 7.86 and 8.68 against MT2, and 6.64 and 6.44 against 5‐HT_2C, respectively.     

Chromophore‐Linked Substrate (CLS405): Probing Metallo‐β‐Lactamase Activity and Inhibition

Serine‐ and metallo‐β‐lactamases present a threat to the clinical use of nearly all β‐lactam antibiotics, including penicillins, cephalosporins, and carbapenems. Efforts to develop metallo‐β‐lactamase (MBL) inhibitors require suitable screening platforms to allow the rapid determination of β‐lactamase activity and efficient inhibition. Unfortunately, the platforms currently available are not ideal for this purpose. Further progress in MBL inhibitor identification requires inexpensive and widely applicable assays. Herein the identification of an inexpensive and stable chromogenic substrate suitable for use in assays of clinically relevant MBLs is described. (6R,7R)‐3‐((4‐Nitrophenoxy)methyl)‐8‐oxo‐7‐(2‐phenylacetamido)‐5‐thia‐1‐azabicyclo[4.2.0]oct‐2‐ene‐2‐carboxylic acid 5,5‐dioxide (CLS405) was synthesised in a three‐step protocol. CLS405 was then characterised spectroscopically, and its stability and kinetic properties evaluated. With a Δλ_max value of 100 nm between the parent and hydrolysis product, a higher analytical accuracy is possible with CLS405 than with commonly used chromogenic substrates. The use of CLS405 in assays was validated by MBL activity measurements and inhibitor screening that resulted in the identification of N‐hydroxythiazoles as new inhibitor scaffolds for MBLs. Further evaluation of the identified N‐hydroxythiazoles against a panel of clinically relevant MBLs showed that they possess inhibitory activities in the mid‐ to low‐micromolar range. The findings of this study provide both a useful tool compound for further inhibitor identification, and novel scaffolds for the design of improved MBL inhibitors with potential as antibiotics against resistant strains of bacteria.     

High yield of monoacylglycerols production through low‐temperature chemical and enzymatic glycerolysis

The present study aimed to produce MAG through low‐temperature chemical glycerolysis. Over 80% MAG yield with 97% TAG conversion was obtained within short reaction times at temperature of 35–55°C, when tert‐butanol (TB) or tert‐pentanol (TP) was used as reaction medium and sodium hydroxide (NaOH) as catalyst. TB gave a faster reaction rate than TP. Catalysts were important for the low‐temperature chemical glycerolysis reaction. Of the eight common base catalysts evaluated, only NaOH and potassium hydroxide (KOH) were effective, and NaOH was better than KOH. Reaction parameters were studied and optimized. The optimum conditions were TB dosage 3:1 (TB to oil in weight ratio), NaOH concentration 0.45 wt% based on oil, molar ratio of glycerol to oil 5:1. Under these conditions, similar MAG yield and TAG conversion was also observed by Novozym 435 catalyzed glycerolysis, however, a 4 h reaction was required. Practical applications: The process of NaOH catalyzed chemical glycerolysis for MAG production in TB solvent system described in this study provides several advantages including short reaction time and high product yield, which is potential for industrial considerations.     

EFFECT OF FREE STREAM TURBULENCE ON HEAT AND MASS TRANSFER FROM A SPHERE

A model has been proposed for the momentum eddy diffusivity induced by free stream turbulence intensity. The eddy diffusivity model is applied to a sphere situated in a uniform crossflow in the presence of free stream turbulence. Numerical solution of the governing momentum and energy equations with the proposed eddy diffusivity model yielded results for the heat/mass transfer rates. The numerical predictions of the present work are compared with experimental data and the agreement between the two is seen to be very good.     

New Insights into Lignin Modification during Chlorine Dioxide Bleaching Sequences (III): The Impact of Modifications in the (EO) versus E Stage on the D1 Stage

Abstract

Chlorine dioxide delignification (D₀) modifies kraft residual lignin by oxidizing phenolic groups to both quinone and muconic acid structures. Alkaline extraction (E), in addition to removing solubilized lignin, converts quinone moieties to polyphenols. These polyphenols are easily oxidized by oxygen in an (EO) stage or by ClO₂ in a D₁ stage to hydroxyquinones (～1.8 mmol/g lignin). Pulps treated by D₀E consume considerably more ClO₂ in the D₁ than D₀(EO), and have lower bleachability, as was quantified by a simple bleaching model. Both D₀E and D₀(EO) pulps approach a common brightness ceiling (～83 ISO) when excess ClO₂ is applied. Examination of the post‐D₁ b* values indicates that D₀E and D₀(EO) also have similar asymptotic b* values (～6), indicating that both pulps have similar residual chromophores. Hydroxyquinone structures appear to be eliminated in the D₁ stage for D₀(EO) pulps, and at high ClO₂ levels for D₀E pulps.