ABSTRACT
Amide functional groups are prominent in a broad range of organic compounds with diverse beneficial applications. In this work, we report the synthesis of these functional groups via an iron(iii) chloride-catalyzed direct amidation of esters. The reactions are conducted under solvent-free conditions and found to be compatible with a range of amine and ester substrates generating the desired amides in short reaction times and good to excellent yields at a catalyst loading of 15 mol%.
Subject(s)
Amides/chemistry , Chlorides/chemistry , Esters/chemistry , Ferric Compounds/chemistry , Solvents/chemistry , Antitubercular Agents/chemistry , Antitubercular Agents/pharmacology , Catalysis , Lactams/chemical synthesis , Lactams/chemistry , Pyrimidines/chemistry , Pyrimidines/pharmacologyABSTRACT
The aim of the study was to isolate and characterise antimicrobial agents from the leaves of Capparis fascicularis using thin-layer chromatography-direct bioautography (TLC-DB). Capparis fascicularis is a medicinal plant used traditionally to treat various ailments. Previous studies have shown that species of the genus Capparis, contain several classes of secondary metabolites, including sterols. In this study, the leaves of C. fascicularis were extracted with 80% aqueous methanol, and the extract's fractions were screened for antimicrobial activity against Staphylococcus aureus ATCC 25923 using a broth micro-dilution assay. The hexane fraction was the most active, with a minimum inhibitory concentration (MIC) of 512 µg/mL. TLC-DB and flash column chromatography of the hexane fraction resulted in the isolation of ß-Sitosterol for the first time from C. fascicularis. The compound was characterised using NMR and HRMS.
ABSTRACT
A temperature-controlled mechanism switch between the Al(OTf)(3)-catalysed direct addition of alcohols or the Ferrier rearrangement reactions in some glycals is presented. The scope and limitations are investigated as are the influence of the stereochemistry and nature of the protecting groups on the glycal substrate.
ABSTRACT
Phenotypic screening of a Medicines for Malaria Venture compound library against Mycobacterium tuberculosis (Mtb) identified a cluster of pan-active 2-pyrazolylpyrimidinones. The biology triage of these actives using various tool strains of Mtb suggested a novel mechanism of action. The compounds were bactericidal against replicating Mtb and retained potency against clinical isolates of Mtb. Although selected MmpL3 mutant strains of Mtb showed resistance to these compounds, there was no shift in the minimum inhibitory concentration (MIC) against a mmpL3 hypomorph, suggesting mutations in MmpL3 as a possible resistance mechanism for the compounds but not necessarily as the target. RNA transcriptional profiling and the checkerboard board 2D-MIC assay in the presence of varying concentrations of ferrous salt indicated perturbation of the Fe-homeostasis by the compounds. Structure-activity relationship studies identified potent compounds with good physicochemical properties and in vitro microsomal metabolic stability with moderate selectivity over cytotoxicity against mammalian cell lines.
Subject(s)
Antitubercular Agents/chemistry , Pyrimidinones/chemistry , Animals , Antitubercular Agents/metabolism , Antitubercular Agents/pharmacology , Bacterial Proteins/antagonists & inhibitors , Bacterial Proteins/genetics , Bacterial Proteins/metabolism , Half-Life , Humans , Iron/metabolism , Male , Membrane Transport Proteins/genetics , Membrane Transport Proteins/metabolism , Mice , Mice, Inbred C57BL , Microbial Sensitivity Tests , Microsomes/metabolism , Mutation , Mycobacterium tuberculosis/drug effects , Mycobacterium tuberculosis/isolation & purification , Pyrazoles/chemistry , Pyrimidinones/metabolism , Pyrimidinones/pharmacology , Rats , Structure-Activity RelationshipABSTRACT
A BioFocus DPI SoftFocus library of â¼35â¯000 compounds was screened against Mycobacterium tuberculosis (Mtb) in order to identify novel hits with antitubercular activity. The hits were evaluated in biology triage assays to exclude compounds suggested to function via frequently encountered promiscuous mechanisms of action including inhibition of the QcrB subunit of the cytochrome bc1 complex, disruption of cell-wall homeostasis, and DNA damage. Among the hits that passed this screening cascade, a 6-dialkylaminopyrimidine carboxamide series was prioritized for hit to lead optimization. Compounds from this series were active against clinical Mtb strains, while no cross-resistance to conventional antituberculosis drugs was observed. This suggested a novel mechanism of action, which was confirmed by chemoproteomic analysis leading to the identification of BCG_3193 and BCG_3827 as putative targets of the series with unknown function. Initial structure-activity relationship studies have resulted in compounds with moderate to potent antitubercular activity and improved physicochemical properties.
Subject(s)
Antitubercular Agents/chemistry , Antitubercular Agents/pharmacology , Mycobacterium tuberculosis/drug effects , Structure-Activity Relationship , Administration, Oral , Animals , Antitubercular Agents/chemical synthesis , Blood Proteins/metabolism , Drug Stability , High-Throughput Screening Assays , Humans , Male , Mice, Inbred C57BL , Microsomes, Liver/drug effects , Mycobacterium tuberculosis/isolation & purification , Proteomics/methods , Pyrimidines/chemistry , Small Molecule Libraries/chemistry , Small Molecule Libraries/pharmacologyABSTRACT
3,4,6-Tri-O-acetyl-D-galactal is selectively converted into 1-O-aryl-2-deoxy derivatives or chiral bridged benzopyrans under Al(OTf)3 catalysis, depending on reaction conditions. The benzopyrans react with Al(OTf)3/acetic anhydride in ring-opening reactions in the absence or presence of acetic acid to selectively produce chiral chromenes or chromans, respectively, in high yields.