Strategies for the production of substituted isoquinoline libraries were developed and explored. Routes involving microwave-assisted variants of the Bischler-Napieralski or Pictet-Spengler reaction allowed for cyclization of substituted beta-arylethylamine derivatives. The dihydroisoquinolines and tetrahydroisoquinolines thus generated could then be oxidized to their corresponding isoquinoline analogues. An alternate strategy, however, involving the preparation and activation of isoquinolin-1(2H)-ones is demonstrated to be a more practical, rapid, and efficient route to C1- and C4-substituted isoquinoline libraries.
Palladium complexes of 1,3,5,7-tetramethyl-2,4,8-trioxa-6-phenyl-6-phosphaadamantane are shown to be effective catalytic systems facilitating the sequential application of a microwave-assisted Sonogashira and carbonylative annulation reaction for the preparation of substituted flavones.
Pantothenamides are N-substituted pantothenate derivatives which are known to exert antimicrobial activity through interference with coenzyme A (CoA) biosynthesis or downstream CoA-utilizing proteins. A previous report has shown that replacement of the ProR methyl group of the benchmark N-pentylpantothenamide with an allyl group (R-anti configuration) yielded one of the most potent antibacterial pantothenamides reported so far (MIC of 3.2 μM for both sensitive and resistant Staphylococcus aureus). We describe herein a synthetic route for accessing the corresponding R-syn diastereomer using a key diastereoselective reduction with Baker's yeast, and report on the scope of this reaction for modified systems. Interestingly, whilst the R-anti diastereomer is the only one to show antibacterial activity, the R-syn isomer proved to be significantly more potent against the malaria parasite (IC 50 of 2.4 ± 0.2 μM). Our research underlines the striking influence that stereochemistry has on the biological activity of pantothenamides, and may find utility in the study of various CoA-utilizing systems.
Keywordspantothenamides; antibacterial; antiplasmodial; baker's yeast; coenzyme A Infectious diseases remain a major contributing factor to worldwide mortality. Moreover, the development of antimicrobial resistance is raising significant concerns about the increasingly limited efficacy of currently available treatments. 1 There have been considerable efforts towards discovering and characterising novel therapeutic targets for antimicrobial drugs. One such target which has emerged as a promising point-of-attack is
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