ABSTRACT
Natural bisindole alkaloids such as Hyrtinadine A and Alocasin A, which are known to exhibit diverse bioactivities, provide promising chemical scaffolds for drug development. By optimizing the Masuda borylation-Suzuki coupling sequence, a library of various natural product-derived and non-natural (di)azine-bridged bisindoles was created. While unsubstituted bisindoles were devoid of antibacterial activity, 5,5'-chloro derivatives were highly active against methicillin-resistant Staphylococcus aureus (MRSA) and further Gram-positive pathogens at minimal inhibitory concentrations ranging from 0.20 to 0.78 µM. These compounds showed strong bactericidal killing effects but only moderate cytotoxicity against human cell lines. Furthermore, the two front-runner compounds 4j and 4n exhibited potent in vivo efficacy against MRSA in a mouse wound infection model. Although structurally related bisindoles were reported to specifically target pyruvate kinase in MRSA, antibacterial activity of 4j and 4n is independent of pyruvate kinase. Rather, these compounds lead to bacterial membrane permeabilization and cellular efflux of low-molecular-weight molecules.
Subject(s)
Alkaloids/chemistry , Anti-Bacterial Agents/pharmacology , Indoles/chemistry , Methicillin-Resistant Staphylococcus aureus/drug effects , Alkaloids/metabolism , Alkaloids/pharmacology , Alkaloids/therapeutic use , Animals , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/metabolism , Anti-Bacterial Agents/therapeutic use , Cell Line , Cell Survival/drug effects , Female , Gram-Negative Bacteria/drug effects , Gram-Positive Bacteria/drug effects , Humans , Mice , Mice, Inbred BALB C , Microbial Sensitivity Tests , Peritonitis/drug therapy , Peritonitis/pathology , Pyruvate Kinase/antagonists & inhibitors , Pyruvate Kinase/metabolism , RabbitsABSTRACT
An air- and moisture-stable fluoroiodane in the presence of AgBF4 is suitable for selective geminal difluorination of styrenes under mild reaction conditions. One of the CF bonds is formed by transfer of electrophilic fluorine from the hypervalent iodine reagent, while the other one arises from the tetrafluoroborate counterion of silver. Deuterium-isotope-labelling experiments and rearrangement of methyl styrene substrates suggest that the reaction proceeds through a phenonium ion intermediate.
Subject(s)
Borates/chemistry , Heterocyclic Compounds, 2-Ring/chemistry , Hydrocarbons, Fluorinated/chemical synthesis , Onium Compounds/chemistry , Silver Compounds/chemistry , Styrenes/chemistry , Air , Deuterium/chemistry , Halogenation , Hydrocarbons, Fluorinated/chemistry , Molecular Structure , Water/chemistryABSTRACT
The Masuda borylation-Suzuki coupling (MBSC) sequence was successfully extended to the challenging coupling of vinylhalides with various (hetero)arylhalides using sterically hindered phosphane ligands. Starting from (hetero)arylhalides and α-bromocinnamaldehyde, the sequentially Pd-catalyzed process selectively furnishes α,ß-substituted cinnamaldehydes without affecting the reactivity of the Michael system. These intermediates were implemented as entries into a novel synthesis of 3,4-diaryl 1H-pyrazoles in the fashion of a three-step one-pot procedure consisting of a Masuda borylation-Suzuki coupling and subsequent Michael addition-cyclocondensation-elimination sequence.
