ABSTRACT
N-Protected 3-iodoindoles were reacted with (di)azine halides in a sequentially Pd-catalyzed one-pot fashion, i.e., by Masuda borylation-Suzuki coupling (MBSC) sequence. This methodology was successfully applied to the concise syntheses of marine indole alkaloids meridianin C, D, F, and G, as well as to the bisindole alkaloid scalaridine A, which were obtained in moderate to excellent yield.
Subject(s)
Alkaloids , Indole Alkaloids , Indoles , Molecular Structure , PyrimidinesABSTRACT
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
A highly potent donor-acceptor biaryl thermally activated delayed fluorescence (TADF) dye is accessible by a concise two-step sequence employing two-fold Ullmann arylation and a sequentially Pd-catalyzed Masuda borylation-Suzuki arylation (MBSA). Photophysical investigations show efficient TADF at ambient temperature due to the sterical hindrance between the donor and acceptor moieties. The photoluminescence quantum yield amounts to ΦPL = 80% in toluene and 90% in PMMA arising from prompt and delayed fluorescence with decay times of 21 ns and 30 µs, respectively. From an Arrhenius plot, the energy gap Δ E(S1 - T1) between the lowest excited singlet S1 and triplet T1 state was determined to be 980 cm-1 (120 meV). A new procedure is proposed that allows us to estimate the intersystem crossing time to â¼102 ns.
