RESUMEN
An efficient and convenient synthesis of 2,2,2-trichloroethyl (TCE) aryl- and vinyldiazoacetates was achieved by palladium-catalyzed cross-coupling reactions between TCE diazoacetates and aryl or vinyl iodides. The broad substrate scope allows for rapid and facile formation of TCE aryl- and vinyldiazoacetates, which recently have emerged as versatile reagents for rhodium-carbene chemistry.
RESUMEN
A Robinson annulation, van Leusen homologation, and a desymmetrizing C-H oxidation enabled an enantiospecific synthesis of the neurotrophic natural product jiadifenolide. From a pulegone-derived building block, a key propellane intermediate was constructed through the use of simple reagents in a highly diastereoselective fashion. A short series of oxidations of this tricylic framework allowed progression to the natural product.
Asunto(s)
Sesquiterpenos/síntesis química , Productos Biológicos/síntesis química , Productos Biológicos/química , Carbono/química , Hidrógeno/química , Conformación Molecular , Oxidación-Reducción , Sesquiterpenos/química , Estereoisomerismo , Terpenos/químicaRESUMEN
Methicillin-resistant Staphylococcus aureus (MRSA), a Gram-positive bacterial pathogen, continues to pose a serious threat to the current public health system in our society. The high level of resistance to ß-lactam antibiotics in MRSA is attributed to the expression of penicillin-binding protein 2a (PBP2a), which catalyzes cell wall cross-linking. According to numerous research reports, the activity of the PBP2a protein is known to be regulated by an allosteric site distinct from the active site where cell wall cross-linking occurs. Here, we conducted a screening of 113 compounds containing a 1,3,4-oxadiazole core to design new covalent inhibitors targeting the allosteric site of PBP2a and establish their structural-activity relationship. The stereochemically selective synthesis of sulfonyl oxadiazole compounds identified in the initial screening resulted in a maximum eightfold enhancement in cell inhibition activity. The sulfonyl oxadiazole-based compounds formulated as PEG-based ointments, with low toxicity test results on human cells (CC 50 : >78µM), demonstrated potent antimicrobial effects not only in a mouse skin wound infection model but also against oxacillin-resistant clinical isolate MRSA (IC 50 ≈ 1µM), as evidenced by the results. Furthermore, additional studies utilizing LC-MS/MS and in-silico approaches clearly support the allosteric site covalent binding mechanism through the nucleophilic aromatic substitution (S N Ar) reaction, as well as its association with the closure of the major active site of PBP2a.
RESUMEN
The judicious selection of 5,7-dibromo-2-methy-8-quinolinol (BQ) as a Mn(II) ionophore results in the synthesis of Mn(BQ)2(DMSO)2·DMSO (1), a potent metalloantibiotic with a dual antimicrobial mode of action against four different strains of Staphylococcus aurous (SA) bacteria (MIC = 0.625 µg mL-1). Additionally, 1 can overcome ciprofloxacin-resistance in methicillin-resistant SA bacteria.
Asunto(s)
Antiinfecciosos , Dimetilsulfóxido , Ciprofloxacina/farmacología , Ionóforos , StaphylococcusRESUMEN
The enantioselective intermolecular sp(3) C-H functionalization at the allylic and benzylic positions was achieved using rhodium-catalyzed reactions with 4-phenyl-N-(methanesulfonyl)-1,2,3-triazole. The optimum dirhodium tetracarboxylate catalyst for these reactions was Rh2(S-NTTL)4. The rhodium-bound α-imino carbene intermediates preferentially reacted with tertiary over primary C-H bonds in good yields and moderate levels of enantioselectivity (66-82% ee). This work demonstrates that N-sulfonyltriazoles can be applied to the effective C-H functionalization at sp(3) C-H bonds of substrates containing additional functionality.