RESUMEN
Polycyclic polyprenylated acylphloroglucinols (PPAPs) comprise a large group of compounds of mostly plant origin. The best-known compound is hyperforin from St. John's wort with its antidepressant, antitumor and antimicrobial properties. The chemical synthesis of PPAP variants allows the generation of compounds with improved activity and compatibility. Here, we studied the antimicrobial activity of two synthetic PPAP-derivatives, the water-insoluble PPAP23 and the water-soluble sodium salt PPAP53. In vitro, both compounds exhibited good activity against methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecium. Both compounds had no adverse effects on Galleria mellonella wax moth larvae. However, they were unable to protect the larvae from infection with S. aureus because components of the larval coelom neutralized the antimicrobial activity; a similar effect was also seen with serum albumin. In silico docking studies with PPAP53 revealed that it binds to the F1 pocket of human serum albumin with a binding energy of -7.5 kcal/mol. In an infection model of septic arthritis, PPAP23 decreased the formation of abscesses and S. aureus load in kidneys; in a mouse skin abscess model, topical treatment with PPAP53 reduced S. aureus counts. Both PPAPs were active against anaerobic Gram-positive gut bacteria such as neurotransmitter-producing Clostridium, Enterococcus or Ruminococcus species. Based on these results, we foresee possible applications in the decolonization of pathogens.
Asunto(s)
Cetonas , Staphylococcus aureus Resistente a Meticilina , Compuestos de Espiro , Animales , Humanos , Ratones , Antibacterianos/farmacología , Antibacterianos/química , Enterococcus faecium/efectos de los fármacos , Cetonas/química , Cetonas/farmacología , Larva/efectos de los fármacos , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Pruebas de Sensibilidad Microbiana , Simulación del Acoplamiento Molecular , Mariposas Nocturnas/efectos de los fármacos , Compuestos de Espiro/química , Compuestos de Espiro/farmacología , Infecciones Estafilocócicas/tratamiento farmacológicoRESUMEN
Based on some very recent results on Fe-catalyzed boron-source-dependent regiodivergent hydroborations of internal alkynes, we report here a boron-source-dependent but also ligand-dependent mechanistic trichotomy in borylative cyclizations. The choice of ligand plus boron source allows the synthesis of three isomeric borylative cyclization products starting from a common substrate and using the same precatalyst ((Ph3P)2Fe(CO)(NO)H) and sets the stage for the development of a unifying concept in Fe-catalyzed borylative cyclizations.
RESUMEN
In response to the pressing global challenge of antibiotic resistance, time efficient design and synthesis of novel antibiotics are of immense need. Polycyclic polyprenylated acylphloroglucinols (PPAP) were previously reported to effectively combat a range of gram-positive bacteria. Although the exact mode of action is still not clear, we conceptualized a late-stage divergent synthesis approach to expand our natural product-based PPAP library by 30 additional entities to perform SAR studies against methicillin-resistant Staphylococcus aureus (MRSA). Although at this point only data from cellular assays are available and understanding of molecular drug-target interactions are lacking, the experimental data were used to generate 3D-QSAR models via an artificial intelligence training and to identify a common pharmacophore model. The experimentally validated QSAR model enabled the estimation of anti-MRSA activities of a virtual compound library consisting of more than 100,000 in-silico generated B PPAPs, out of which the 20 most promising candidates were synthesized. These novel PPAPs revealed significantly improved cellular activities against MRSA with growth inhibition down to concentrations less than 1â µm.
Asunto(s)
Antibacterianos , Productos Biológicos , Staphylococcus aureus Resistente a Meticilina , Pruebas de Sensibilidad Microbiana , Floroglucinol , Relación Estructura-Actividad Cuantitativa , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Antibacterianos/farmacología , Antibacterianos/química , Antibacterianos/síntesis química , Productos Biológicos/química , Productos Biológicos/farmacología , Productos Biológicos/síntesis química , Floroglucinol/química , Floroglucinol/farmacología , Floroglucinol/síntesis química , Diseño de Fármacos , Compuestos Policíclicos/química , Compuestos Policíclicos/farmacología , Compuestos Policíclicos/síntesis químicaRESUMEN
We present a straightforward one-step process to access a range of novel p-diindolepyrazines via an unprecedented [n-Bu4N][Fe(CO)3(NO)] (TBA[Fe])-catalyzed intermolecular nitrogenative dimerization of various indole derivatives. Remarkably, tosylazide functions as a N1-synthon forming the central pyrazine unit that joins the two indole subunits. The catalytic transformation shows a good substrate scope, and the obtained products show interesting electronic properties.
RESUMEN
Zinc ion hybrid capacitors suffer from lack of reversibility and dendrite formation. An electrolyte, based on a solution of a zinc salt in acetonitrile and tetramethylene sulfone, allows smooth zinc deposition with high coulombic efficiency in a Zn||stainless steel cell (99.6% for 2880 cycles at 1.0 mA cm-2 , 1.0 mAh cm-2 ). A Zn||Zn cell operates stably for at least 7940 h at 1.0 mA cm-2 with an area capacity of 10 mAh cm-2 , or 648 h at 90% depth of discharge and 1 mA cm-2 , 9.0 mAh cm-2 . Molecular dynamics simulations reveal the reason for the excellent reversibility: The zinc cation is only weakly solvated than in pure tetramethylene sulfone with the closest atoms at 3.3 to 3.8 Å. With this electrolyte, a zinc||activated-carbon hybrid capacitor exhibits an operating voltage of 2.0 to 2.5 V, an energy-density of 135 Wh kg-1 and a power-density of 613 W kg-1 at 0.5 A g-1 . At the very high current-density of 15 A g-1 , 29.3 Wh kg-1 and 14 250 W kg-1 are achieved with 81.2% capacity retention over 9000 cycles.
RESUMEN
Benzylic amine derivatives are ubiquitous structural motifs in organic chemistry. Herein we report a direct synthesis of these compounds via a direct desulfonylative C-arylation of O-tosyl hydroxamates. The applicability of this Ru-catalyzed aminoalkylation is being exemplified by a set of late-stage functionalizations of natural products.
RESUMEN
Selective modulation of TRPC6 ion channels is a promising therapeutic approach for neurodegenerative diseases and depression. A significant advancement showcases the selective activation of TRPC6 through metalated type-B PPAP, termed PPAP53. This success stems from PPAP53's 1,3-diketone motif facilitating metal coordination. PPAP53 is water-soluble and as potent as hyperforin, the gold standard in this field. In contrast to type-A, type-B PPAPs offer advantages such as gram-scale synthesis, easy derivatization, and long-term stability. Our investigations reveal PPAP53 selectively binding to the C-terminus of TRPC6. Although cryoelectron microscopy has resolved the majority of the TRPC6 structure, the binding site in the C-terminus remained unresolved. To address this issue, we employed state-of-the-art artificial-intelligence-based protein structure prediction algorithms to predict the missing region. Our computational results, validated against experimental data, indicate that PPAP53 binds to the 777LLKL780-region of the C-terminus, thus providing critical insights into the binding mechanism of PPAP53.
Asunto(s)
Canales Catiónicos TRPC , Sitios de Unión , Microscopía por Crioelectrón , Canales Catiónicos TRPC/efectos de los fármacos , Canales Catiónicos TRPC/metabolismo , Canal Catiónico TRPC6/efectos de los fármacos , Floroglucinol/farmacología , Compuestos Policíclicos/farmacologíaRESUMEN
Pre-SARS-CoV-2, tuberculosis was the leading cause of death by a single pathogen. Repetitive exposure of Mycobacterium tuberculosis(Mtb) supported the development of multidrug- and extensively drug-resistant strains, demanding novel drugs. Hyperforin, a natural type A polyprenylated polycyclic acylphloroglucinol from St. John's wort, exhibits antidepressant and antibacterial effects also against Mtb. Yet, Hyperforin's instability limits the utility in clinical practice. Here, we present photo- and bench-stable type B PPAPs with enhanced antimycobacterial efficacy. PPAP22 emerged as a lead compound, further improved as the sodium salt PPAP53, drastically enhancing solubility. PPAP53 inhibits the growth of virulent extracellular and intracellular Mtb without harming primary human macrophages. Importantly, PPAP53 is active against drug-resistant strains of Mtb. Furthermore, we analyzed the in vitro properties of PPAP53 in terms of CYP induction and the PXR interaction. Taken together, we introduce type PPAPs as a new class of antimycobacterial compounds, with remarkable antibacterial activity and favorable biophysical properties.
Asunto(s)
Mycobacterium tuberculosis , Tuberculosis , Humanos , Terpenos/farmacología , Antibacterianos/farmacología , Antituberculosos/farmacologíaRESUMEN
Growth of dendrites, limited coulombic efficiency (CE), and the lack of high-voltage electrolytes restrict the commercialization of zinc batteries and capacitors. These issues are resolved by a new electrolyte, based on the zinc(II)-betaine complex [Zn(bet)2 ][NTf2 ]2 . Solutions in acetonitrile (AN) avoid dendrite formation. A Zn||Zn cell operates stably over 10 110 h (5055 cycles) at 0.2 mA cm-2 or 110 h at 50 mA cm-2 , and has an area capacity of 113 mAh cm-2 at 80% depth of discharge. A zinc-graphite battery performs at 2.6 V with a midpoint discharge-voltage of 2.4 V. The capacity-retention at 3 A g-1 (150 C) is 97% after 1000 cycles and 68% after 10 000 cycles. The charge/discharge time is about 24 s at 3.0 A g-1 with an energy density of 49 Wh kg-1 at a power density of 6864 W kg-1 based on the cathode. A zinc||activated-carbon ion-capacitor (coin cell) exhibits an operating-voltage window of 2.5 V, an energy density of 96 Wh kg-1 with a power density of 610 W kg-1 at 0.5 A g-1 . At 12 A g-1 , 36 Wh kg-1 , and 13 600 W kg-1 are achieved with 90% capacity-retention and an average CE of 96% over 10 000 cycles. Quantum-chemical methods and vibrational spectroscopy reveal [Zn(bet)2 (AN)2 ]2+ as the dominant complex in the electrolyte.
RESUMEN
Cycloisomerizations are powerful skeletal rearrangements that allow the construction of complex molecular architectures in an atom-economic way. We present here an unusual type of cyclopropyl enyne cycloisomerization that couples the process of a cycloisomerization with the activation of a C-C bond in cyclopropanes. A set of substituted non-canonical tricyclic cyclobutanes were synthesized under mild conditions using [(Ph3 P)2 Fe(CO)(NO)]BF4 as catalyst in good to excellent yields with high levels of stereocontrol.
Asunto(s)
Ciclobutanos , Catálisis , Ciclobutanos/química , Ciclopropanos/química , HierroRESUMEN
Covalent organic frameworks (COFs) offer vast structural and chemical diversity enabling a wide and growing range of applications. While COFs are well-established as heterogeneous catalysts, so far, their high and ordered porosity has scarcely been utilized to its full potential when it comes to spatially confined reactions in COF pores to alter the outcome of reactions. Here, we present a highly porous and crystalline, large-pore COF as catalytic support in α,ω-diene ring-closing metathesis reactions, leading to increased macrocyclization selectivity. COF pore-wall modification by immobilization of a Grubbs-Hoveyda-type catalyst via a mild silylation reaction provides a molecularly precise heterogeneous olefin metathesis catalyst. An increased macro(mono)cyclization (MMC) selectivity over oligomerization (O) for the heterogeneous COF-catalyst (MMC:O=1.35) of up to 51 % compared to the homogeneous catalyst (MMC:O=0.90) was observed along with a substrate-size dependency in selectivity, pointing to diffusion limitations induced by the pore confinement.
Asunto(s)
Alquenos , Estructuras Metalorgánicas , Catálisis , Ciclización , PorosidadRESUMEN
The nucleophilic Fe-complex Bu4N[Fe(CO)3(NO)] (TBA[Fe]) catalyzes the cyclopropanation of enynes to substituted propargyl cyclopropanes using diazoesters as carbene surrogates. The catalyst can be activated either thermally in the presence of catalytic amounts of 4-nitroanisole or under photochemical conditions. Cyclopropanation occurs selectively at the enyne moiety; alternative olefinic moieties remain intact.
RESUMEN
A method for the selective deuteration of polyfunctional organic molecules using catalytic amounts of [RuCl2 (PPh3 )3 ] and D2 O as a deuterium source is presented. Through variation of additives like CuI, KOH, and various amounts of zinc powder, orthogonal chemoselectivities in the deuteration process are observed. Mechanistic investigation indicates the presence of different, defined Ru-complexes under the given specific conditions.
RESUMEN
The nucleophilic iron complex Bu4 N[Fe(CO)3 (NO)] (TBA[Fe]) is an active catalyst in C-H-amination but also in proton-transfer catalysis. Herein, we describe the successful use of this complex as a proton-transfer catalyst in the cyclocondensation reaction between azides and ketones to the corresponding 1,2,3-triazoles. Cross-experiments indicate that the proton-transfer catalysis is significantly faster than the nitrene-transfer catalysis, which would lead to the C-H amination product. An example of a successful sequential Dimroth triazole-indoline synthesis to the corresponding triazole-substituted indolines is presented.
RESUMEN
A practical method for generation of acylcyanides devoid of any external cyanide sources is presented that relies on a mild Ru-catalyzed selective C-H-oxidation of benzylic nitriles. The starting materials are smoothly generated through condensation of the corresponding carboxylic acid amides using silanes. The obtained acylcyanides can be employed in a plethora of transformation as exemplified to some larger extend in the sequence of C-H-oxidation-Tischenko-rearrangement for the generation of structurally diverse benzoyloxycyanohydrines.
RESUMEN
A short enantioselective total synthesis of englerinâ A, a guaiane sesquiterpene with significant inâ vitro antitumor activity, is reported. Key features of this total synthesis are an organocatalytic asymmetric decarboxylative aldol reaction, a neighboring-group-participating [4+3] cycloaddition, a novel one-pot Heck coupling/regioselective 1,4-hydrosilylation/Tamao-Fleming oxidation cascade, and a kinetic CBS reduction, generating the optically pure natural product in 6.7 % overall yield over twelve steps starting from methylglyoxal. Selective saponification of the more reactive glycolic ester moiety of englerinâ A also gave (-)-englerinâ B.
Asunto(s)
Productos Biológicos/síntesis química , Sesquiterpenos de Guayano/síntesis química , Productos Biológicos/química , Conformación Molecular , Sesquiterpenos de Guayano/química , EstereoisomerismoRESUMEN
Recently, a series of endo-type B polycyclic polyprenylated acylphloroglucinols (PPAP) derivatives with high antimicrobial activities were chemically synthesized. One of the derivatives, PPAP 23, which showed high antimicrobial activity and low cytotoxicity, was chosen for further investigation of its bactericidal profiles and mode of action. PPAP 23 showed a better efficacy in killing methicillin resistant Staphylococcus aureus (MRSA) and decreasing the metabolic activity of 5-day-old biofilm cells than vancomycin. Moreover, S. aureus did not appear to develop resistance against PPAP 23. The antimicrobial mechanism of PPAP 23 was investigated by RNA-seq combined with phenotypic and biochemical approaches. RNA-seq suggested that PPAP 23 signaled iron overload to the bacterial cells because genes involved in iron transport were downregulated and iron storage gene was upregulated by PPAP 23. PPAP 23 affected the membrane integrity but did not induce pore formation; it inhibited bacterial respiration. PPAP 23 preferentially inhibited Fe-S cluster enzymes; it has a mild iron chelating activity and supplementation of exogenous iron attenuated its antimicrobial activity. PPAP 23 was more effective in inhibiting the growth of S. aureus under iron-restricted condition. The crystal structure of a benzylated analog of PPAP 23 showed a highly defined octahedral coordination of three PPAP ligands around a Fe (3+) core. This suggests that PPAPs are generally capable of iron chelation and are able to form defined stable complexes. PPAP 23 was found to induce reactive oxygen species (ROS) and oxidative stress. Fluorescence microscopic analysis showed that PPAP 23 caused an enlargement of the bacterial cells, perturbed the membrane, and dislocated the nucleoid. Taken together, we postulate that PPAP 23 interacts with the cytoplasmic membrane with its hydrophobic pocket and interferes with the iron metabolism to exert its antimicrobial activity in Staphylococcus aureus.
RESUMEN
Cationic Fe complexes of the general type [(Ph3 P)2 Fe(CO)(NO)]X (X=BF4 , BArF4 ) catalyze the redox-neutral cycloisomerization of 1,6- and 1,7-enyneacetates to afford bicyclic cyclobutanes under mild conditions in good yields and diastereoselectivities.
RESUMEN
A concise enantioselective total synthesis of three sesquiterpenoid alkaloids-(-)-dendrobine, (-)-mubironine B, and (-)-dendroxine-is presented, which highlights the state-of-art catalytic methods, including enantioselective Diels-Alder cycloaddition, iron-catalyzed aerobic lactonization, copper-catalyzed cycloisomerization, and free-radical-initiated hydroazidation.
RESUMEN
A cycloisomerization of aryl allenyl ketones to 3-arylidene-indan-1-ones using a cationic Fe-complex as a catalyst is reported. The catalyst opens a synthetically interesting reaction pathway to this surprisingly underrepresented class of indanones that are not accessible using alternative catalytic systems.