Synthesis of Bisindole Alkaloids and Their Mode of Action against Methicillin-Resistant Staphylococcus Aureus.

About 100,000 deaths are attributed annually to infections with methicillin-resistant Staphylococcus aureus (MRSA) despite concerted efforts toward vaccine development and clinical trials involving several preclinically efficacious drug candidates. This necessitates the development of alternative therapeutic options against this drug-resistant bacterial pathogen. Using the Masuda borylation-Suzuki coupling (MBSC) sequence, we previously synthesized and modified naturally occurring bisindole alkaloids, alocasin A, hyrtinadine A and scalaradine A, resulting in derivatives showing potent in vitro and in vivo antibacterial efficacy. Here, we report on a modified one-pot MBSC protocol for the synthesis of previously reported and several undescribed N-tosyl-protected bisindoles with anti-MRSA activities and moderate cytotoxicity against human monocytic and kidney cell lines. In continuation of the mode of action investigation of the previously synthesized membrane-permeabilizing hit compounds, mechanistic studies reveal that bisindoles impact the cytoplasmic membrane of Gram-positive bacteria by promiscuously interacting with lipid II and membrane phospholipids while rapidly dissipating membrane potential. The bactericidal and lipid II-interacting lead compounds 5c and 5f might be interesting starting points for drug development in the fight against MRSA.

Novel meriolin derivatives potently inhibit cell cycle progression and transcription in leukemia and lymphoma cells via inhibition of cyclin-dependent kinases (CDKs).

A key feature of cancer is the disruption of cell cycle regulation, which is characterized by the selective and abnormal activation of cyclin-dependent kinases (CDKs). Consequently, targeting CDKs via meriolins represents an attractive therapeutic approach for cancer therapy. Meriolins represent a semisynthetic compound class derived from meridianins and variolins with a known CDK inhibitory potential. Here, we analyzed the two novel derivatives meriolin 16 and meriolin 36 in comparison to other potent CDK inhibitors and could show that they displayed a high cytotoxic potential in different lymphoma and leukemia cell lines as well as in primary patient-derived lymphoma and leukemia cells. In a kinome screen, we showed that meriolin 16 and 36 prevalently inhibited most of the CDKs (such as CDK1, 2, 3, 5, 7, 8, 9, 12, 13, 16, 17, 18, 19, 20). In drug-to-target modeling studies, we predicted a common binding mode of meriolin 16 and 36 to the ATP-pocket of CDK2 and an additional flipped binding for meriolin 36. We could show that cell cycle progression and proliferation were blocked by abolishing phosphorylation of retinoblastoma protein (a major target of CDK2) at Ser612 and Thr82. Moreover, meriolin 16 prevented the CDK9-mediated phosphorylation of RNA polymerase II at Ser2 which is crucial for transcription initiation. This renders both meriolin derivatives as valuable anticancer drugs as they target three different Achilles' heels of the tumor: (1) inhibition of cell cycle progression and proliferation, (2) prevention of transcription, and (3) induction of cell death.

The complexometric behavior of selected aroyl-S,N-ketene acetals shows that they are more than AIEgens.

Using the established synthetic methods, aroyl-S,N-ketene acetals and subsequent bi- and multichromophores can be readily synthesized. Aside from pronounced AIE (aggregation induced emission) properties, these selected examples possess distinct complexometric behavior for various metals purely based on the underlying structural motifs. This affects the fluorescence properties of the materials which can be readily exploited for metal ion detection and for the formation of different metal-aroyl-S,N-ketene acetal complexes that were confirmed by Job plot analysis. In particular, gold(I), iron(III), and ruthenium (III) ions reveal complexation enhanced or quenched emission. For most dyes, weakly coodinating complexes were observed, only in case of a phenanthroline aroyl-S,N-ketene acetal multichromophore, measurements indicate the formation of a strongly coordinating complex. For this multichromophore, the complexation results in a loss of fluorescence intensity whereas for dimethylamino-aroyl-S,N-ketene acetals and bipyridine bichromophores, the observed quantum yield is nearly tripled upon complexation. Even if no stable complexes are formed, changes in absorption and emission properties allow for a simple ion detection.

Synthesis, Electronic, and Antibacterial Properties of 3,7-Di(hetero)aryl-substituted Phenothiazinyl N-Propyl Trimethylammonium Salts.

In this study, a library of 3,7-di(hetero)aryl-substituted 10-(3-trimethylammoniumpropyl)10H-phenothiazine salts is prepared. These title compounds and their precursors are reversible redox systems with tunable potentials. The Hammett correlation gives a very good correlation of the first oxidation potentials with σp parameters. Furthermore, the title compounds and their precursors are blue to green-blue emissive. Screening of the salts reveals for some derivatives a distinct inhibition of several pathogenic bacterial strains (Mycobacterium tuberculosis, Staphylococcus aureus, Escherichia coli, Aconetobacter baumannii, and Klebsiella pneumoniae) in the lower micromolar range.

Chemoselective Synthesis and Anti-Kinetoplastidal Properties of 2,6-Diaryl-4H-tetrahydro-thiopyran-4-one S-Oxides: Their Interplay in a Cascade of Redox Reactions from Diarylideneacetones.

2,6-Diaryl-4H-tetrahydro-thiopyran-4-ones and corresponding sulfoxide and sulfone derivatives were designed to lower the major toxicity of their parent anti-kinetoplatidal diarylideneacetones through a prodrug effect. Novel diastereoselective methodologies were developed and generalized from diarylideneacetones and 2,6-diaryl-4H-tetrahydro-thiopyran-4-ones to allow the introduction of a wide substitution profile and to prepare the related S-oxides. The in vitro biological activity and selectivity of diarylideneacetones, 2,6-diaryl-4H-tetrahydro-thiopyran-4-ones, and their S-sulfoxide and sulfone metabolites were evaluated against Trypanosoma brucei brucei, Trypanosoma cruzi, and various Leishmania species in comparison with their cytotoxicity against human fibroblasts hMRC-5. The data revealed that the sulfides, sulfoxides, and sulfones, in which the Michael acceptor sites are temporarily masked, are less toxic against mammal cells while the anti-trypanosomal potency was maintained against T. b. brucei, T. cruzi, L. infantum, and L. donovani, thus confirming the validity of the prodrug strategy. The mechanism of action is proposed to be due to the involvement of diarylideneacetones in cascades of redox reactions involving the trypanothione system. After Michael addition of the dithiol to the double bonds, resulting in an elongated polymer, the latter-upon S-oxidation, followed by syn-eliminations-fragments, under continuous release of reactive oxygen species and sulfenic/sulfonic species, causing the death of the trypanosomal parasites in the micromolar or submicromolar range with high selectivity indexes.

Polyacetylenes with (hetero)aryl-, styryl-, and amino-phenothiazinyl sidechains: synthesis and photophysics.

A novel generation of 7-aryl phenothiazinyl substituted polyacetylenes is readily accessible via controlled rhodium-catalyzed polymerization of the corresponding 3-ethynyl 7-aryl phenothiazines. The monomers are synthesized by Suzuki coupling, Heck coupling, or Buchwald-Hartwig amination, and Bestmann-Ohira reaction. This allows for the introduction of electron donating and releasing substituents with different ligation patterns. The obtained polymers display narrow molecular weight distributions, with very few exceptions, and are soluble in many organic solvents. The photophysical properties of novel monosubstituted polyacetylenes and corresponding monomers were compared. While the monomers exhibit strong emission in solution with quantum yields of up to 0.84 only selected polymers are luminescent (Φf = 0.06) and display moderate Stokes shifts and positive emission solvatochromism.

Novel meriolin derivatives activate the mitochondrial apoptosis pathway in the presence of antiapoptotic Bcl-2.

Meriolin derivatives represent a new class of kinase inhibitors with a pronounced cytotoxic potential. Here, we investigated a newly synthesized meriolin derivative (termed meriolin 16) that displayed a strong apoptotic potential in Jurkat leukemia and Ramos lymphoma cells. Meriolin 16 induced apoptosis in rapid kinetics (within 2-3 h) and more potently (IC50: 50 nM) than the previously described derivatives meriolin 31 and 36 [1]. Exposure of Ramos cells to meriolin 16, 31, or 36 for 5 min was sufficient to trigger severe and irreversible cytotoxicity. Apoptosis induction by all three meriolin derivatives was independent of death receptor signaling but required caspase-9 and Apaf-1 as central mediators of the mitochondrial death pathway. Meriolin-induced mitochondrial toxicity was demonstrated by disruption of the mitochondrial membrane potential (ΔΨm), mitochondrial release of proapoptotic Smac, processing of the dynamin-like GTPase OPA1, and subsequent fragmentation of mitochondria. Remarkably, all meriolin derivatives were able to activate the mitochondrial death pathway in Jurkat cells, even in the presence of the antiapoptotic Bcl-2 protein. In addition, meriolins were capable of inducing cell death in imatinib-resistant K562 and KCL22 chronic myeloid leukemia cells as well as in cisplatin-resistant J82 urothelial carcinoma and 2102EP germ cell tumor cells. Given the frequent inactivation of the mitochondrial apoptosis pathway by tumor cells, such as through overexpression of antiapoptotic Bcl-2, meriolin derivatives emerge as promising therapeutic agents for overcoming treatment resistance.

Acute effects of military aircraft noise on sedative and analgesic drug administrations in psychiatric patients: A case-time series analysis.

BACKGROUND: Existing evidence suggests that psychiatric patients are highly noise sensitive, and that noise exposure increases the risk for adverse mental health outcomes, such as psychiatric hospitalizations and even suicide. To investigate acute effects of noise in this vulnerable population, we assessed short-term associations between fighter jet noise and on-demand sedative and analgesic drug administrations in a psychiatric clinic located close to a military airfield in Switzerland. METHODS: We applied a case time series analysis with an hourly time resolution using distributed-lag models. Analysis was adjusted for long-term and seasonal trends, day of week, time of day, time-varying weather conditions and the week of stay. Noise exposure (hourly A-weighted equivalent continuous sound pressure levels (LAeq)) was modelled using detailed flight plans and noise footprints for different fighter jet and route combinations. Outcome data were available from the clinic's records. OUTCOMES: During the study period (06/2016-12/2021), 23,486 flights occurred. 5,968 clinical stays with a median length of 41 days (IQR: 28d, 50d) were recorded. The odds ratio (OR) for medication administration over the lag period of 3 hours after exposure was 1.016 (95 %CI: 1.006, 1.026) per 10 dB LAeq for sedatives and 1.032 (95 %CI: 1.016, 1.048) per 10 dB for analgesics. Effects were larger in multimorbid patients. INTERPRETATION: Case time series analysis is a novel method to investigate transient associations in observational data while minimizing risk of bias. Using an objectively recorded outcome measure, our results demonstrate that psychiatric patients are a vulnerable population, in which noise exposure can lead to symptom exacerbations and adverse events.

A Rational Design of Electrochemically and Photophysically Tunable Triarylamine Luminophores by Consecutive (Pseudo-)Four-Component Syntheses.

The concatenation of Suzuki coupling and two-fold Buchwald-Hartwig amination in sequentially palladium-catalyzed consecutive multicomponent syntheses paves a concise, convergent route to diversely functionalized para-biaryl-substituted triarylamines (p-bTAAs) from simple, readily available starting materials. An extensive library of p-bTAAs permits comprehensive investigations of their electronic properties by absorption and emission spectroscopy, cyclic voltammetry, and quantum chemical calculations, which contribute to a deep understanding of their electronic structure. The synthesized p-bTAAs exhibit tunable fluorescence from blue to yellow upon photonic excitation with quantum yields up to 98 % in solution and 92 % in the solid state. Furthermore, a pronounced bathochromic shift of the emission maxima by increasing solvent polarity indicates positive emission solvatochromism. Aggregation-induced enhanced emission (AIEE) in dimethyl sulfoxide (DMSO)/water mixtures causes the formation of intensely blue fluorescent aggregates. Cyclic voltammetry shows reversible first and second oxidations of p-bTAAs at low potentials, which are tunable by variation of the introduced para substituents. 3D Hammett plots resulting from the correlation of oxidation potentials and emission maxima with electronic substituent parameters emphasize the rational design of tailored p-bTAAs with predictable electrochemical and photophysical properties.

Synthesis and Photophysical Properties of Luminescent Phenothiazinyl Merocyanine Substituted Polyacetylenes.

A new generation of soluble phenothiazinyl merocyanine substituted polyacetylenes can be readily synthesized by rhodium-catalyzed polymerization of the corresponding 3-ethynyl phenothiazines, accessible by Sonogashira coupling and Knoevenagel condensation. UV/Vis and fluorescence spectroscopy of 7-acceptor-substituted phenothiazinyl polyacetylenes reveal that these polyacetylenes with conjugatively ligated merocyanines are luminescent in solution with positive emission solvatochromism and, in some cases, with distinct solid-state luminescence.

Electrocorticographic Activation Patterns of Electroencephalographic Microstates.

Electroencephalography (EEG) microstates are short successive periods of stable scalp field potentials representing spontaneous activation of brain resting-state networks. EEG microstates are assumed to mediate local activity patterns. To test this hypothesis, we correlated momentary global EEG microstate dynamics with the local temporo-spectral evolution of electrocorticography (ECoG) and stereotactic EEG (SEEG) depth electrode recordings. We hypothesized that these correlations involve the gamma band. We also hypothesized that the anatomical locations of these correlations would converge with those of previous studies using either combined functional magnetic resonance imaging (fMRI)-EEG or EEG source localization. We analyzed resting-state data (5 min) of simultaneous noninvasive scalp EEG and invasive ECoG and SEEG recordings of two participants. Data were recorded during the presurgical evaluation of pharmacoresistant epilepsy using subdural and intracranial electrodes. After standard preprocessing, we fitted a set of normative microstate template maps to the scalp EEG data. Using covariance mapping with EEG microstate timelines and ECoG/SEEG temporo-spectral evolutions as inputs, we identified systematic changes in the activation of ECoG/SEEG local field potentials in different frequency bands (theta, alpha, beta, and high-gamma) based on the presence of particular microstate classes. We found significant covariation of ECoG/SEEG spectral amplitudes with microstate timelines in all four frequency bands (p = 0.001, permutation test). The covariance patterns of the ECoG/SEEG electrodes during the different microstates of both participants were similar. To our knowledge, this is the first study to demonstrate distinct activation/deactivation patterns of frequency-domain ECoG local field potentials associated with simultaneous EEG microstates.

Domino Three-Component N-Acylation/[4 + 2] Cycloaddition/Alder-ene Synthesis of Polysubstituted Benzo[f]isoindole-4-carboxylic Acids.

Diversely substituted, partially saturated benzo[f]isoindole-4-carboxylic acids were synthesized by a new three-component reaction (3CR) starting from cinnamic amines (3-arylallylamines), maleimides, and maleic anhydride. The process consists of N-acylation of the amines by maleic anhydride, intramolecular [4 + 2] cycloaddition in vinylarenes (the IMDAV reaction), and the concluding Alder-ene reaction between Diels-Alder intermediates and maleimides. All of the reaction steps proceed in a highly regio- and stereoselective manner, furnishing five adjacent chiral centers and leading to a single diastereoisomer of the title compound. The efficiency of the transformation is secured by thermal conditions or utilization of soft Lewis acids (Yb(OTf)3) as catalysts. The kinetics and mechanism of the 3CR were studied by using dynamic 19F NMR. Based on the NMR data and density functional theory (DFT) calculations, the IMDAV, not the Alder-ene, reaction is the rate-limiting step of the entire process.

Alkynylated and triazole-linked aroyl-S,N-ketene acetals: one-pot synthesis of solid-state emissive dyes with aggregation-induced enhanced emission characteristics.

Alkynylated aroyl-S,N-ketene acetals are readily synthesized in mostly excellent yields by a Sonogashira reaction resulting in a substance library of more than 20 examples. Upon expansion of the reaction sequence by deprotection and concatenating of the copper-click reaction in a one-pot fashion, a library of 11 triazole-ligated aroyl-S,N-ketene acetals is readily accessible. All derivatives show pronounced solid-state emission and aggregation-induced emission properties depending on the nature of the alkynyl or the triazole substituents.

Cyclohexene-Embedded Dicyanomethylene Merocyanines - Consecutive Three-Component Coupling-Addition Synthesis and Chromophore Characteristics.

A concise and efficient consecutive three-component alkynylation-addition synthesis of cyclohexene-embedded dicyanomethylene merocyanines furnishes a small library of dyes in moderate to excellent yield. The dyes possess strong absorption coefficients of the longest wavelength absorption bands. According to the crystal structure, the small bond length alternations account for a highly delocalized electronic ground state. The electronic structure of the absorption bands is qualitatively rationalized by TDDFT calculations, which explain that intense HOMO-LUMO transitions along the merocyanine axis lead to cyanine similar Stokes shifts.

Consecutive four-component synthesis of trisubstituted 3-iodoindoles by an alkynylation-cyclization-iodination-alkylation sequence.

A library of 19 differently substituted 3-iodoindoles is generated by a consecutive four-component reaction starting from ortho-haloanilines, terminal alkynes, N-iodosuccinimide, and alkyl halides in yields of 11-69%. Initiated by a copper-free alkynylation, followed by a base-catalyzed cyclizive indole formation, electrophilic iodination, and finally electrophilic trapping of the intermediary indole anion with alkyl halides provides a concise one-pot synthesis of 3-iodoindoles. The latter are valuable substrates for Suzuki arylations, which are exemplified with the syntheses of four derivatives, some of them are blue emitters in solution and in the solid state, in good yield.

Aroyl-S,N-Ketene Acetals: Luminous Renaissance of a Class of Heterocyclic Compounds.

Aroyl-S,N-ketene acetals represent a peculiar class of heterocyclic merocyanines, compounds bearing pronounced and rather short dipoles with great push-pull characteristics that define their rich properties. They are accessible via a wide array of synthetic concepts and procedures, ranging from addition-elimination and condensation procedures up to rearrangement and metal-mediated reactions. With our work from 2020, aroyl-S,N-ketene acetals have been identified as powerful and promising dyes with pronounced and vastly tunable solid-state emission and aggregation-induced emission properties. One characteristic trademark of this class of dye molecules is the level of control that could be exerted, and which was thoroughly explored. Based on these results, the field was opened to extend the system to bi- and multichromophoric systems by the full toolkit of synthetic organic chemistry thus giving access to even more exciting properties and manifolded substance libraries capitalizing on the AIE properties. This review aims at outlining the reaction-based principles that allow for a swift and facile access to aroyl-S,N-ketene acetals, their methodical and structural evolution and the plethora of fluorescence and aggregation properties.

Diaroyl-S,N-ketene Acetals: Red-Shifted Solid-State and Aggregation-Induced Emitters from a One-Pot Synthesis.

Symmetric and unsymmetric diaroyl-S,N-ketene acetals can be readily accessed in consecutive syntheses in good to excellent yields by exploiting the inherent nucleophilic character of the methine position. Different aroyl-S,N-ketene acetals as well as acid chlorides yield a library of 19 diaroyl compounds with substitution and linker pattern-tunable emission properties, leading to a significant red-shift of emission in the solid and aggregated state, which was thoroughly investigated. Additionally, the stability of the luminescent aggregates is highly increased. In a follow-up one-pot procedure, pyrazolo-S,N-ketene acetals can easily be accessed employing a nucleophilic cyclocondensation.

Synthesis of Polysubstituted Pyrimidines through Palladium-Catalyzed Isocyanide Insertion to 2H-Azirines.

The domino process of the palladium-catalyzed coupling reaction of isocyanides with 2H-azirine provides various tetrasubstituted pyrimidines via one C-C bond and two C-N bond formations with satisfactory yields. The title compounds are obtained with good functional group tolerance, high atom economy, and broad substrate scopes.

Single molecule aggregation-induced dual and white-light emissive etherified aroyl-S,N-ketene acetals via one-pot synthesis.

Etherified aroyl-S,N-ketene acetals are readily synthesized by a novel one-pot addition-elimination-Williamson-etherification sequence. Although the underlying chromophore remains constant, derivatives show pronounced color-tuning of solid-state emission and AIE characteristics, whereas a hydroxy-methyl derivative represents an easily accessible mono molecular aggregation-induced white-light emitter.