In-depth analysis of isochorismate synthase-derived metabolism in plant immunity: Identification of meta-substituted benzoates and salicyloyl-malate.

Isochorismate-derived metabolism enables biosynthesis of the plant defense hormone salicylic acid (SA) and its derivatives. In Arabidopsis thaliana, the stress-induced accumulation of SA depends on ISOCHORISMATE SYNTHASE1 (ICS1) and also requires the presumed isochorismate transporter ENHANCED DISEASE SUSCEPTIBILITY5 (EDS5) and the GH3 enzyme avrPphB SUSCEPTIBLE3 (PBS3). By comparative metabolite and structural analyses, we identified several hitherto unreported ICS1- and EDS5-dependent, biotic stress-inducible Arabidopsis metabolites. These involve meta-substituted SA derivatives (5-formyl-SA, 5-carboxy-SA, 5-carboxymethyl-SA), their benzoic acid (BA) analogs (3-formyl-BA, 3-carboxy-BA, 3-carboxymethyl-BA), and besides the previously detected salicyloyl-aspartate (SA-Asp), the ester conjugate salicyloyl-malate (SA-Mal). SA functions as a biosynthetic precursor for SA-Mal and SA-Asp, but not for the meta-substituted SA- and BA-derivatives, which accumulate to moderate levels at later stages of bacterial infection. Interestingly, Arabidopsis leaves possess oxidizing activity to effectively convert meta-formyl- into meta-carboxy-SA/BAs. In contrast to SA, exogenously applied meta-substituted SA/BA-derivatives and SA-Mal exert a moderate impact on plant immunity and defence-related gene expression. While the isochorismate-derived metabolites are negatively regulated by the SA receptor NON-EXPRESSOR OF PR GENES1, SA conjugates (SA-Mal, SA-Asp, SA-glucose conjugates) and meta-substituted SA/BA-derivatives are oppositely affected by PBS3. Notably, our data indicate a PBS3-independent path to isochorismate-derived SA at later stages of bacterial infection, which does not considerably impact immune-related characteristics. Moreover, our results argue against a previously proposed role of EDS5 in the biosynthesis of the immune signal N-hydroxypipecolic acid and associated transport processes. We propose a significantly extended biochemical scheme of plant isochorismate metabolism that involves an alternative generation mode for benzoate- and salicylate-derivatives.

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, 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.

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.

Multicomponent syntheses of pyrazoles via (3 + 2)-cyclocondensation and (3 + 2)-cycloaddition key steps.

Pyrazoles are rarely found in nature but are traditionally used in the agrochemical and pharmaceutical industries, while other areas of use are also actively developing. However, they have also found numerous other applications. The search for new and efficient syntheses of these heterocycles is therefore highly relevant. The modular concept of multicomponent reactions (MCR) has paved a broad alley to heteroaromatics. The advantages over traditional methods are the broader scope and increased efficiency of these reactions. In particular, traditional multistep syntheses of pyrazoles have considerably been extended by MCR. Progress has been made in the cyclocondensation of 1,3-dielectrophiles that are generated in situ. Limitations in the regioselectivity of cyclocondensation with 1,3-dicarbonyls were overcome by the addition-cyclocondensation of α,ß-unsaturated ketones. Embedding 1,3-dipolar cycloadditions into a one-pot process has additionally been developed for concise syntheses of pyrazoles. The MCR strategy also allows for concatenating classical condensation-based methodology with modern cross-coupling and radical chemistry, as well as providing versatile synthetic approaches to pyrazoles. This overview summarizes the most important MCR syntheses of pyrazoles based on ring-forming sequences in a flashlight fashion.

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.

3-Ligated Phenothiazinyl-terephthalonitrile Dyads and Triads - Synthesis, Electronic Properties, Delayed Fluorescence and Electronic Structure.

The bromine-lithium exchange-borylation-Suzuki sequence efficiently furnishes phenothiazine-terephthalonitrile donor-acceptor dyads and triads in high yields. In contrast to most phenothiazine-acceptor conjugates the title compounds are ligated in p-position to the phenothiazine nitrogen atom. Moreover, the acceptors are either directly linked or ligated by an arylene bridge and p-anisyl N-substituents on the phenothiazine are chosen to lock the tricycle into an intra-configuration. Cyclic voltammetry reveals effects of bridging and ligation of the N-substituent. Optical spectroscopy likewise displays similar band gaps, large Stokes shifts and substantial to high quantum yields in solution, in the solid state and in PMMA matrix. Time-resolved fluorescence spectroscopy indicates quite long fluorescence decay times in solution and emission components in the microsecond time range. TADF properties are further assessed by fluorescence increase in deoxygenated solution, gated emission spectroscopy and temperature-dependent determination of phosphorescence. The nature of the electronically excited states is investigated by DFT/MRCI. While for the directly ligated dyad a singlet-triplet energy gap Δ E ( S 1 - T 1 ) ${{E}_{{({\rm S}}_{1}-{{\rm T}}_{1})}{\rm \ }}$ of 0.24 eV can be estimated and is consistently confirmed by quantum chemical calculations on the lowest energy conformer, even lower Δ E ( S 1 - T 1 ) ${{\rm \Delta }{E}_{{(S}_{1}-{T}_{1})}{\rm \ }}$ of 0.029 and 0.008 eV are estimated for the investigated dyads and the triad in the solid state and in PMMA matrix.

A Thermally Activated Delayed Fluorescence Emitter Investigated by Time-Resolved Near-Infrared Spectroscopy.

Emitters for organic light-emitting diodes (OLEDs) based on thermally activated delayed fluorescence (TADF) require small singlet (S1 )-triplet (T1 ) energy gaps as well as fast intersystem crossing (ISC) transitions. These transitions can be mediated by vibronic mixing with higher excited states Sn and Tn (n=2, 3, 4, …). For a prototypical TADF emitter consisting of a triarylamine and a dicyanobenzene moiety (TAA-DCN) it is shown that these higher states can be located energetically by time-resolved near-infrared (NIR) spectroscopy.

Bis[1]benzothieno[1,4]thiaborins as a Platform for BODIPY Singlet Oxygen Photosensitizers.

A synthetic approach to two regioisomeric π-electron extended [1,4]thiaborins annulated with two benzothiophene units has been developed. The central thiaborin rings of the boracycles obtained exhibit different electronic properties; this is reflected in their different aromatic characters, boron Lewis acidity and UV-vis spectroscopic behavior. Thiaborins were converted to boron dipyrromethene (BODIPY) complexes. Their emission spectra exhibit two distinct bands resulting from 1 LE and 1 CT transitions. Strong near-infrared phosphorescence in Zeonex thin films at 77 K indicates efficient intersystem crossing and the formation of triplet states. Separation of HOMO and LUMO orbitals between boracyclic and BODIPY moieties facilitates electron transfer to a 1 CT state followed by a transition to the 3 LE triplet state located on the ligand. These unique properties of spiro thiaborin-BODIPY complexes were explored for their application as singlet-oxygen photosensitizers. They show excellent photocatalytic performance with singlet oxygen quantum yields reaching 77 % and full conversion of the model organic substrate achieved after 1.5 h with only 0.05 % mol catalyst load.

Bis[1]benzothieno[1,4]thiaborins as a Platform for BODIPY Singlet Oxygen Photosensitizers.

Invited for the cover of this issue are Krzysztof Durka and co-workers at Warsaw University of Technology, University of Warsaw, Silesian University of Technology and Heinrich-Heine-Universität. The image depicts the generation of singlet oxygen by the BODIPY photosensitizer. Read the full text of the article at 10.1002/chem.202300680.

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.

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.

A Survey on the Synthesis of Variolins, Meridianins, and Meriolins-Naturally Occurring Marine (aza)Indole Alkaloids and Their Semisynthetic Derivatives.

Marine natural products are a source of essential significance due to a plethora of highly diverse biological properties. The naturally occurring (aza)indole alkaloids variolin B (1), meridianins (2), and their synthetic hybrids meriolins (3) exhibit potent kinase inhibitory activities and have aroused considerable interest in the past two decades. Therefore, the immense demand for versatile synthetic accesses to these structures has considerably increased. This review surveys the synthetic pathways to these naturally occurring alkaloids and their semisynthetic derivatives.

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.

Solid-State Emission and Aggregate Emission of Aroyl- S,N-Ketene Acetals Are Controlled and Tuned by Their Substitution Pattern.

Aroyl-S,N-ketene acetals are a novel highly diverse class of aggregation-induced emission fluorogens (AIEgens) with a plethora of interesting properties. An expanded compound library of more than 110 dyes set the stage for the first qualitative control and tuneability of all aspects of their photophysical properties. The interplay of substituents not only allows tuning and prediction of the emission color, but also of the intensity, and quantum yields both in solids and in the aggregated state; these can be rationalized by scrutinizing intermolecular interactions in the crystalline solid state.

Highly Deep-Blue Luminescent Twisted Diphenylamino Terphenyl Emitters by Bromine-Lithium Exchange Borylation-Suzuki Sequence.

Four novel intensively blue luminescent chromophores were readily synthesized by bromine-lithium exchange borylation-Suzuki (BLEBS) sequence in moderate to good yields. Their electronic properties were studied by absorption and emission spectroscopy and quantum chemical calculations revealing deep-blue emission in solution as well as in the solid state and upon embedding into a PMMA (polymethylmethacrylate) matrix with small FWHM (full width at half maximum) values and CIE y values smaller than 0.1. Moreover, high photoluminescence quantum yields (PLQY), partially close to unity, are found.

BOPPY-based novel fluorescent dopamine D2 and D3 receptor ligands.

Dopamine is one of the crucial neurotransmitters in the human brain. Its out-of-range concentration can lead to various neurological diseases with special interest for dopamine D2 and D3 receptor subtypes. Although BODIPY is a highly versatile structural moiety for fluorescence labeling, we have looked out for structurally related pyridine-based moieties. We used BOPPY labelling of well-described D2R/D3R pharmacophores to obtain ligands with moderate to low nanomolar binding affinities as well as low to excellent quantum yields for bright fluorescence ligands. To best of our knowledge, this is the first report on the application of BOPPY fluorophores to GPCR ligands. This approach offers a general applicable way for fluorescence labelling via primary aliphatic amine elements.

Concise Syntheses of Marine (Bis)indole Alkaloids Meridianin C, D, F, and G and Scalaridine A via One-Pot Masuda Borylation-Suzuki Coupling Sequence.

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.