Helvetica Chimica Acta最新文献

Pyrrole is recognized as a critical component in various natural molecules and bioactive products, making it a focal point in organic synthesis. In this study, we report a novel photoredox strategy that leverages visible light to catalyze the synthesis of tetra-C-substituted pyrrole derivatives from enamines, employing acridine and a cobaloxime as catalysts. This method offers significant advantages, including the elimination of external oxidants and the capability to conduct reactions under mild conditions, thereby expanding the range of viable pyrrole derivatives while maintaining functional group compatibility. Mechanism investigations demonstrated that radical species were involved in the process and light irradiation was essential for the efficient transformation.

Infectious diseases pose a significant threat to global healthcare, especially with the rapid emergence of antimicrobial resistance and limited development of antimicrobials. Hence, the search for new and effective antimicrobial is paramount. Benzimidazole represents a unique, aromatic heterocycle with broad spectrum of biological applications. The present study aimed to evaluate the antibacterial and antifungal activities, and molecular docking studies of N1-substituted 5-alkylsulfonyl benzimidazole derivatives (23–36) synthesized in our previous work. The compounds were tested for their in vitro antimicrobial activity against diverse strains of Gram-positive and Gram-negative bacteria, and fungal species using the microdilution assay. In silico docking analysis of the most promising compounds was also investigated against DNAGyr and DHFR targets to simulate the ligand-receptor interaction. Compound 26, bearing cyclohexyl and 3,4-difluorophenyl moieties at the N1 and C2 positions of the benzimidazole ring, respectively displayed the most potent antibacterial activity against E. faecalis (MIC = 12.5 µg/mL), and the most potent antifungal activity (MIC = 16 µg/mL) against Candida albicans and Candida parapsilosis. The molecular docking analysis provided useful insights into the interaction of the molecules with key amino acid residues. This compound provides useful lead for the development of novel antibacterial and antifungal agent against susceptible organisms.

Dynamic covalent chemistry involving conjugate addition requires reversibility under specific conditions. In classical systems, reversible Michael addition of thiols is achieved using α-cyano acrylamides. The more recent oxSTEF reagents introduce β,β-bissulf(ox)ido enones instead to achieve reversibility of conjugate addition. The objective of this study was to investigate the activity of oxSTEF reagents in the context of thiol-mediated uptake (TMU) into cells, in comparison as well as in combination with conventional reversible Michael acceptors. Whereas none of tested oxSTEF reagents enables or inhibits TMU significantly, some activate the TMU of conventional α-cyano acrylamides (cyclic β-sulfido-β-sulfoxido enones), and others activate TMU of α-helical thioredoxin mimics through intriguing and selective tetrel-centered dynamic covalent exchange cascades. Activated by an unorthodox oxSTEF Michael acceptor, classical reversible Michael acceptors emerge as the most active monomeric TMU probes known today.

1,3-Dialkyltriazenides are isolobal to amidinates, and both ligands are popular in atomic layer deposition. Given our recent success with the N,N’-diisopropylacetamidinate (DIA) ligand in surface organometallic chemistry, we investigated the 1,3-tert-butyltriazenide (DTZ) ligand to stabilize Ni- and Pd-allyl complexes for the generation of supported nanoparticles. Using the analogous synthetic pathway employed for allyl-amidinate complexes, the formation of dinuclear structures was obtained, where two triazenide ligands bridge the metal centers. Grafting on SiO_2-700 was almost quantitative for {Ni(η³-allyl)(µ-DTZ)}₂ while only partial for {Pd(η³-allyl)(µ-DTZ)}₂ (ca. 50%), contrasting what was observed for the corresponding amidinate derivatives that grafted almost quantitatively for both Ni and Pd. Heat treatment of the grafted materials under a flow of H₂ yielded supported nanoparticles (Ni: 1.1 nm, Pd: 1.3 nm) that were significantly smaller than those obtained with the respective amidinate complexes and feature very narrow size distribution (standard deviation σ = 0.2 nm for Ni, 0.3 nm for Pd). Hence, the presented complexes are viable precursors for the generation of small and narrowly dispersed supported nanoparticles.

Nitroxides such as 2,2,6,6-tetramethylpiperidin-N-oxyl (TEMPO) are the quintessential organic radicals. They are commonly used to trap alkyl radicals in controlled radical polymerizations, synthetic transformations and mechanistic experiments, and peroxyl radicals when applied as radical-trapping antioxidants (RTAs). Relatively little is known about their sulfur analogs (N-thiyl radicals, R₂NS• and dithiobisamines, R₂NS-SNR₂). We found that dithiobisamines of moderate steric bulk (including (TEMPS)₂, the dimer of the sulfur analog of TEMPO), trapped peroxyl radicals with rate constants up to 1.2 × 10⁶ m⁻¹s⁻¹ (at 100 °C) – similar to TEMPO. Unlike TEMPO, their radical-trapping activity was not catalytic, independent of the rate of radical initiation and still operative in saturated hydrocarbons – implying a distinct mechanism. Additional experimental data and computations point to a homolytic substitution mechanism, analogous to that recently elucidated for tetrasulfides. In the absence of O₂, alkyl radicals and dithiobisamines react to form sulfenamides, which may be exploited for synthetic purposes.

I chose chemistry/biology as a career because I enjoy cooking and baking, i.e., synthesizing compounds seemed like the natural next step. The secret of being a successful scientist is to stay true to yourself. I chose my field of research because it lets me combine various scientific interests, from the materials synthesis (chemistry) to fundamental light-matter interactions (physics) and devices (engineering).

I chose my field of research (photochemistry) because I find it fascinating. The combination of lasers and colorful molecules makes me feel like I am inside a Sci-Fi show. My motivation in difficult times is that there is always light at the end of the tunnel, and that it will always be sunny after a storm. My favorite quote is “it's better to have it and not need it than to need it and not have it”.

This study presents a workflow for rapidly assessing the applicability of Ir-catalyzed C─H borylation across structurally diverse heterocyclic fragments relevant to discovery chemistry. Leveraging cheminformatics, we have selected different N-containing bicyclic scaffolds and evaluated various reaction conditions via a high-throughput experimentation (HTE) platform. The diversified screening approach revealed suitable substrate-specific catalytic systems. The workflow integrates several key steps: 1) defining a focused subset of relevant heterocyclic scaffolds, 2) selecting structurally diverse scaffolds using clustering algorithms, 3) conducting HTE screening with multiple catalytic systems, and 4) scaling up promising hits in a high-throughput fashion. This approach enabled rapid exploration of reaction scope and identification of suitable conditions for various substrates. The study demonstrates the power of combining cheminformatics, HTE, and strategic experimental design to accelerate the evaluation and optimization of synthetic methodologies, with potential future implications for lead optimization in drug discovery and agrochemical development.

In this study, we report on the use of mechanochemistry for the synthesis of trifluoromethylated isoindolinones via a cascade radical sequence involving intermolecular addition/cyclization reactions of ynamides. This minimum solvent approach, involving liquid-assisted grinding, provides the products in good yields with complete E stereoselectivity, contrasting with the E/Z mixtures obtained under previously reported photoredox conditions. Mechanistic investigations revealed two complementary activation pathways: mechanical activation alone can trigger the radical cascade, while the presence of piezoelectric materials (BaTiO₃) significantly accelerates product formation. Furthermore, we identified an unexpected role of Celite® as an abrasive agent that promotes metal leaching and enables alternative activation pathways. This methodology showcases mechanochemistry as a valuable alternative to photoredox catalysis for stereoselective radical transformations, with distinct mechanistic advantages that can be strategically exploited.

Plasmodium falciparum dihydrofolate reductase-thymidylate synthase (PfDHFR-TS) is a well-defined antimalarial target of antifolate drugs. However, the emergence of parasite resistance to antifolate medications is the primary reason for the unsuccessful treatment of malaria. In this work, repurposing of anticancer drugs through virtual screening was conducted to identify critical interactions with quadruple type (qmPfDHFR-TS) and hDHFR (human dihydrofolate reductase). Three anticancer drugs-pralatrexate (PRA), pemetrexed (PME), and dasatinib (DAS) - exhibited significant binding interactions with qmPfDHFR-TS and hDHFR. The binding stability of PRA and the reference compound, P218, was determined using principal component analysis (PCA) and free energy landscape (FEL) analyses. Additionally, the key binding interaction patterns of qmPfDHFR-TS and hDHFR was further investigated through quantum chemical calculations. The PRA complex and P218 complex display meaningful H-bond interactions with Asp54, Arg59, and Arg122, as well as a π–π interaction with Phe58, in the qmPfDHFR-TS structure. For hDHFR, it was found that P218 and PRA do not establish H-bond interactions with Arg70, which is the conserved residue in hDHFR. Furthermore, this discovery was validated by conducting enzyme inhibition tests, which demonstrated the capacity of these compounds to inhibit PfDHFR enzymes. As a result, pralatrexate shows potential as an effective inhibitor against the mutant type of the PfDHFR enzyme.