Search

The growing demands for X-ray imaging applications impose diverse and stringent requirements on advanced X-ray detectors. Among these, flexibility stands out as the most expected characteristic for next-generation X-ray detectors. Flexible X-ray detectors can spatially conform to nonflat surfaces, substantially improving the imaging resolution, reducing the X-ray exposure dosage, and enabling extended application opportunities that are hardly achievable by conventional rigid flat-panel detectors. Over the past years, indirect- and direct-conversion flexible X-ray detectors have made marvelous achievements. In particular, microscale and nanoscale engineering technologies play a pivotal role in defining the optical, electrical, and mechanical properties of flexible X-ray detectors. In this Perspective, we spotlight recent landmark advancements in flexible X-ray detectors from the aspects of micro/nano engineering strategies, which are broadly categorized into two prevailing modalities: materials-in-substrate and materials-on-substrate. We also discuss existing challenges hindering the development of flexible X-ray detectors, as well as prospective research opportunities to mitigate these issues.

Multicomponent reactions represent a powerful method for building complex molecules from structurally simple starting materials. Herein, we report a novel three-component radical-polar crossover reaction involving a tandem addition reaction of two different olefins, which is initiated by the selective addition of fluorosulfonyl radicals to alkyl alkenes. This tandem process provides facile and effective access to multiple functionalized aliphatic sulfonyl fluoride molecules. Further transformation of the products is also demonstrated.

The introduction of sulfonyl fluoride groups into bioactive molecules can often bring about enhanced biological activity, which has attracted more research interest in chemical biology and drug development in recent years. Here, we report the development of a radical fluorosulfonylation of alkenes/intramolecular arylation cascade for the construction of chromanes with sulfonyl fluoride groups attached. The radical 1,2-fluorosulfonyl arylation reactions proceed well in both endo and exo cyclization fashions, allowing for further variation of the distance between the chromane core and the sulfonyl fluoride group.

In this study, from experiments and theoretical calculation, we reported that Ti 3 C 2 MXene can be applied as sensors for NH 3 detection at room temperature with high selectivity. Ti 3 C 2 MXene, a novel two-dimensional carbide, was prepared by etching off Al atoms from Ti 3 AlC 2 . The as-prepared multilayer Ti 3 C 2 MXene powders were delaminated to a single layer by intercalation and ultrasonic dispersion. The colloidal suspension of single-layer Ti 3 C 2 -MXene was coated on the surface of ceramic tubes to construct sensors for gas detection. Thereafter, the sensors were used to detect various gases (CH 4 , H 2 S, H 2 O, NH 3 , NO, ethanol, methanol, and acetone) with a concentration of 500 ppm at room temperature. Ti 3 C 2 MXene-based sensors have high selectivity to NH 3 compared with other gases. The response to NH 3 was 6.13%, which was four times the second highest response (1.5% to ethanol gas). To understand the high selectivity, first-principles calculations were conducted to explore adsorption behaviors. From adsorption energy, adsorbed geometry, and charge transfer, it was confirmed that Ti 3 C 2 MXene theoretically has a high selectivity to NH 3 , compared with other gases in this experiment. Moreover, the response of the sensor to NH 3 increased almost linearly with NH 3 concentration from 10 to 700 ppm. The humidity tests and cycle tests of NH 3 showed that the Ti 3 C 2 MXene-based gas sensor has excellent performances for NH 3 detection at room temperature.

In the preceding manuscript [ Moreau et al. 2018 , 10.1021/acs.jmedchem.7b01691 ] we described a successful fragment-based lead discovery (FBLD) strategy for discovery of bacterial phosphopantetheine adenylyltransferase inhibitors (PPAT, CoaD). Following several rounds of optimization two promising lead compounds were identified: triazolopyrimidinone 3 and 4-azabenzimidazole 4. Here we disclose our efforts to further optimize these two leads for on-target potency and Gram-negative cellular activity. Enabled by a robust X-ray crystallography system, our structure-based inhibitor design approach delivered compounds with biochemical potencies 4-5 orders of magnitude greater than their respective fragment starting points. Additional optimization was guided by observations on bacterial permeability and physicochemical properties, which ultimately led to the identification of PPAT inhibitors with cellular activity against wild-type E. coli.

The discovery and development of new antibiotics capable of curing infections due to multidrug-resistant and pandrug-resistant Gram-negative bacteria are a major challenge with fundamental importance to our global healthcare system. Part of our broad program at Novartis to address this urgent, unmet need includes the search for new agents that inhibit novel bacterial targets. Here we report the discovery and hit-to-lead optimization of new inhibitors of phosphopantetheine adenylyltransferase (PPAT) from Gram-negative bacteria. Utilizing a fragment-based screening approach, we discovered a number of unique scaffolds capable of interacting with the pantetheine site of E. coli PPAT and inhibiting enzymatic activity, including triazolopyrimidinone 6. Structure-based optimization resulted in the identification of two lead compounds as selective, small molecule inhibitors of bacterial PPAT: triazolopyrimidinone 53 and azabenzimidazole 54 efficiently inhibited E. coli and P. aeruginosa PPAT and displayed modest cellular potency against the efflux-deficient E. coli Δ tolC mutant strain.

Over the past several decades, the frequency of antibacterial resistance in hospitals, including multidrug resistance (MDR) and its association with serious infectious diseases, has increased at alarming rates. Pseudomonas aeruginosa is a leading cause of nosocomial infections, and resistance to virtually all approved antibacterial agents is emerging in this pathogen. To address the need for new agents to treat MDR P. aeruginosa, we focused on inhibiting the first committed step in the biosynthesis of lipid A, the deacetylation of uridyldiphospho-3-O-(R-hydroxydecanoyl)-N-acetylglucosamine by the enzyme LpxC. We approached this through the design, synthesis, and biological evaluation of novel hydroxamic acid LpxC inhibitors, exemplified by 1, where cytotoxicity against mammalian cell lines was reduced, solubility and plasma-protein binding were improved while retaining potent anti-pseudomonal activity in vitro and in vivo.

The synthesis of polyfunctionalized aminothioalkenes has been realized via the direct C-H sulfenylation of enaminones and analogous enamines. These cross-coupling reactions have been achieved by simple KIO3 catalysis under aerobic conditions without employing any transition metal catalyst or additional oxidant. The employment of bio-based green solvent ethyl lactate as the reaction medium constitutes another sustainable feature of the present work.

Nonimmunosuppressive cyclophilin inhibitors have demonstrated efficacy for the treatment of hepatitis C infection (HCV). However, alisporivir, cyclosporin A, and most other cyclosporins are potent inhibitors of OATP1B1, MRP2, MDR1, and other important drug transporters. Reduction of the side chain hydrophobicity of the P4 residue preserves cyclophilin binding and antiviral potency while decreasing transporter inhibition. Representative inhibitor 33 (NIM258) is a less potent transporter inhibitor relative to previously described cyclosporins, retains anti-HCV activity in cell culture, and has an acceptable pharmacokinetic profile in rats and dogs. An X-ray structure of 33 bound to rat cyclophilin D is reported.

Lacticin 481 synthetase (LctM) catalyzes the ATP-dependent conversion of a ribosomally synthesized peptide to a polycyclic thioether antibiotic. It is a bifunctional enzyme that dehydrates four Ser/Thr residues to the corresponding dehydro amino acids and catalyzes the conjugate addition of Cys residues to these dehydro residues in a regio- and stereoselective process. We show here that incubation of truncated substrates with LctM results in products that are phosphorylated in the region of dehydration. Furthermore, synthetic peptides containing phosphorylated Ser and/or Thr residues are accepted by the enzyme as substrates resulting in the elimination of phosphate and dehydro amino acid production. This activity is only observed if ADP is added as cosubstrate. These results argue strongly that the enzyme utilizes ATP to phosphorylate the Ser/Thr residues that are targeted for dehydration. ATP does not appear to be required for peptide translocation or cyclization.