Exploration and structure-activity relationship research of benzenesulfonamide derivatives as potent TRPV4 inhibitors for treating acute lung injury.

RN-9893, a TRPV4 antagonist identified by Renovis Inc., showcased notable inhibition of TRPV4 channels. This research involved synthesizing and evaluating three series of RN-9893 analogues for their TRPV4 inhibitory efficacy. Notably, compounds 1b and 1f displayed a 2.9 to 4.5-fold increase in inhibitory potency against TRPV4 (IC50 = 0.71 ± 0.21 µM and 0.46 ± 0.08 µM, respectively) in vitro, in comparison to RN-9893 (IC50 = 2.07 ± 0.90 µM). Both compounds also significantly outperformed RN-9893 in TRPV4 current inhibition rates (87.6 % and 83.2 % at 10 µM, against RN-9893's 49.4 %). For the first time, these RN-9893 analogues were profiled in an in vivo mouse model, where intraperitoneal injections of 1b or 1f at 10 mg/kg notably mitigated symptoms of acute lung injury induced by lipopolysaccharide (LPS). These outcomes indicate that compounds 1b and 1f are promising candidates for acute lung injury treatment.

Dual Control of Enhanced Quasi-Bound States in the Continuum Emission from Resonant c-Si Metasurfaces.

Optical bound states in the continuum (BICs) offer strong interactions with quantum emitters and have been extensively studied for manipulating spontaneous emission, lasing, and polariton Bose-Einstein condensation. However, the out-coupling efficiency of quasi-BIC emission, crucial for practical light-emitting devices, has received less attention. Here, we report an adaptable approach for enhancing quasi-BIC emission from a resonant monocrystalline silicon (c-Si) metasurface through lattice and multipolar engineering. We identify dual-BICs originating from electric quadrupoles (EQ) and out-of-plane magnetic dipoles, with EQ quasi-BICs exhibiting concentrated near-fields near the c-Si nanodisks. The enhanced fractional radiative local density of states of EQ quasi-BICs overlaps spatially with the emitters, promoting efficient out-coupling. Furthermore, coupling the EQ quasi-BICs with Rayleigh anomalies enhances directional emission intensity, and we observe inherent opposite topological charges in the multipolarly controlled dual-BICs. These findings provide valuable insights for developing efficient nanophotonic devices based on quasi-BICs.

Precisely constructing hybrid nanogap arrays via wet-transfer of dielectric metasurfaces onto a plasmonic mirror.

We propose a new method for fabricating hybrid metasurfaces by combining Mie and plasmonic resonances. Our approach involves obtaining an ultrasmooth gold film and separately structuring monocrystalline silicon (c-Si) nanoantenna arrays, which are then wet-transferred and finally immobilized onto the gold film. The experimental and simulation analysis reveals the importance of the native oxide layer of Si and demonstrates fascinating dispersion curves with nanogap resonances and bound states in the continuum. The localized field enhancements in the nanogap cavities result from the coupling between multipolar Mie resonances and their mirror images in the gold film. This effective method improves our understanding of hybrid modes and offers opportunities for developing active metasurfaces, such as depositing c-Si nanoantenna arrays onto stretchable polydimethylsiloxane substrates or electro-optic and piezoelectric sensitive lithium niobate films for potential applications in MEMS, LiDAR, and beyond.

Vibration Analysis and Damping Effect of Blade-Hard Coating Composite Structure Based on Base Excitation.

Hard coatings are widely employed on blades to enhance impact resistance and mitigate fatigue failure caused by vibration. While previous studies have focused on the dynamic characteristics of beams and plates, research on real blades remains limited. Specifically, there is a lack of investigation into the dynamic characteristics of hard-coated blades under base excitation. In this paper, the finite element model (FEM) of blade-hard coating (BHC) composite structure is established based on finite element methods in which the hard coating (HC) material and the substrate are considered as the isotropic material. Harmonic response analysis is conducted to calculate the resonance amplitude of the composite under base excitation. Numerical simulations and experimental tests are performed to examine the effects of various HC parameters, including energy storage modulus, loss factors, coating thickness, and coating positions, on the dynamic characteristics and vibration reduction of the hard-coated blade composite structures. The results indicate that the difference in natural frequency and modal loss factor of blades increases with higher storage modulus and HC thickness. Moreover, the vibration response of the BHC decreases with higher storage modulus, loss factor, and coating thickness of the HC material. Blades with a complete coating exhibit superior damping effects compared to other coating distributions. These findings are significant for establishing accurate dynamic models of HC composite structures, assessing the effectiveness of HC vibration suppression, and guiding the selection and preparation of HC materials.

Design, synthesis and antitubercular activity of novel N-(amino)piperazinyl benzothiazinones with improved safety.

Tuberculosis (TB), caused by Mycobacterium tuberculosis (MTB) remains a major global health problem and new therapeutic antitubercular agents are urgent needed. Among the novel antituberculosis drugs in the pipeline, Benzothiazinones (BTZs) are among the most potent antituberculosis agents against both drug-susceptible and multidrug-resistant (MDR) tuberculosis. Our group has focused on structural modifications of the side chain at C-2 position of the BTZ core and WAP-2101/2102 with excellent in vitro activity were discovered in our lab. However, the severe in vivo toxicity was observed during subsequent acute toxicity evaluation. Herein, a series of novel N-(amino)piperazinyl benzothiazinone derivatives were designed and synthesized as new anti-TB agents to reduce the in vivo toxicity. Our results show that majority of them exhibit the same potent or comparable activity against both MTB H37Rv and MDR-MTB strains (MIC: 4.00 - <1 ng/mL) as PBTZ169. Especially, compound 2c with low cardiac toxicity, low cell cytotoxicity and acceptable oral pharmacokinetic (PK) profiles have low acute toxicity in mice (LD50 > 500 mg/kg), suggesting it may serve as a promising lead compound for further antitubercular drug discovery.

Optimization and SAR research at the benzoxazole and tetrazole rings of JNJ4796 as new anti-influenza A virus agents, part 2.

We have already reported the modification on the piperazine and phenyl rings of JNJ4796, a small-molecule fuse inhibitor targeting hemagglutinin (HA). In this study, we described the structure-activity relationship of the benzoxazole and tetrazole rings of JNJ4796. Many derivatives demonstrated good in vitro activity against IAV H1N1and Oseltamivir-resistant IAV H1N1 stains. Although compounds (R)-1e and (R)-1h exhibited excellent in vitro activity, high drug exposure level and low hERG inhibition, they displayed low oral efficacy. Excitedly, (R)-1a, a representative identified in our previous study, was found to show potent in vivo anti-IAV activity with the survival rates of 100%, 100% and 70% at 15, 5 and 1.67 mg/kg, respectively, comparable to JNJ4796. Currently, we are exploring different ways to ease its gastrointestinal response.