Novel Coumarins Derivatives for A. baumannii Lung Infection Developed by High-Throughput Screening and Reinforcement Learning.

With the increasing resistance of Acinetobacter baumannii (A. baumannii) to antibiotics, researchers have turned their attention to the development of new antimicrobial agents. Among them, coumarin-based heterocycles have attracted much attention due to their unique biological activities, especially in the field of antibacterial infection. In this study, a series of coumarin derivatives were synthesized and screened for their bactericidal activities (Ren et al. 2018; Salehian et al. 2021). The inhibitory activities of these compounds on bacterial strains were evaluated, and the related mechanism of the new compounds was explored. Firstly, the MIC values and bacterial growth curves were measured after compound treatment to evaluate the antibacterial activity in vitro. Then, the in vivo antibacterial activities of the new compounds were assessed on A. baumannii-infected mice by determining the mice survival rates, counting bacterial CFU numbers, measuring inflammatory cytokine levels, and histopathology analysis. In addition, the ROS levels in the bacterial cells were measured with DCFH-DA detection kit. Furthermore, the potential target and detailed mechanism of the new compounds during infection disease therapy were predicted and evidenced with molecular docking. After that, ADMET characteristic prediction was completed, and novel, synthesizable, drug-effective molecules were optimized with reinforcement learning study based on the probed compound as a training template. The interaction between the selected structures and target proteins was further evidenced with molecular docking. This series of innovative studies provides important theoretical and experimental data for the development of new anti-A. baumannii infection drugs.

Terpolymer Containing a meta-Octyloxy-phenyl-Modified Dithieno[3,2-f:2',3'-h]quinoxaline Unit Enabling Efficient Organic Solar Cells.

With the rapid development of small-molecule electron acceptors, polymer electron donors are becoming more important than ever in organic photovoltaics, and there is still room for the currently available high-performance polymer donors. To further develop polymer donors with finely tunable structures to achieve better photovoltaic performances, random ternary copolymerization is a useful technique. Herein, by incorporating a new electron-withdrawing segment 2,3-bis(3-octyloxyphenyl)dithieno[3,2-f:2',3'-h]quinoxaline derivative (C12T-TQ) to PM6, a series of terpolymers were synthesized. It is worth noting that the introduction of the C12T-TQ unit can deepen the highest occupied molecular orbital energy levels of the resultant polymers. In addition, the polymer Z6 with a 10% C12T-TQ ratio possesses the highest film absorption coefficient (9.86 × 104 cm-1) among the four polymers. When blended with Y6, it exhibited superior miscibility and mutual crystallinity enhancement between Z6 and Y6, suppressed recombination, better exciton separation and charge collection characteristics, and faster hole transfer in the D-A interface. Consequently, the device of Z6:Y6 successfully achieved enhanced photovoltaic parameters and yielded an efficiency of 17.01%, higher than the 16.18% of the PM6:Y6 device, demonstrating the effectiveness of the meta-octyloxy-phenyl-modified dithieno[3,2-f:2',3'-h]quinoxaline moiety to build promising terpolymer donors for high-performance organic solar cells.

Potential Application Values of Two Multicoloured Coordination Compounds as Multicolor Luminescent Materials.

Two Co(II)-based coordination compounds, namely {[Co(apc)2]·H2O}n (1) and [Co(apc)2(H2O)2] (2), have been successfully prepared via reaction of a multifunctional ligand 2-aminopyrimidine-5-carboxylic acid (Hapc) with Co(NO3)2·6H2O based on different reaction environments. Both compounds were studied via elemental analysis (EA), single crystal X-ray diffraction analysis (SC-XRD), thermogravimetric analysis (TG), powder X-ray diffraction (PXRD) and infrared spectroscopy (IR). Fluorescence spectroscopy was employed to analyze the fluorescence properties of the ligand and the two compounds. The results revealed that the two compounds exhibited green and blue fluorescence, surpassing the original ligand in terms of properties. Based on the distinct fluorescence colors of the two compounds, there is potential to create multicolored fluorescent materials by adjusting their material ratios. This prospect could further extend their applications in the field of fluorescent materials.

Synthesis and Fluorescent Characteristics Study of Two Novel Co(II) Complexes.

In this work, two novel mixed-ligand CPs that has a compositions of [Co2(µ-Hdppa)2(phen)2(H2O)2] (1) and {[Co(µ-Hdppa)(µ-4,4'-bipy)(H2O)]·H2O}n (2) is achieved through reaction of cobalt salts with the 5-(3,4-Dicarboxylphenyl)picolinic acid (H3dppa) with various N-donor co-ligands (1,10-phenanthroline (phen) for 1 and 4,4'-bipyridine (4,4'-bipy) for 2). The structures and characteristics of these two complexes were fully examined via IR, TGA, and SXRD. Furthermore, their superior blue fluorescence properties compared to the original ligands were confirmed through fluorescence spectroscopy. These two complexes prepared in this study have enriched the choices for blue fluorescent materials.

Medium-chain triglyceride-stabilized docetaxel-loaded HSA nanoparticles effectively inhibited metastatic non-small cell lung cancer.

Metastatic non-small cell lung cancer (NSCLC) is refractory with a very poor prognosis. Docetaxel (DTX) injection (Taxotere®) has been approved for the treatment of locally advanced or metastatic NSCLC. However, its clinical application is restricted by severe adverse effects and non-selective tissue distribution. In this study, we successfully developed DTX-loaded human serum albumin (HSA) nanoparticles (DNPs) with modified Nab technology, by introducing medium-chain triglyceride (MCT) as a stabilizer. The optimized formulation had a particle size of approximately 130 nm and a favorable stabilization time of more than 24 h. DNPs dissociated in circulation in a concentration-dependent manner and slowly released DTX. Compared with DTX injection, DNPs were more effectively taken up by NSCLC cells, thus exerting stronger inhibitory effects on their proliferation, adhesion, migration, and invasion. In addition, DNPs showed prolonged blood retention and increased tumor accumulation relative to DTX injection. Ultimately, DNPs produced more potent inhibitory effects on primary or metastatic tumor foci than DTX injections but caused markedly lower organ toxicity and hematotoxicity. Overall, these results support that DNPs hold great potential for the treatment of metastatic NSCLC in clinical.

Brain-neuron targeted nanoparticles for peptide synergy therapy at dual-target of Alzheimer's disease.

Since the complex interactions of multiple mechanisms involved in Alzheimer's disease (AD) preclude the monotherapeutic approaches from clinical application, combination therapy has become an attractive strategy for AD treatment. However, to be emphasized, the realization of the edges of combination therapy greatly depends on the reasonable choice of targets and the rational design of combination scheme. Acknowledgedly, amyloid plaques and hyperphosphorylated tau (p-tau) are two main hallmarks in AD with close pathological correlations, implying the hopeful prospect of combined intervention in them for AD treatment. Herein, we developed the nano-combination system, neuron-targeting PEG-PLA nanoparticles (CT-NP) loading two peptide drugs H102, a ß-sheet breaker acting on Aß, and NAP, a microtubule stabilizer acting on p-tau. Compared with free peptide combination, nano-combination system partly aligned the in vivo behaviors of combined peptides and enhanced peptide accumulation in lesion neurons by the guidance of targeting peptide CGN and Tet1, facilitating the therapeutic performance of peptide combination. Further, to maximize the therapeutic potential of nano-combination system, the combination ratio and mode were screened by the quantitative evaluation with combination index and U test, respectively, in vitro and in vivo. The results showed that the separated-loading CT-NP at the combination molar ratio of 2:1 (H102:NAP), CT-NP/H102 + CT-NP/NAP(2:1), generated the strongest synergistic therapeutic effects on Aß, p-tau and their linkage, and effectually prevented neuroinflammation, reversed the neuronal damage and restored cognitive performance in 3 × Tg-AD transgenic mice. Our studies provide critical data on the effectiveness of nano-combination therapy simultaneously intervening in Aß and p-tau, confirming the promising application of nano-combination strategy in AD treatment.

Chronic loss of muscarinic M5 receptor function manifests disparate impairments in exploratory behavior in male and female mice despite common dopamine regulation.

There are five cloned muscarinic acetylcholine receptors (M1-M5). Of these, the muscarinic type 5 receptor (M5) is the only one localized to dopamine neurons in the ventral tegmental area and substantia nigra. Unlike M1-M4, the M5 receptor has relatively restricted expression in the brain, making it an attractive therapeutic target. Here we performed an in-depth characterization of M5-dependent potentiation of dopamine transmission in the nucleus accumbens and accompanying exploratory behaviors in male and female mice. We show that M5 receptors potentiate dopamine transmission by acting directly on the terminals within the nucleus accumbens. Using the muscarinic agonist oxotremorine, we revealed a unique concentration-response curve and a sensitivity to repeated forced swim stress or restraint stress exposure. We found that constitutive deletion of M5 receptors reduced exploration of the center of an open field while at the same time impairing normal habituation only in male mice. In addition, M5 deletion reduced exploration of salient stimuli, especially under conditions of high novelty, yet had no effect on hedonia assayed using the sucrose preference test or on stress coping strategy assayed using the forced swim test. We conclude that M5 receptors are critical for both engaging with the environment and updating behavioral output in response to environment cues, specifically in male mice. A cardinal feature of mood and anxiety disorders is withdrawal from the environment. These data indicate that boosting M5 receptor activity may be a useful therapeutic target for ameliorating these symptoms of depression and anxiety.Significance Statement:The basic physiological and behavioral functions of the muscarinic M5 receptor remain understudied. Furthermore, its presence on dopamine neurons, relatively restricted expression in the brain, and recent crystallization make it an attractive target for therapeutic development. Yet, most preclinical studies of M5 receptor function have primarily focused on substance use disorders in male rodents. Here we characterized the role of M5 receptors in potentiating dopamine transmission in the nucleus accumbens, finding impaired functioning after stress exposure. Furthermore, we show that M5 receptors can modulate exploratory behavior in a sex-specific manner, without impacting hedonic behavior. These findings further illustrate the therapeutic potential of the M5 receptor, warranting further research in the context of treating mood disorders.

Effects of the Isomerized Thiophene-Fused Ending Groups on the Performances of Twisted Non-Fullerene Acceptor-Based Polymer Solar Cells.

Recently, benefiting from the merits of small-molecule acceptors (NFAs), polymer solar cells (PSCs) have achieved tremendous advances. From the perspective of the structural characteristics of the π-conjugated acceptor-donor-acceptor (A-D-A) type of organic molecules, the backbone's planarity and the terminal groups and their substituents have strong influences on the performances of the constructed NFAs. Through enlarging the dihedral angle of the conjugated main chain of NFAs, a certain degree of enhancement of photovoltaic parameters has been achieved. To further probe the influences of ending groups on the performances of nonplanar NFAs, we synthesized two new NFAs i-cc23 and i-cc34 with isomerized thiophene-fused ending groups and a twisted π-conjugated main chain. Compared to i-cc23 containing the 2-(6-oxo-5,6-dihydro-4H-cyclopenta[b]thiophen-4-ylidene)malononitrile ending group, the acceptor i-cc34 containing 2-(6-oxo-5,6-dihydro-4H-cyclopenta[c]thiophen-4-ylidene)malononitrile has a relatively higher molar extinction coefficient, bathochromic-shifted absorption spectrum, and deepened energy levels. When mixed with PBDB-T in solar cells, the i-cc23-based device achieved an excellent open-circuit voltage (VOC) of 1.10 V and a moderate power conversion efficiency of 7.34%. Although the VOC of the i-cc34-related device was decreased to 0.96 V, the short-circuit current density and fill factor were improved, giving rise to an enhanced efficiency of 9.51%. Apart from the distinct photovoltaic performances, the two isomer-based devices exhibit a high radiative efficiency of 8 × 10-4, leading to a very small nonradiative loss of 0.19 V. Our results emphasize the importance of the isomerized thiophene-fused ending groups on the performances of nonplanar NFA-based PSCs.

Neuronal mitochondria-targeted micelles relieving oxidative stress for delayed progression of Alzheimer's disease.

Mitochondrial dysfunction is an early event of Alzheimer's disease (AD), contributes the onset and progression of AD, and may represent an effective therapeutic target for AD intervention. Since mitochondria in central neurons are more susceptible to oxidative damage than non-neuronal cells, the specific delivery of the antioxidants to the mitochondria of impaired central neurons is crucial for achieving the therapeutic effect on AD. Here, we prepare the neuronal mitochondria-targeted micelles (CT-NM) through co-decoration with neural cell adhesion molecule (NCAM) mimetic peptide C3 for brain neuron specific binding and the triphenylphosphonium (TPP) for mitochondrial targeting. CT-NM significantly increase the encapsulated resveratrol's concentration in the neuronal mitochondria compared to the micelles modified with C3 only or the resveratrol solution. The resveratrol-loaded CT-NM alleviate the oxidative stress in the neuronal cells, resulting in stabilization of the dynamic balance of mitochondrial fission and fusion. The targeted micelles restore the cognitive performance in APP/PS1 transgenic mice to the level of wild-type mice characterized by up-regulation of sirtuin 1 expression, reduction of amyloid deposition and tau hyperphosphorylation, protection of synapses and inhibition of microglia proliferation. The results demonstrate the delay of the progression of AD through reversing neuronal mitochondrial dysfunction by the targeted delivery of antioxidants.

Effects of Monofluorinated Positions at the End-Capping Groups on the Performances of Twisted Non-Fullerene Acceptor-Based Polymer Solar Cells.

Recently, main-chain twisted small molecules are attractive as electron-acceptors in polymer solar cells (PSCs) for their upshifted molecular energy levels, enhanced extinction coefficients, and better charge extraction properties along with longer carrier lifetimes and lower recombination rates relative to their planar analogues, which are conducive to the power conversion efficiency (PCE) promotion of PSCs. To further probe the "structure-performance" correlation of main-chain twisted acceptors, in particular the monofluorine-substituted sites on the performances of the resultant acceptors, two new main-chain twisted small molecules were synthesized, in which a fluorine atom was introduced at different sites on the end-capping group 2-(3-oxo-2,3-dihydro-1H-inden-1-ylidene)malononitrile (INCN). Although fine structural modification was adopted, quite different performances were obtained for the two acceptors. Compared to the 3-fluorinated analogue (i-IEICO-F3), a mixture of 4-fluorinated and 5-fluorinated isomers (i-IEICO-2F) exhibited a higher dipole moment, enlarged molar extinction coefficient with a bathochromic-shifted absorption region, suppressed charge recombinations with balanced charge mobilities, and slightly enhanced crystallinity. In combination with a fluorobenzotriazole-based medium-band gap polymer (J52), a high efficiency of 12.86% was resultantly achieved in an i-IEICO-2F-based device, which is superior to the result (7.65%) of the i-IEICO-F3 device, revealing the importance of monofluorinated positions on the performances of main-chain twisted non-fullerene acceptors.

Small interfering RNA delivery to the neurons near the amyloid plaques for improved treatment of Alzheimer׳s disease.

Gene therapy represents a promising treatment for the Alzheimer׳s disease (AD). However, gene delivery specific to brain lesions through systemic administration remains big challenge. In our previous work, we have developed an siRNA nanocomplex able to be specifically delivered to the amyloid plaques through surface modification with both CGN peptide for the blood-brain barrier (BBB) penetration and QSH peptide for ß-amyloid binding. But, whether the as-designed nanocomplex could indeed improve the gene accumulation in the impaired neuron cells and ameliorate AD-associated symptoms remains further study. Herein, we prepared the nanocomplexes with an siRNA against ß-site amyloid precursor protein-cleaving enzyme 1 (BACE1), the rate-limiting enzyme of Aß production, as the therapeutic siRNA of AD. The nanocomplexes exhibited high distribution in the Aß deposits-enriched hippocampus, especially in the neurons near the amyloid plaques after intravenous administration. In APP/PS1 transgenic mice, the nanocomplexes down-regulated BACE1 in both mRNA and protein levels, as well as Aß and amyloid plaques to the level of wild-type mice. Moreover, the nanocomplexes significantly increased the level of synaptophysin and rescued memory loss of the AD transgenic mice without hematological or histological toxicity. Taken together, this work presented direct evidences that the design of precise gene delivery to the AD lesions markedly improves the therapeutic outcome.

Efficient Polymer Solar Cells Having High Open-Circuit Voltage and Low Energy Loss Enabled by a Main-Chain Twisted Small Molecular Acceptor.

A new main-chain twisted small molecular acceptor with nonhalogenated end groups (i-IEICO) is designed and synthesized. In contrast to its planar analogue IECIO, i-IEICO possesses an obviously twisted backbone, leading to significant hypsochromic shift in film absorption, slight enhancement in solution extinction coefficient, and significantly elevated molecular energy level. Benefited from these features, i-IEICO is matched well with two wide band gap polymer donor materials (J52 and PBDB-T) both in absorption spectra and molecular energy levels. Relative to the planar-molecule IEICO-based devices, the open-circuit voltage ( VOC), short-circuit current density, and fill factor of the i-IEICO-based devices are simultaneously improved, giving rising to a 10.48% (with J52) and 8.79% (with PBDB-T) power conversion efficiency, respectively. Moreover, J52:i-IEICO device exhibits a high VOC of 0.96 V accompanied by a small energy loss of 0.64 eV, which can be further improved to 1.01 V and 0.59 eV for the PBDB-T-based device. The obtained VOC of i-IEICO-based devices are among one of the highest values of either J52 or PBDB-T-based binary devices, suggesting the effectiveness of main-chain twisted strategy coupled with end-group modification to achieve highly efficient nonfullerene acceptors with low energy loss and high VOC.

Design, Synthesis, and Antitumor Activity of Novel Quinazoline Derivatives.

In an attempt to explore a new class of epidermal growth factor receptor (EGFR) inhibitors, novel 4-stilbenylamino quinazoline derivatives were synthesized through a Dimorth rearrangement reaction and characterized via IR, ¹H-NMR, 13C-NMR, and HRMS. Methoxyl, methyl, halogen, and trifluoromethyl groups on stilbeneamino were detected. These synthesized compounds were evaluated for antitumor activity in vitro against eight human tumor cell lines with an MTS assay. Most synthesized compounds exhibited more potent activity (IC50 = ~2.0 µM) than gefitinib (IC50 > 10.0 µM) against the A431, A549, and BGC-823 cell lines. Docking methodology of compound 6c and 6i binding into the ATP site of EGFR was carried out. The results showed that fluorine and trifluoromethyl played an important role in efficient cell activity.