A Facile Ugi/Ullmann Cascade Reaction to Access Fused Indazolo-Quinoxaline Derivatives with Potent Anticancer Activity.

A facile methodology for the construction of a complex heterocycle indazolo-fused quinoxalinone has been developed via an Ugi four-component reaction (U-4CR) followed by an intramolecular Ullmann reaction. The expeditious process features an operationally simple approach, time efficiency, and a broad substrate scope. Biological activity was evaluated and demonstrated that compound 6e inhibits human colon cancer cell HCT116 proliferation with an IC50 of 2.1 µM, suggesting potential applications for developing a drug lead in medicinal chemistry.

3DFaceShop: Explicitly Controllable 3D-Aware Portrait Generation.

In contrast to the traditional avatar creation pipeline which is a costly process, contemporary generative approaches directly learn the data distribution from photographs. While plenty of works extend unconditional generative models and achieve some levels of controllability, it is still challenging to ensure multi-view consistency, especially in large poses. In this work, we propose a network that generates 3D-aware portraits while being controllable according to semantic parameters regarding pose, identity, expression and illumination. Our network uses neural scene representation to model 3D-aware portraits, whose generation is guided by a parametric face model that supports explicit control. While the latent disentanglement can be further enhanced by contrasting images with partially different attributes, there still exists noticeable inconsistency in non-face areas when animating expressions. We solve this by proposing a volume blending strategy in which we form a composite output by blending dynamic and static areas, with two parts segmented from the jointly learned semantic field. Our method outperforms prior arts in extensive experiments, producing realistic portraits with vivid expression in natural lighting when viewed from free viewpoints. It also demonstrates generalization ability to real images as well as out-of-domain data, showing great promise in real applications.

Insights into a class of natural eugenol and its optimized derivatives as potential tobacco mosaic virus helicase inhibitors by structure-based virtual screening.

Plant diseases caused by malignant and refractory phytopathogenic viruses have considerably restricted crop yields and quality. To date, drug design targeting functional proteins or enzymes of viruses is an efficient and viable strategy to guide the development of new pesticides. Herein, a series of novel eugenol derivatives targeting the tobacco mosaic virus (TMV) helicase have been designed using structure-based virtual screening (SBVS). Structure-activity relationship indicated that 2 t displayed the most powerful bonding capability (Kd = 0.2 µM) along with brilliant TMV helicase ATPase inhibitory potency (IC50 = 141.9 µM) and applausive anti-TMV capability (EC50 = 315.7 µg/mL), ostentatiously outperforming that of commercial Acyclovir (Kd = 23.0 µM, IC50 = 183.7 µM) and Ribavirin (EC50 = 624.3 µg/mL). Molecular dynamics simulations and docking suggested ligand 2 t was stable and bound in the active pocket of the TMV helicase by multiple interactions. Given these superior properties, eugenol-based derivatives could be considered as the novel potential plant viral helicase inhibitors. Furthermore, this effective and feasible SBVS strategy established a valuable screening platform for helicase-targeted drug development.

Discovery of phosphonate derivatives containing different substituted 1,2,3-triazole motif as promising tobacco mosaic virus (TMV) helicase inhibitors for controlling plant viral diseases.

BACKGROUND: The discovery and identification of targets is of far-reaching significance for developing novel pesticide candidates and increasing the probability of success. To explore and identify highly effective tobacco mosaic virus (TMV) helicase-targeted lead structures, a series of novel phosphonate derivatives containing a 1,2,3-triazole motif were rationally engineered and their antiviral activity was assessed. RESULTS: Bioassay results showed that the optimized B17 exhibited more potent curative activity (EC50 = 271.5 µg mL-1 ) against TMV in vivo, which was superior to that of commercial Ribavirin (EC50 = 689.3 µg mL-1 ). B17 presented a stronger binding capacity through binding analysis with helicase, affording a corresponding value of 12.7 µM. Enzyme activity assay showed B17 exhibited excellent inhibitory activity on TMV helicase (39.2% at 300 µM). Furthermore, molecular docking simulations demonstrated that B17 displayed strong hydrogen-bond interactions (2.1, 2.1, 2.2, and 3.2 Å) with Ala-33, Gly-10, Gly-8, and Glu-217 of TMV helicase. Encouragingly, transmission electron microscopy analysis revealed that B17 could remarkably disrupt surface morphology and inhibit TMV proliferation. Additionally, these compounds also displayed potential anti-CMV (cucumber mosaic virus) and antipathogens (Xanthomonas oryzae pv. oryzae and Xanthomonas axonopodis pv. citri) by expanding their applications in agriculture. CONCLUSION: Current research demonstrated that B17 could be considered as a potential antiviral agent alternative though targeting TMV helicase. © 2023 Society of Chemical Industry.

Novel cinnamic acid derivatives as a versatile tool for developing agrochemicals for controlling plant virus and bacterial diseases by enhancing plant defense responses.

BACKGROUND: Plant pathogens have led to large yield and quality losses in crops worldwide. The discovery and study of novel agrochemical alternatives based on the chemical modification of bioactive natural products is a highly efficient approach. Here, two series of novel cinnamic acid derivatives incorporating diverse building blocks with alternative linking patterns were designed and synthesized to identify their antiviral capacity and antibacterial activity. RESULTS: The bioassay results demonstrated that most cinnamic acid derivatives had excellent antiviral competence toward tobacco mosaic virus (TMV) in vivo, especially compound A5 (median effective concentration [EC50 ] = 287.7 µg mL-1 ), which had a notable protective effect against TMV when compared with the commercial virucide ribavirin (EC50  = 622.0 µg mL-1 ). In addition, compound A17 had a protective efficiency of 84.3% at 200 µg mL-1 against Xac in plants. Given these outstanding results, the engineered title compounds could be regarded as promising leads for controlling plant virus and bacterial diseases. Preliminary mechanistic studies suggest that compound A5 could enhance the host's defense responses by increasing the activity of defense enzymes and upregulating defense genes, thereby suppressing phytopathogen invasion. CONCLUSION: This research lays a foundation for the practical application of cinnamic acid derivatives containing diverse building blocks with alternative linking patterns in pesticide exploration. © 2023 Society of Chemical Industry.

Novel spiro[chromanone-2,4'-piperidine]-4-one derivatives as potential inhibitors of fatty acid synthesis in pathogens: Design, synthesis, and biological evaluation.

Bacterial survival depends on membrane lipid homeostasis that enables to regulate lipid composition to adapt and optimize their growth in diverse environments. Therefore, the development of inhibitors that interfere with the bacterial fatty acid synthesis process is considered to be a promising tactic. In this study, 58 novel spirochromanone derivatives were prepared and their structure-activity relationship (SAR) was investigated. The bioassay results showed that all most of the compounds showed excellent biological activities, exampled by compounds B14, C1, B15, and B13, which had outstanding inhibitory activities toward various pathogenic bacteria with EC50 values of 0.78 µg/mL ∼3.48 µg/mL. Preliminary antibacterial behavior was studied by a series of biochemical assays including, but not limited to, fluorescence imaging patterns, GC-MS analysis, TEM images, and fluorescence titration experiments. Notably, compound B14 decreased the lipid content of the cell membrane, and increased cell membrane permeability, thereby destroying the integrity of the bacterial cell membrane. Further qRT-PCR results indicated that compound B14 interfered with the mRNA expression levels of fatty acid synthesis process-related genes including ACC, ACP, and Fab family genes. Herein, we highlight the promising bactericidal skeleton based on the spiro[chromanone-2,4'-piperidine]-4-one as a potential inhibitor of fatty acid synthesis.

The Discovery of Novel Ferulic Acid Derivatives Incorporating Substituted Isopropanolamine Moieties as Potential Tobacco Mosaic Virus Helicase Inhibitors.

Target-based drug design, a high-efficiency strategy used to guide the development of novel pesticide candidates, has attracted widespread attention. Herein, various natural-derived ferulic acid derivatives incorporating substituted isopropanolamine moieties were designed to target the tobacco mosaic virus (TMV) helicase. Bioassays demonstrating the optimized A19, A20, A29, and A31 displayed excellent in vivo antiviral curative abilities, affording corresponding EC50 values of 251.1, 336.2, 347.1, and 385.5 µg/mL, which visibly surpassed those of commercial ribavirin (655.0 µg/mL). Moreover, configurational analysis shows that the R-forms of target compounds were more beneficial to aggrandize antiviral profiles. Mechanism studies indicate that R-A19 had a strong affinity (Kd = 5.4 µM) to the TMV helicase and inhibited its ability to hydrolyze ATP (50.61% at 200 µM). Meanwhile, A19 could down-regulate the expression of the TMV helicase gene in the host to attenuate viral replication. These results illustrate the excellent inhibitory activity of A19 towards the TMV helicase. Additionally, docking simulations uncovered that R-A19 formed more hydrogen bonds with the TMV helicase in the binding pocket. Recent studies have unambiguously manifested that these designed derivatives could be considered as promising potential helicase-based inhibitors for plant disease control.

Trickle-Down Effects of Entrepreneurial Bricolage and Business Model Innovation on Employee Creativity: Evidence From Entrepreneurial Internet Firms in China.

Although most existing studies have considered entrepreneurial bricolage as a means to overcome resource constraints in new ventures, few have explored the direct effects of entrepreneurial bricolage on employee creativity, particularly in the context of entrepreneurial internet firms. Drawing from multiple theories (i.e., social learning theory and social cognitive theory), this study proposes a cross-level mediation model for the trickle-down effects of entrepreneurial bricolage and business model innovation on employee creativity. By using a 2-wave longitudinal design, survey data were collected from multiple sources, including 49 leaders and 336 employees from entrepreneurial internet firms in China. Multilevel structural equation modeling (MSEM) was applied to analyze the cross-level mediation model. The results show that both entrepreneurial bricolage and business model innovation failed to significantly and positively direct employee creativity. Furthermore, entrepreneurial bricolage exerted a cross-level influence on employee creativity that was sequentially transmitted through between-level business model innovation and within-level creative self-efficacy. The theoretical and managerial implications of these findings are also discussed.

Lattice Boltzmann method coupled with the Oldroyd-B constitutive model for a viscoelastic fluid.

We developed a lattice Boltzmann method coupled with the Oldroyd-B constitutive equation to simulate a viscoelastic fluid. In this work, the flow field of the solvent is solved using an incompressible lattice Boltzmann Bhatnagar-Gross-Krook (BGK) model, while the advection operator of the polymer stress tensor is directly calculated with the help of the particle distribution functions. Specifically, we present a numerical scheme for the advection of the polymer stress tensor through the truncation of second-order Taylor expansion, which does not need to introduce the extra distribution functions and has better numerical accuracy. We consider two types of numerical tests to examine the performance of the presented method, including a two-dimensional (2D) channel flow and the 4:1 contraction problem. Our numerical results for the 2D channel flow agree well with the analytical results and some experimental results reported in the previous studies. Moreover, the numerical results also indicate that the current method can capture some complex rheological behaviors of the 4:1 contraction flow.