Multi-LiDAR human joint recognition algorithm in hospital wards based on improved V2V-Posenet.

To prevent convulsions and falls of patients in the absence of medical staff, it is crucial to monitor their physical condition in hospital wards. However, several unresolved challenges in human joint recognition remain, such as object occlusion, human self-occlusion and complex backgrounds, resulting in difficulties in its practical application. In this paper, a multi-LiDAR system is proposed to obtain a multi-view human body point cloud. An improved V2V-Posenet model was introduced to detect the actual position of the human joint. In this system, each point cloud was spliced into a full point cloud and voxelized into the model. We also used a random voxel zero setting for data enhancement, constraining the relative length between human joints into a loss function and three-dimensional Gaussian filtering in a heat map for model learning. The improved model exhibited excellent performance in detecting human joints in hospital wards. The experimental results showed that the improved model achieved 91.6 % mean average precision, compared to 80.1 % for the original model and 77.4 % for the comparison algorithm A2J-Posenet. The speed of the improved model meets the requirements for real-time target detection.

Discovery of benzamide-based PI3K/HDAC dual inhibitors with marked pro-apoptosis activity in lymphoma cells.

Inhibition of PI3K and histone deacetylase (HDAC) activity simultaneously using a single molecule appears to be a promising approach for cancer treatment. Current PI3K/HDAC dual inhibitors commonly use hydroxamate moiety as zinc binding group, which lack HDAC isoform selectivity and have potential genotoxicity. In this study, a novel series of benzamide-based PI3K/HDAC dual inhibitors were rationally designed and synthesized. Representative compound PH14 showed potent inhibitory activity toward PI3Kα and HDAC3, with IC50 values of 20.3 nM and 24.5 nM, respectively. This was further supported by the blockage of AKT phosphorylation and an increase in acetylated histone H3 levels in Western blot study. The advantage of simultaneously targeting PI3Kα and HDAC is not only reflected in the significant antiproliferative activity, but also in its ability to promote the apoptosis in Jeko-1 cells. Moreover, PH14 had weak inhibitory effects on CYP450 enzymes and hERG. In the pharmacokinetic study, the administration of 1 mg/kg of PH14 the administration of 1 mg/kg of PH14 resulted in a t1/2 of 10 h and an AUC (0-∞) of 2772 h ng/mL. Our study may provide ideas for the further development of novel HDAC/PI3K dual inhibitors.

Design, Synthesis, and Biological Evaluation of Novel Thioureidobenzamide (TBA) Derivatives as HBV Capsid Assembly Modulators.

Hepatitis B virus (HBV) capsid assembly modulators (CAMs) represent a promising therapeutic approach for the treatment of HBV infection. In this study, we designed and synthesized five series of benzamide derivatives based on a multisite-binding strategy at the tolerant region and diversity modification in the solvent-exposed region. Among them, thioureidobenzamide compound 17i exhibited significantly increased anti-HBV activity in HepAD38 (EC50 = 0.012 µM) and HBV-infected HLCZ01 cells (EC50 = 0.033 µM). Moreover, 17i displayed a better inhibitory effect on the assembly of HBV capsid protein compared with NVR 3-778 and a inhibitory effect similar to the clinical drug GLS4. In addition, 17i showed moderate metabolic stability in human microsomes, had excellent oral bioavailability in Sprague-Dawley (SD) rats, and inhibited HBV replication in the HBV carrier mice model, which could be considered as a promising candidate drug for further development.

Design, synthesis and biological evaluation of biphenyl-benzamides as potent FtsZ inhibitors.

The rapid emergence of antibiotic resistance has become a prevalent threat to public health, thereby development of new antibacterial agents having novel mechanisms of action is in an urgent need. Targeting at the cytoskeletal cell division protein filamenting temperature-sensitive mutant Z (FtsZ) has been validated as an effective and promising approach for antibacterial drug discovery. In this study, a series of novel biphenyl-benzamides as FtsZ inhibitors has been rationally designed, synthesized and evaluated for their antibacterial activities against various Gram-positive bacteria strains. In particular, the most promising compound 30 exhibited excellent antibacterial activities, especially against four different Bacillus subtilis strains, with an MIC range of 0.008 µg/mL to 0.063 µg/mL. Moreover, compound 30 also showed good pharmaceutical properties with low cytotoxicity (CC50 > 20 µg/mL), excellent human metabolic stability (T1/2 = 111.98 min), moderate pharmacokinetics (T1/2 = 2.26 h, F = 61.2%) and in vivo efficacy, which can be identified as a promising FtsZ inhibitor worthy of further profiling.

Small Molecule Inhibitors of Programmed Cell Death Ligand 1 (PD-L1): A Patent Review (2019-2021).

INTRODUCTION: The blockade of immune checkpoints, especially the PD-1/PD-L1 pathway with therapeutic antibodies, has shown success in treating cancers in recent years. Seven monoclonal antibodies (mAbs) targeting PD-1 or PD-L1 have been approved by FDA. However, mAbs exhibit several disadvantages as compared to small molecules such as poor permeation, high manufacturing costs, immunogenicity as well as lacking oral bioavailability. Recently, small-molecule inhibitors targeting PD-L1 have been disclosed with the ability to modulate the PD-1/PD-L1 pathway. AREAS COVERED: The authors reviewed small molecules targeting PD-L1 that block the PD-1/PD-L1 protein-protein interaction for the treatment of various diseases. EXPERT OPINION: Compared with mAbs, PD-1/PD-L1 small-molecule inhibitors show several advantages such as improved tissue penetration, low immunogenicity, well-understood formulation and lower manufacturing costs. They can serve as complementary or synergistically with mAbs for immune therapy. However, at this time most of the reported inhibitors are still inferior to therapeutic antibodies in their inhibitory activities due to smaller molecular weight. Therefore, better small molecules need to be developed to improve their potencies. Moreover, although several PD-L1 small-molecule inhibitors have shown excellent preclinical results, their safety and efficacy in the clinic still awaits further validation.

Molecular design of dual inhibitors of PI3K and potential molecular target of cancer for its treatment: A review.

Aberrant activation of the phosphoinositide 3-kinase (PI3K) signaling network is a key event in many human cancers and therefore enormous efforts have been made in the development of PI3K inhibitors. However, due to intrinsic and acquired resistance as well as poor drug tolerance, limited therapeutic efficacy has been achieved with these agents. In view of the fact that PI3K inhibitors can show synergistic antitumor effects with other cancer agents, namely mammalian target of rapamycin (mTOR) inhibitors, histone deacetylase (HDAC) inhibitors and mitogen-activated protein kinase (MEK) inhibitors, dual inhibition of both targets by a single-molecule is regarded as a promising complementary or alternative therapeutic strategy to overcome the drawbacks of just PI3K monotherapy. In this review, we discuss the theoretical foundation for designing PI3K-based dual-target inhibitors and summarize the structure-activity relationships and clinical progress of these dual-binding agents.

Acoustic Droplet Ejection Enabled Automated Reaction Scouting.

Miniaturization and acceleration of synthetic chemistry are critically important for rapid property optimization in pharmaceutical, agrochemical, and materials research and development. However, in most laboratories organic synthesis is still performed on a slow, sequential, and material-consuming scale and not validated for multiple substrate combinations. Herein, we introduce fast and touchless acoustic droplet ejection (ADE) technology into small-molecule chemistry to transfer building blocks by nL droplets and to scout a newly designed isoquinoline synthesis. With each compound in a discrete well, 384 random derivatives were synthesized in an automated fashion, and their quality was monitored by SFC-MS and TLC-UV-MS analysis. We exemplify a pipeline of fast and efficient nmol scouting to mmol- and mol-scale synthesis for the discovery of a useful novel reaction with great scope.

Diverse Isoquinoline Scaffolds by Ugi/Pomeranz-Fritsch and Ugi/Schlittler-Müller Reactions.

The Pomeranz-Fritsch reaction and its Schlittler-Müller modification were successfully applied in the Ugi postcyclization strategy by using orthogonally protected aminoacetaldehyde diethyl acetal and complementary electron rich building blocks. Several scaffolds, including isoquinolines, carboline, alkaloid-like tetrazole-fused tetracyclic compounds, and benzo[ d]azepinone scaffolds, were synthesized in generally moderate to good yield. All our syntheses provide a short MCR-based sequence to novel or otherwise difficult to access scaffolds. Hence, we foresee multiple applications of these synthesis technologies.

ß-Carbolinone Analogues from the Ugi Silver Mine.

Here we describe a facile, tandem synthetic route for ß-carbolinones, a class of natural products of high biological significance. Commercially available building blocks yield highly diverse analogues in just two simple steps.

A Systematic Protein Refolding Screen Method using the DGR Approach Reveals that Time and Secondary TSA are Essential Variables.

Refolding of proteins derived from inclusion bodies is very promising as it can provide a reliable source of target proteins of high purity. However, inclusion body-based protein production is often limited by the lack of techniques for the detection of correctly refolded protein. Thus, the selection of the refolding conditions is mostly achieved using trial and error approaches and is thus a time-consuming process. In this study, we use the latest developments in the differential scanning fluorimetry guided refolding approach as an analytical method to detect correctly refolded protein. We describe a systematic buffer screen that contains a 96-well primary pH-refolding screen in conjunction with a secondary additive screen. Our research demonstrates that this approach could be applied for determining refolding conditions for several proteins. In addition, it revealed which "helper" molecules, such as arginine and additives are essential. Four different proteins: HA-RBD, MDM2, IL-17A and PD-L1 were used to validate our refolding approach. Our systematic protocol evaluates the impact of the "helper" molecules, the pH, buffer system and time on the protein refolding process in a high-throughput fashion. Finally, we demonstrate that refolding time and a secondary thermal shift assay buffer screen are critical factors for improving refolding efficiency.

Two Cycles with One Catch: Hydrazine in Ugi 4-CR and Its Postcyclizations.

Isocyanide-based multicomponent reactions (IMCR) are by far the most versatile reactions that can construct relatively complex molecules by one-pot synthesis. More importantly, the development of post IMCR modifications significantly improves the scaffold's diversity. Here, we describe the use of N-Boc protected hydrazine together with α-amino acid derived isocyanides in the Ugi tetrazole reaction and its post cyclization under both acidic and basic conditions. The cyclization in acidic conditions was conducted in a one pot fashion, which give 7-aminotetrazolopyrazinone (6) and tetrazolotriazepinone (7) cyclic products. The post cyclization under basic condition could selectively afford Boc-protected 7-aminotetrazolopyrazinone (8) products in yield of 38-87%.

Drug Target Validation Methods in Malaria - Protein Interference Assay (PIA) as a Tool for Highly Specific Drug Target Validation.

BACKGROUND: The validation of drug targets in malaria and other human diseases remains a highly difficult and laborious process. In the vast majority of cases, highly specific small molecule tools to inhibit a proteins function in vivo are simply not available. Additionally, the use of genetic tools in the analysis of malarial pathways is challenging. These issues result in difficulties in specifically modulating a hypothetical drug target's function in vivo. OBJECTIVE: The current "toolbox" of various methods and techniques to identify a protein's function in vivo remains very limited and there is a pressing need for expansion. New approaches are urgently required to support target validation in the drug discovery process. METHOD: Oligomerisation is the natural assembly of multiple copies of a single protein into one object and this self-assembly is present in more than half of all protein structures. Thus, oligomerisation plays a central role in the generation of functional biomolecules. A key feature of oligomerisation is that the oligomeric interfaces between the individual parts of the final assembly are highly specific. However, these interfaces have not yet been systematically explored or exploited to dissect biochemical pathways in vivo. RESULTS AND CONCLUSION: This mini review will describe the current state of the antimalarial toolset as well as the potentially druggable malarial pathways. A specific focus is drawn to the initial efforts to exploit oligomerisation surfaces in drug target validation. As alternative to the conventional methods, Protein Interference Assay (PIA) can be used for specific distortion of the target protein function and pathway assessment in vivo.

Synthesis and antibacterial evaluation of novel 11,4″-disubstituted azithromycin analogs with greatly improved activity against erythromycin-resistant bacteria.

A series of novel 11,4″-disubstituted azithromycin analogs were synthesized and evaluated for their antibacterial activity. All the 11,4″-disubstituted analogs exhibited excellent activity (0.03-0.12 µg/ml) against erythromycin-susceptible Streptococcus pneumoniae, and significantly improved activity against three phenotypes of erythromycin-resistant S. pneumoniae compared with erythromycin A, clarithromycin or azithromycin. Among them, compounds 26-28 showed the most potent activity (0.25, 0.03 and 2 µg/ml) against S. pneumoniae expressing the erm gene, the mef gene and the erm and mef genes, respectively. In addition, compound 28 was the most effective (0.03 and 0.12 µg/ml) against erythromycin-susceptible S. pneumoniae and Staphylococcus aureus as well. It is noteworthy that the most active compounds described above possess the same terminal 3,5-dinitrophenyl groups on their C-4″ bisamide side chains.