Design, synthesis, and biological evaluation of 2-substituted-pyridin-4-yl macrocyclic derivatives as new selective HPK1 inhibitors.

Hematopoietic progenitor kinase 1 (HPK1) is a negative regulator of T-cell receptor (TCR) signaling and a promising therapeutic target in immunotherapy. Herein, based on the reported HPK1 inhibitor Compound K, a series of 2-substituted-pyridin-4-yl macrocyclic HPK1 inhibitors was designed and synthesized through structure-based drug design and macrocyclization strategies. Detailed SAR studies led to the discovery of compound 2 t, which exhibits excellent HPK1 inhibitory activity (IC = 1.

Structure-Based Directed Evolution of Rice 4-Hydroxyphenylpyruvate Dioxygenase Confers Enhanced Herbicide Tolerance.

Precise gene modification is pivotal in molecular breeding. 4-Hydroxyphenylpyruvate dioxygenase (HPPD) plays a crucial role in the development of herbicide-resistant crops. But how to modify HPPD and thereby confer herbicide resistance in plants remains unclear.

Repurposing 4-Hydroxyphenylpyruvate dioxygenase inhibitors as novel agents for mosquito control: A structure-based design approach.

Mosquito-borne diseases remain a significant global health burden, necessitating innovative vector control strategies. 4-Hydroxyphenylpyruvate dioxygenase (HPPD) inhibitors, widely used as herbicides, have been recently explored for their potential to disrupt mosquito tyrosine metabolic pathways, offering a novel approach to mosquito control. This study utilized a structure-based rational design strategy to repurpose existing HPPD inhibitors, such as pyrazole-benzene 2,2-dioxothiadiazole and pyrazole-1,3-isoindolinone hybrids, targeting Aedes aegypti HPPD (AaHPPD).

Complementary Fluorescent Probe Pair Targeting Histidinol Dehydrogenase Provides a Useful Tool for Target Validation.

Recent advances in target-based pesticide design have identified numerous novel candidate targets, although their agrochemical potential requires rigorous validation. Fluorescent probes serve as critical tools for tracing molecular interactions and elucidating the target functionality. Herein, we developed a complementary fluorescent probe pair ( and ) to systematically reveal the challenge of targeting histidinol dehydrogenase (HDH) as an agrochemical target.

High-Throughput Fluorescence Screening Enables Globally Consistent Identification of ABA Signaling Modulators.

Frequent exposure to environmental stresses can potentially reduce plant yield by up to 60%. The regulation of abscisic acid (ABA) signaling, especially its core receptors, is crucial for the adaptation of plants to environmental stress. However, efficient identification of ABA-signaling modulators remains a challenge.

A Rapid pH-Responsive Pyraclostrobin Delivery System with Enhanced Membrane Passing Property and Fungicidal Activity against .

As the second most important fungal pathogen, () poses a serious threat to crop yields and agricultural safety. Pyraclostrobin (PYR), a broad-spectrum QoI fungicide, has been widely utilized since its launch in 2003. However, the inhibitory effects of both PYR technical and PYR formulations on are not outstanding.

Design and Syntheses of Proherbicides Targeting 4-Hydroxyphenylpyruvate Dioxygenase.

4-Hydroxyphenylpyruvate dioxygenase (HPPD, EC 1.13.11.

Discovery of Triketone-Indazolones as Novel 4-Hydroxyphenylpyruvate Dioxygenase Inhibiting-Based Herbicides.

4-Hydroxyphenylpyruvate dioxygenase (HPPD) is a crucial herbicide target in current research, playing an important role in the comprehensive management of resistant weeds. However, the limited crop selectivity and less effectiveness against grass weeds of many existing HPPD inhibitors, limit their further application. To address these issues, a series of novel HPPD inhibitors with fused ring structures were designed and synthesized by introducing an electron-rich indazolone ring and combining it with the classical triketone pharmacophore structure.

The resistance mechanism of B_P225F and B_H272R mutations in succinate dehydrogenase in Botrytis cinerea.

Botrytis cinerea populations resistant to succinate dehydrogenase inhibitors (SDHIs) represent a major problem for the sustainable development of modern agriculture. In the present study, the resistance mechanism of B_P225F and B_H272R mutations in B. cinerea SDH (BcSDH) resistant to SDHIs fungicides, including boscalid (BOS), penflufen (PEN), pydiflumetofen (PYD), fluopyram (FLU), and benzovindiflupyr (BEN), was uncovered.

3D molecular generation models expand chemical space exploration in drug design.

Drug discovery is essential in human diseases but faces challenges because of the vast chemical space. Molecular generation models have become powerful tools to accelerate drug design by efficiently exploring chemical space. 3D molecular generation has gained popularity for explicitly incorporating spatial structural information to generate rational molecules.

Fluorescence imaging opens a new window for the diagnosis of early-stage Alzheimer's disease.

As the global population ages, the incidence and prevalence of Alzheimer's disease (AD) continues to rise, posing a serious threat to human health. Butyrylcholinesterase (BChE), which is overexpressed in the brains of patients with AD, is a potential drug target and biomarker. However, the molecular mechanism underlying BChE's role in the AD process remains unclear.

Cryo-EM Structures Reveal the Unique Binding Modes of Metyltetraprole in Yeast and Porcine Cytochrome Complex Enabling Rational Design of Inhibitors.

Cytochrome (complex III) represents a significant target for the discovery of both drugs and fungicides. Metyltetraprole (MET) is commonly classified as a quinone site inhibitor (QI) that combats the G143A mutated isolate, which confers high resistance to strobilurin fungicides such as pyraclostrobin (PYR). The binding mode and antiresistance mechanism of MET remain unclear.

Triazole Sulfonamide Derivates: Inhibitors of the Complex to Control Cucumber Downy Mildew.

Cucumber downy mildew (CDM), caused by , is a destructive disease that affects greenhouse cucumbers and causes significant losses for growers. Amisulbrom, a triazole sulfonamide fungicide targeting the Qi site in the complex, has shown potential in effectively combating CDM. However, its detailed binding mode with the target is unclear.

Comprehensive Overview of the Amide Linker Modification in the Succinate Dehydrogenase Inhibitors.

Succinate dehydrogenase inhibitors (SDHIs) have become one of the most important classes of agrochemical fungicides. According to the data from FRAC, the resistance risk for SDHIs had reached up to medium and even to high. In general, the chemical structure of SDHIs mainly contained three fragments: an acid core, a hydrophobic tail, and an amide linker, corresponding to three modification directions for each fragment.

AquaticTox: A Web-Based Tool for Aquatic Toxicity Evaluation Based on Ensemble Learning to Facilitate the Screening of Green Chemicals.

The widespread use of chemical products inevitably brings many side effects as environmental pollutants. Toxicological assessment of compounds to aquatic life plays an important role in protecting the environment from their hazards. However, animal testing approaches for aquatic toxicity evaluation are time-consuming, expensive, and ethically limited, especially when there are a great number of compounds.

Visualizing plant salt stress with a NaCl-responsive fluorescent probe.

Salt stress is an adverse environmental condition that harms plant growth and development. The development of salt stress probes is critical for tracking the growth dynamics of plants, molecular breeding or screening of growth regulators. The sodium chloride (NaCl)-responsive fluorescent probe Aza-CyBz is designed based on the tenet that NaCl induces formation of ordered aggregates, and the sensitive fluorescence response can enable the visualization of plant salt stress in root tip tissues and live plants.

Stabilization of dimeric PYR/PYL/RCAR family members relieves abscisic acid-induced inhibition of seed germination.

Abscisic acid (ABA) is the primary preventing factor of seed germination, which is crucial to plant survival and propagation. ABA-induced seed germination inhibition is mainly mediated by the dimeric PYR/PYL/RCAR (PYLs) family members. However, little is known about the relevance between dimeric stability of PYLs and seed germination.

An artificially evolved gene for herbicide-resistant rice breeding.

Discovering and engineering herbicide-resistant genes is a crucial challenge in crop breeding. This study focuses on the 4-hydroxyphenylpyruvate dioxygenase Inhibitor Sensitive 1-Like (HSL) protein, prevalent in higher plants and exhibiting weak catalytic activity against many β-triketone herbicides (β-THs). The crystal structures of maize HSL1A complexed with β-THs were elucidated, identifying four essential herbicide-binding residues and explaining the weak activity of HSL1A against the herbicides.

Discovery of Novel Oxathiapiprolin Derivatives as Potent Fungicide Candidates.

Oxathiapiprolin (OXA), which targets the oxysterol-binding protein (OSBP), is an outstanding piperidinyl thiazole isoxazoline (PTI) fungicide that can be used to control oomycetes diseases. In this study, starting from the structure of OXA, a series of novel OSBP inhibitors were designed and synthesized by introducing an indole moiety to replace the pyrazole in OXA. Finally, compound was found to exhibit the highest control effect (82%) against cucumber downy mildew (CDM) in the greenhouse at a very low dosage of 0.

Design, Synthesis, and Biological Evaluation of Pyridazinone-Containing Derivatives As Novel Protoporphyrinogen IX Oxidase Inhibitor.

Protoporphyrinogen IX oxidase (PPO, E.C. 1.

Multi-level bioinformatics resources support drug target discovery of protein-protein interactions.

Drug discovery often begins with a new target. Protein-protein interactions (PPIs) are crucial to multitudinous cellular processes and offer a promising avenue for drug-target discovery. PPIs are characterized by multi-level complexity: at the protein level, interaction networks can be used to identify potential targets, whereas at the residue level, the details of the interactions of individual PPIs can be used to examine a target's druggability.