Enzyme Inhibitory and Anti-cancer Properties of Moringa peregrina / Propiedades inhibidoras Enzimáticas y Anticancerígenas de la Moringa peregrina

Background: Moringa peregrina is widely used in the traditional medicine of the Arabian Peninsula to treat various ailments, because it has many pharmacologically active components with several therapeutic effects. Objective: This study aimed to investigate the inhibitory effect of Moringaperegrina seed ethanolic extract (MPSE) against key enzymes involved in human pathologies, such as angiogenesis (thymidine phosphorylase), diabetes (α-glucosidase), and idiopathic intracranial hypertension (carbonic anhydrase). In addition, the anticancer properties were tested against the SH-SY5Y (human neuroblastoma). Results: MPSE extract significantly inhibited α-glucosidase, thymidine phosphorylase, and carbonic anhydrase with half-maximal inhibitory concentrations (IC50) values of 303.1 ± 1.3, 471.30 ± 0.3, and 271.30 ± 5.1 µg/mL, respectively. Furthermore, the antiproliferative effect of the MPSE was observed on the SH-SY5Y cancer cell line with IC50 values of 55.1 µg/mL. Conclusions: MPSE has interesting inhibitory capacities against key enzymes and human neuroblastoma cancer cell line.

Antecedentes: La Moringa peregrina se utiliza ampliamente en la medicina tradicional de la Península Arábiga para tratar diversas dolencias, ya que posee numerosos componentes farmacológicamente activos con varios efectos terapéuticos. Objetivo: Este estudio tenía como objetivo investigar el efecto inhibidor del extracto etanólico de semillas de Moringaperegrina (MPSE) frente a enzimas clave implicadas en patologías humanas, como la angiogénesis (timidina fosforilasa), la diabetes (α-glucosidasa) y la hipertensión intracraneal idiopática (anhidrasa carbónica). Además, se comprobaron las propiedades anticancerígenas frente al SH-SY5Y (neuroblastoma humano). Resultados: El extracto de MPSE inhibió significativamente la α-glucosidasa, la timidina fosforilasa y la anhidrasa carbónica con concentraciones inhibitorias semimáximas (IC50) de 303,1 ± 1,3, 471,30 ± 0,3 y 271,30 ± 5,1 µg/mL, respectivamente. Además, se observó el efecto antiproliferativo del MPSE en la línea celular del cáncer SH-SY5Y con valores de IC50 de 55,1 µg/mL. Conclusiones: MPSE posee interesantes capacidades inhibitorias frente a enzimas clave y línea celular de neuroblastoma canceroso humano.

[Natural 5α-reductase inhibitors in treatment of benign prostatic hyperplasia].

Benign prostatic hyperplasia(BPH) is a common disease of the male urinary system, and its incidence rate in China is increasing. However, the mechanism underlying the pathogenesis of BPH remains unclear. Some studies demonstrated that the incidence of BPH was related to the change in the levels of steroid hormones. Too high content of dihydrotestosterone(DHT) in the body may cause BPH and other related diseases. Testosterone(T) is converted to DHT by 5α-reductase(SRD5A). By inhibiting the activity of this enzyme, the production of DHT can be reduced, and then the incidence of BPH can be lowered. Therefore, it has drawn great attention to screen and discover safer and more effective 5α-reductase inhibitors from natural medicines to treat prostatic hyperplasia without affecting the physiological function of men. This review summarizes the characteristics and tissue distribution of 5α-reductase, the discovery of 5α-reductase inhibitors in traditional Chinese medicine and natural medicines, 5α-reductase inhibitors commonly used in clinical practice and their side effects, as well as the animal models of prostatic hyperplasia and common detection indicators, aiming to provide a reference for more in-depth understanding and research about BPH and development of drugs.

Novel diarylated tacrine derivatives: Synthesis, characterization, anticancer, antiepileptic, antibacterial, and antifungal activities.

In this study, our goal was to synthesize novel aryl tacrine derivatives and assess their potential as anticancer, antibacterial agents, and enzyme inhibitors. We adopted a two-step approach, initiating with the synthesis of dibromotacrine derivatives 3 and 4 through the Friedlander reaction. These intermediates underwent further transformation into diarylated tacrine derivatives 3a-e and 4a-e using a Suzuki-Miyaura cross-coupling reaction. Thorough characterization of these novel diarylated tacrines was achieved using various spectroscopic techniques. Our findings highlighted the potent anticancer effects of these innovative compounds across a range of cancer cell lines, including lung, gynecologic, bone, colon, and breast cancers, while demonstrating low cytotoxicity against normal cells. Notably, these compounds surpassed the control drug, 5-Fluorouracil, in terms of antiproliferative activity in numerous cancer cell lines. Moreover, our investigation included an analysis of the inhibitory properties of these novel compounds against various microorganisms and cytosolic carbonic anhydrase enzymes. The results suggest their potential for further exploration as cancer-specific, enzyme inhibitory, and antibacterial therapeutic agents. Notably, four compounds, namely, 5,7-bis(4-(methylthio)phenyl)tacrine (3d), 5,7-bis(4-(trifluoromethoxy)phenyl)tacrine (3e), 2,4-bis(4-(trifluoromethoxy)phenyl)-7,8,9,10-tetrahydro-6H-cyclohepta[b]quinolin-11-amine (4e), and 6,8-dibromotacrine (3), emerged as the most promising candidates for preclinical studies.

Epiberberine: a potential rumen microbial urease inhibitor to reduce ammonia release screened by targeting UreG.

Rumen microbial urease inhibitors have been proposed for regulating nitrogen emission and improving nitrogen utilization efficiency in ruminant livestock industry. However, studies on plant-derived natural inhibitors of rumen microbial urease are limited. Urease accessory protein UreG, plays a crucial role in facilitating urease maturation, is a new target for design of urease inhibitor. The objective of this study was to select the potential effective inhibitor of rumen microbial urease from major protoberberine alkaloids in Rhizoma Coptidis by targeting UreG. Our results showed that berberine chloride and epiberberine exerted superior inhibition potential than other alkaloids based on GTPase activity study of UreG. Berberine chloride inhibition of UreG was mixed type, while inhibition kinetics type of epiberberine was uncompetitive. Furthermore, epiberberine was found to be more effective than berberine chloride in inhibiting the combination of nickel towards UreG and inducing changes in the second structure of UreG. Molecular modeling provided the rational structural basis for the higher inhibition potential of epiberberine, amino acid residues in G1 motif and G3 motif of UreG formed interactions with D ring of berberine chloride, while interacted with A ring and D ring of epiberberine. We further demonstrated the efficacy of epiberberine in the ruminal microbial fermentation with low ammonia release and urea degradation. In conclusion, our study clearly indicates that epiberberine is a promising candidate as a safe and effective inhibitor of rumen microbial urease and provides an optimal strategy and suitable feed additive for regulating nitrogen excretion in ruminants in the future. KEY POINTS: • Epiberberine is the most effective inhibitor of rumen urease from Rhizoma Coptidis. • Urease accessory protein UreG is an effective target for design of urease inhibitor. • Epiberberine may be used as natural feed additive to reducing NH3 release in ruminants.

A phase I open-label, dose-escalation study of NUC-3373, a targeted thymidylate synthase inhibitor, in patients with advanced cancer (NuTide:301).

PURPOSE: 5-fluorouracil (5-FU) is inefficiently converted to the active anti-cancer metabolite, fluorodeoxyuridine-monophosphate (FUDR-MP), is associated with dose-limiting toxicities and challenging administration schedules. NUC-3373 is a phosphoramidate nucleotide analog of fluorodeoxyuridine (FUDR) designed to overcome these limitations and replace fluoropyrimidines such as 5-FU. PATIENTS AND METHODS: NUC-3373 was administered as monotherapy to patients with advanced solid tumors refractory to standard therapy via intravenous infusion either on Days 1, 8, 15 and 22 (Part 1) or on Days 1 and 15 (Part 2) of 28-day cycles until disease progression or unacceptable toxicity. Primary objectives were maximum tolerated dose (MTD) and recommended Phase II dose (RP2D) and schedule of NUC-3373. Secondary objectives included pharmacokinetics (PK), and anti-tumor activity. RESULTS: Fifty-nine patients received weekly NUC-3373 in 9 cohorts in Part 1 (n = 43) and 3 alternate-weekly dosing cohorts in Part 2 (n = 16). They had received a median of 3 prior lines of treatment (range: 0-11) and 74% were exposed to prior fluoropyrimidines. Four experienced dose-limiting toxicities: two Grade (G) 3 transaminitis; one G2 headache; and one G3 transient hypotension. Commonest treatment-related G3 adverse event of raised transaminases occurred in < 10% of patients. NUC-3373 showed a favorable PK profile, with dose-proportionality and a prolonged half-life compared to 5-FU. A best overall response of stable disease was observed, with prolonged progression-free survival. CONCLUSION: NUC-3373 was well-tolerated in a heavily pre-treated solid tumor patient population, including those who had relapsed on prior 5-FU. The MTD and RP2D was defined as 2500 mg/m2 NUC-3373 weekly. NUC-3373 is currently in combination treatment studies. TRIAL REGISTRATION: Clinicaltrials.gov registry number NCT02723240. Trial registered on 8th December 2015. https://clinicaltrials.gov/study/NCT02723240 .

Identification of benzo[b]thiophene-1,1-dioxide derivatives as novel PHGDH covalent inhibitors.

The increased de novo serine biosynthesis confers many advantages for tumorigenesis and metastasis. Phosphoglycerate dehydrogenase (PHGDH), a rate-limiting enzyme in serine biogenesis, exhibits hyperactivity across multiple tumors and emerges as a promising target for cancer treatment. Through screening our in-house compound library, we identified compound Stattic as a potent PHGDH inhibitor (IC50 = 1.98 ± 0.66 µM). Subsequent exploration in structural activity relationships led to the discovery of compound B12 that demonstrated the increased enzymatic inhibitory activity (IC50 = 0.29 ± 0.02 µM). Furthermore, B12 exhibited robust inhibitory effects on the proliferation of MDA-MB-468, NCI-H1975, HT1080 and PC9 cells that overexpress PHGDH. Additionally, using a [U-13C6]-glucose tracing assay, B12 was found to reduce the production of glucose-derived serine in MDA-MB-468 cells. Finally, mass spectrometry-based peptide profiling, mutagenesis experiment and molecular docking study collectively suggested that B12 formed a covalent bond with Cys421 of PHGDH.

Understanding the Effects of Ligand Configuration on Protoporphyrinogen IX Oxidase with Rationally Designed 3-(N-Phenyluracil)but-2-enoates.

Protoporphyrinogen IX oxidase (PPO, EC 1.3.3.4) is a promising target for green herbicide discovery. However, the ligand configuration effects on PPO activity were still poorly understood. Herein, we designed 3-(N-phenyluracil)but-2-enoates using our previously developed active fragments exchange and link (AFEL) approach and synthesized a series of novel compounds with nanomolar ranges of Nicotiana tabacum PPO (NtPPO) inhibitory potency and promising herbicidal potency. Our systematic structure-activity relationship investigations showed that the E isomers of 3-(N-phenyluracil)but-2-enoates displayed improved bioactivity than their corresponding Z isomers. Using molecular simulation studies, we found that the E isomers showed a relatively lower entropy change and could sample more stable binding conformation to the receptor than the Z isomers. Our density functional theory (DFT) calculations showed that the E isomers showed higher chemical reactivity and lower electronic chemical potential than their corresponding Z isomers. Compound E-Ic emerged as the optimal compound with a Ki value of 3.0 nM against NtPPO, exhibiting a broader spectrum of weed control than saflufenacil at 37.5-75 g ai/ha and also safe to maize at 75 g ai/ha, which could be considered as a promising lead herbicide for further development.

Virological and clinical outcomes in outpatients treated with baloxavir or neuraminidase inhibitors for A(H3N2) influenza: A multicenter study of the 2022-2023 season.

While clinical trials have illuminated both the virological and clinical efficacy of baloxavir for influenza and post-treatment viral resistance, these aspects warrant further study in real-world settings. In response, we executed a prospective, observational study of the Japanese 2022-2023 influenza season. A cohort of 73 A(H3N2)-diagnosed outpatients-36 treated with baloxavir, 20 with oseltamivir, and 17 with other neuraminidase inhibitors (NAIs)-were analyzed. Viral samples were collected before and after administering an antiviral on days 1, 5, and 10, respectively. Cultured viruses were amplified using RT-PCR and sequenced to detect mutations. Fever and other symptoms were tracked via self-reporting diaries. In the baloxavir cohort, viral detection was 11.1% (4/36) and 0% (0/36) on day 5 and day 10, respectively. Two isolates from day 5 (5.6%, 2/36) manifested I38T/M-substitutions in the polymerase acidic protein (PA). For oseltamivir and other NAIs, viral detection rates were 60.0% (12/20) and 52.9% (9/17) on day 5, and 16.7% (3/18) and 6.3% (1/16) on day 10, respectively. No oseltamivir-resistant neuraminidase mutations were identified after treatment. Median fever durations for the baloxavir, oseltamivir, and other NAI cohorts were 27.0, 38.0, and 36.0 h, respectively, with no significant difference. Two patients harboring PA I38T/M-substitutions did not exhibit prolonged fever or other symptoms. These findings affirm baloxavir's virological and clinical effectiveness against A(H3N2) in the 2022-2023 season and suggest limited clinical influence of post-treatment resistance emergence.

Design, synthesis and activity evaluation of pseudilin analogs against cyanobacteria as IspD inhibitors.

The discovery of safe, effective, and selective chemical algicides is the stringent need for the algicides development, and it is also one of the effective routes to control cyanobacteria harmful algal blooms and to meet the higher requirements of environmental and ecological. In this work, a series of novel bromo-N-phenyl-5-o-hydroxyphenylpyrazole-3-carboxyamides were rationally designed as pseudilin analogs by bioisosteric replacement and molecular hybridization strategies, in which the pyrrole unit of pseudilin was replaced with pyrazole and further combined with the dominant structural fragments of algicide diuron. The synthesis was carried out by a facile four-step routeincluding cyclization, amidation, transanulation, and halogenation. The biological activity evaluation on AtIspD, EcIspD, Synechocystis sp. PCC6803 and Microcystis aeruginosa FACHB905 revealed that most compounds had good EcIspD and excellent cyanobacteria inhibitory activity. In particular, compound 6bb exhibited potent algicidal activity against PCC6803 and FACHB905 with EC50 = 1.28 µM and 0.37 µM, respectively, 1.4-fold and 4.0-fold enhancement compared to copper sulfate (EC50 = 1.79 and 1.49 µM, respectively), and it also showed the best inhibitory activity of EcIspD. The binding of 6bb to EcIspD was explored by molecular docking, and it was confirmed that 6bb could bind to the EcIspD active site. Compound 6bb was proven to be a potential structure for the further development of novel algicides that targets IspD in the MEP pathway.

Nitric Oxide (NO) Synthase Inhibitors: Potential Candidates for the Treatment of Anxiety Disorders?

Close to 19% of the world population suffers from anxiety. Current medications for this chronic mental disorder have improved treatment over the last half century or more, but the newer anxiolytics have proved disappointing, and enormous challenges remain. Nitric oxide (NO), an intra- and inter-cellular messenger in the brain, is involved in the pathogenesis of anxiety. In particular, excessive NO production might contribute to its pathology. This implies that it might be useful to reduce nitrergic activity; therefore, molecules aiming to downregulate NO production such as NO synthase inhibitors (NOSIs) might be candidates. Here, it was intended to critically review advances in research on these emerging molecules for the treatment of anxiety disorders. Current assessment indicates that, although NOSIs are implicated in anxiety, their potential anti-anxiety action remains to be established.

Impact of the H274Y Substitution on N1, N4, N5, and N8 Neuraminidase Enzymatic Properties and Expression in Reverse Genetic Influenza A Viruses.

The H274Y substitution (N2 numbering) in neuraminidase (NA) N1 confers oseltamivir resistance to A(H1N1) influenza viruses. This resistance has been associated with reduced N1 expression using transfected cells, but the effect of this substitution on the enzymatic properties and on the expression of other group-1-NA subtypes is unknown. The aim of the present study was to evaluate the antiviral resistance, enzymatic properties, and expression of wild-type (WT) and H274Y-substituted NA for each group-1-NA. To this end, viruses with WT or H274Y-substituted NA (N1pdm09 or avian N4, N5 or N8) were generated by reverse genetics, and for each reverse-genetic virus, antiviral susceptibility, NA affinity (Km), and maximum velocity (Vm) were measured. The enzymatic properties were coupled with NA quantification on concentrated reverse genetic viruses using mass spectrometry. The H274Y-NA substitution resulted in highly reduced inhibition by oseltamivir and normal inhibition by zanamivir and laninamivir. This resistance was associated with a reduced affinity for MUNANA substrate and a conserved Vm in all viruses. NA quantification was not significantly different between viruses carrying WT or H274Y-N1, N4 or N8, but was lower for viruses carrying H274Y-N5 compared to those carrying a WT-N5. In conclusion, the H274Y-NA substitution of different group-1-NAs systematically reduced their affinity for MUNANA substrate without a significant impact on NA Vm. The impact of the H274Y-NA substitution on viral NA expression was different according to the studied NA.

Novel Multiplexed High Throughput Screening of Selective Inhibitors for Drug-Metabolizing Enzymes Using Human Hepatocytes.

Selective chemical inhibitors are critical for reaction phenotyping to identify drug-metabolizing enzymes that are involved in the elimination of drug candidates. Although relatively selective inhibitors are available for the major cytochrome P450 enzymes (CYP), they are quite limited for the less common CYPs and non-CYPs. To address this gap, we developed a multiplexed high throughput screening (HTS) assay using 20 substrate reactions of multiple enzymes to simultaneously monitor the inhibition of enzymes in a 384-well format. Four 384-well assay plates can be run at the same time to maximize throughput. This is the first multiplexed HTS assay for drug-metabolizing enzymes reported. The HTS assay is technologically enabled with state-of-the-art robotic systems and highly sensitive modern LC-MS/MS instrumentation. Virtual screening is utilized to identify inhibitors for HTS based on known inhibitors and enzyme structures. Screening of ~4600 compounds generated many hits for many drug-metabolizing enzymes including the two time-dependent and selective aldehyde oxidase inhibitors, erlotinib and dibenzothiophene. The hit rate is much higher than that for the traditional HTS for biological targets due to the promiscuous nature of the drug-metabolizing enzymes and the biased compound selection process. Future efforts will focus on using this method to identify selective inhibitors for enzymes that do not currently have quality hits and thoroughly characterizing the newly identified selective inhibitors from our screen. We encourage colleagues from other organizations to explore their proprietary libraries using a similar approach to identify better inhibitors that can be used across the industry.

First-in-class MKK4 inhibitors enhance liver regeneration and prevent liver failure.

Diminished hepatocyte regeneration is a key feature of acute and chronic liver diseases and after extended liver resections, resulting in the inability to maintain or restore a sufficient functional liver mass. Therapies to restore hepatocyte regeneration are lacking, making liver transplantation the only curative option for end-stage liver disease. Here, we report on the structure-based development and characterization (nuclear magnetic resonance [NMR] spectroscopy) of first-in-class small molecule inhibitors of the dual-specificity kinase MKK4 (MKK4i). MKK4i increased liver regeneration upon hepatectomy in murine and porcine models, allowed for survival of pigs in a lethal 85% hepatectomy model, and showed antisteatotic and antifibrotic effects in liver disease mouse models. A first-in-human phase I trial (European Union Drug Regulating Authorities Clinical Trials [EudraCT] 2021-000193-28) with the clinical candidate HRX215 was conducted and revealed excellent safety and pharmacokinetics. Clinical trials to probe HRX215 for prevention/treatment of liver failure after extensive oncological liver resections or after transplantation of small grafts are warranted.

Discovery of Novel 11-Membered Templates as Squalene Synthase Inhibitors.

Squalene synthase is one of the most promising pharmaceutical targets to treat hyperlipidemia. Inhibition of the squalene synthase causes a decrease in the hepatic cholesterol concentration. We have already reported the design and synthesis of highly potent benzhydrol-type squalene inhibitors. Although these templates showed unique and potent cyclic active conformations via intramolecular hydrogen bonds, the in vivo cholesterol-lowering efficacy was insufficient. We attempted to improve their potential as an orally active medicine. In our medicinal chemistry effort, cyclized 11-membered ring templates were acquired. The novel series of compounds exhibited potent squalene synthase inhibitory activity, and one of the derivatives, isomer A-(1S, 3R)-14i, showed plasma lipid-lowering efficacy in hamster and marmoset repeated-dose studies. Our findings provide valuable insights into the design and development of novel and unique 11-membered ring-type highly potent squalene synthase inhibitors.

Multivalent pyrrolidines acting as pharmacological chaperones against Gaucher disease.

A concise asymmetric synthesis of clickable enantiomeric pyrrolidines was achieved using Crabbé-Ma allenation. The synthesized iminosugars were grafted by copper-free strain-promoted alkyne-azide cycloaddition onto phosphorus dendrimers. The hexavalent and dodecavalent pyrrolidines were evaluated as ß-glucocerebrosidase inhibitors. The level of inhibition suggests that monofluorocyclooctatriazole group may contribute to the affinity for the protein leading to potent multivalent inhibitors. Docking studies were carried out to rationalize these results. Then, the iminosugars clusters were evaluated as pharmacological chaperones in Gaucher patients' fibroblasts. An increase in ß-glucocerebrosidase activity was observed with hexavalent and dodecavalent pyrrolidines at concentrations as low as 1 µM and 0.1 µM, respectively. These iminosugar clusters constitute the first example of multivalent pyrrolidines acting as pharmacological chaperones against Gaucher disease.

Can a Small Change in the Heterocyclic Substituent Significantly Impact the Physicochemical and Biological Properties of (Z)-2-(5-Benzylidene-4-oxo-2-thioxothiazolidin-3-yl)acetic Acid Derivatives?

Rhodanine-3-acetic acid derivatives are attractive compounds with versatile effects. What is very important is that compounds of this type have many biological properties. They are tested, among others, as fluorescent probes for bioimaging and aldose reductase inhibitors. Rhodanine-3-acetic acid derivatives also have antibacterial, antifungal and anticancer activity. The presented work demonstrates that a slight change in the five-membered heterocyclic substituent significantly affects the properties of the compounds under consideration. Three rhodanine-3-acetic acid derivatives (A-1-A-3) were obtained in the Knoevenagel condensation reaction with good yields, ranging from 54% to 71%. High thermal stability of the tested compounds was also demonstrated above 240 °C. The absorption and emission maxima in polar and non-polar solvents were determined. Then, the possibility of using the considered derivatives for fluorescence bioimaging was checked. Compounds A-1 and A-2 were successfully used as fluorescent dyes of fixed cells of mammalian origin. In addition, biological activity tests against bacteria and fungi were carried out. Our results showed that A-1 and A-2 showed the most excellent antimicrobial activity among the newly synthesized compounds, especially against Gram-positive bacteria.

Decoding selectivity: computational insights into AKR1B1 and AKR1B10 inhibition.

Understanding selectivity mechanisms of inhibitors towards highly homologous proteins is of paramount importance in the design of selective candidates. Human aldo-keto reductases (AKRs) pertain to a superfamily of monomeric oxidoreductases, which serve as NADPH-dependent cytosolic enzymes to catalyze the reduction of carbonyl groups to primary and secondary alcohols using electrons from NADPH. Among AKRs, AKR1B1 is emerging as a promising target for cancer treatment and diabetes, despite its high structural similarity with AKR1B10, which leads to severe adverse events. Therefore, it is crucial to understand the selectivity mechanisms of AKR1B1 and AKR1B10 to discover safe anticancer candidates with optimal therapeutic efficacy. In this study, multiple computational strategies, including sequence alignment, structural comparison, Protein Contacts Atlas analysis, molecular docking, molecular dynamics simulation, MM-GBSA calculation, alanine scanning mutagenesis and pharmacophore modeling analysis were employed to comprehensively understand the selectivity mechanisms of AKR1B1/10 inhibition based on selective inhibitor lidorestat and HAHE. This study would provide substantial evidence in the design of potent and highly selective AKR1B1/10 inhibitors in future.

Design, Synthesis, and Biological Activity of Novel Phenyltriazolinone PPO Inhibitors Containing Five-Membered Heterocycles.

Protoporphyrinogen oxidase (PPO, EC 1.3.3.4) catalyzes the oxidation of protoporphyrinogen IX to protoporphyrin IX, which is a key step in the synthesis of porphyrins in vivo. PPO inhibitors use protoporphyrinogen oxidase as the target and block the biosynthesis process of porphyrin by inhibiting the activity of the enzyme, eventually leading to plant death. In this paper, phenyl triazolinone was used as the parent structure, and the five-membered heterocycle with good herbicidal activity was introduced by using the principle of substructure splicing. According to the principle of bioisosterism, the sulfur atoms on the thiophene ring were replaced with oxygen atoms. Finally, 33 phenyl triazolinones and their derivatives were designed and synthesized, and their characterizations and biological activities were investigated. The in vitro PPO inhibitory activity and greenhouse herbicidal activity of 33 target compounds were determined, and compound D4 with better activity was screened out. The crop safety determination, field weeding effect determination, weeding spectrum determination, and crop metabolism study were carried out. The results showed that compound D4 showed good safety to corn, soybean, wheat, and peanut but poor selectivity to cotton. The field weeding effect of this compound is comparable to that of the commercial herbicide sulfentrazone. The herbicidal spectrum experiment showed that compound D4 had a wide herbicidal spectrum and a good growth inhibition effect on dicotyledonous weeds. Molecular docking results showed that compound D4 forms a hydrogen bond with amino acid residue Arg-98 in the tobacco mitochondria (mtPPO)-active pocket and forms two π-π stacking interactions with Phe-392. This indicates that compound D4 has stronger PPO inhibitory activity. This indicates that compound D4 has wide prospects for development.

Discovery of a novel class of reversible monoacylglycerol lipase inhibitors for potential treatment of depression.

Biological studies on the endocannabinoid system (ECS) have suggested that monoacylglycerol lipase (MAGL), an essential enzyme responsible for the hydrolysis of 2-arachidonoylglycerol (2-AG), is a novel target for developing antidepressants. A decrease of 2-AG levels in the hippocampus of the brain has been observed in depressive-like models induced by chronic stress. Herein, employing a structure-based approach, we designed and synthesized a new class of (piperazine-1-carbonyl) quinolin-2(1H)-one derivatives as potent, reversible and selective MAGL inhibitors. And detailed structure-activity relationships (SAR) studies were discussed. Compound 27 (IC50 = 10.3 nM) exhibited high bioavailability (92.7%) and 2-AG elevation effect in vivo. Additionally, compound 27 exerted rapid antidepressant effects caused by chronic restraint stress (CRS) and didn't show signs of addictive properties in the conditioned place preference (CPP) assays. Our study is the first to report that reversible MAGL inhibitors can treat chronic stress-induced depression effectively, which may provide a new potential therapeutic strategy for the discovery of an original class of safe, rapid antidepressant drugs.

Exploring the anti-gout potential of sunflower receptacles alkaloids: A computational and pharmacological analysis.

Gout, a painful condition marked by elevated uric acid levels often linked to the diet's high purine and alcohol content, finds a potential treatment target in xanthine oxidase (XO), a crucial enzyme for uric acid production. This study explores the therapeutic properties of alkaloids extracted from sunflower (Helianthus annuus L.) receptacles against gout. By leveraging computational chemistry and introducing a novel R-based clustering algorithm, "TriDimensional Hierarchical Fingerprint Clustering with Tanimoto Representative Selection (3DHFC-TRS)," we assessed 231 alkaloid molecules from sunflower receptacles. Our clustering analysis pinpointed six alkaloids with significant gout-targeting potential, particularly emphasizing the fifth cluster's XO inhibition capabilities. Through molecular docking and the BatchDTA prediction model, we identified three top compounds-2-naphthylalanine, medroxalol, and fenspiride-with the highest XO affinity. Further molecular dynamics simulations assessed their enzyme active site interactions and binding free energies, employing MM-PBSA calculations. This investigation not only highlights the discovery of promising compounds within sunflower receptacle alkaloids via LC-MS but also introduces medroxalol as a novel gout treatment candidate, showcasing the synergy of computational techniques and LC-MS in drug discovery.