Enzyme Inhibitors Research Articles

Association of ACEI/ARB therapy with total and cardiovascular death in coronary artery disease patients with advanced chronic kidney disease: a large multi-center longitudinal study.

Advanced chronic kidney disease (CKD) is common among patients with coronary artery disease (CAD), and angiotensin‑converting enzyme inhibitors (ACEI) or angiotensin‑receptor blockers (ARB) can improve cardiac and renal function, but whether ACEI/ARB therapy improves long-term prognosis remains unclear among these high-risk patients. Therefore, this research aimed to investigate the relationship between ACEI/ARB therapy and long-term prognosis among CAD patients with advanced CKD. CAD patients with advanced CKD were included in five hospitals. Advanced CKD was defined as estimated glomerular filtration rate (eGFR)<30 ml/min per 1.73 m2. Cox regression models and competing risk Fine and Gray models were used to examine the relationship between ACEI/ARB therapy and all-cause and cardiovascular death, respectively. Of 2527 patients, 47.6% population of our cohort was discharged on ACEI/ARB. The overall all-cause and cardiovascular mortality were 38.6% and 24.7%, respectively. Multivariate Cox regression analyses indicated that ACEI/ARB therapy was found to be associated with lower rates of both all-cause mortality (hazard ratio (HR)=0.836, 95% confidence interval (CI): 0.738-0.948, p = 0.005) and cardiovascular mortality (HR = 0.817, 95%CI: 0.699-0.956, p = 0.011). In the propensity-matched cohort, the survival benefit was consistent, and significantly better survival was observed for all-cause mortality (HR = 0.856, 95%CI: 0.752-0.974, p = 0.019) and cardiovascular mortality (HR = 0.830, 95%CI: 0.707-0.974, p = 0.023) among patients treated with ACEI/ARB. ACEI/ARB therapy showed a better survival benefit among high-risk CAD patients with advanced CKD at long-term follow-up, which manifested that strategies to maintain ACEI/ARB treatment may improve clinical outcomes among these high-risk populations.

Phytochemical profile, antioxidant and contractile activity of plants extracts used by parturients to manage childbirth in Niger

The widespread use of herbal preparations during childbirth and postnatal care in some developing countries is generating interest in scientific research about their standardized use. This study aims to compare the phytochemical profiles, the antioxidant properties, and the contractile effects of plants used to manage the childbirth of seven samples of plants (bark of Acacia senegal (L.) Willd, leaves and bark of Sclerocarya birrea, leaves of Lawsonia inermis L, whole plant of Sesamum alatum, whole plant of Ceratotheca sesamoides Endl. and brak of Ficus platyphylla). Qualitative and quantitative phytochemical screening was carried out using HPTLC and colorimetric methods. Antioxidant activity was evaluated using DPPH, ABTS and FRAP methods. Enzyme inhibition was performed on lipid peroxidation (LPO) and 15-Lipoxygenase (15-LOX). The contractile effect of uterine smooth muscle in NMRI mice was assessed ex vivo. The screening revealed the presence of several phytoconstituents, such as tannins, flavonoids, coumarins, saponins, sterols, and triterpenes. The highest content of phenolic compounds and tannins, respectively 980.61 ± 0.60 and 764.80 ± 0.54 µg GAE/mg dE, were obtained with the ethanolic extract of bark of Sclerocarya birrea (eth-Dn-e). The highest content of flavonoids (456.95 ± 0.89 µg QE/mg dE) was obtained with the ethanolic extract of Ceratotheca sesamoides (eth-Y). The ethanolic extract of Ficus platyphylla bark (eth-G) effectively reduced DPPH, with an IC50 of 1.46 ± 0.06 µg/mL. The highest ferric ion-reducing power was obtained with Sclerocarya birrea bark decoction (Da-Dn-e), (78.95 ± 5.74 mmol AAE/g). Ethanolic macerate of Acacia senegal bark (eth-D) showed the lowest IC50 against 15-LOX at 32.18 µg/mL. The aqueous macerate of Ceratotheca sesamoides (Ma-Y) gave the highest percentage inhibition of LPO, at 62.07 ± 0.01 %. The highest uterine contraction at 10 mg/mL was 1.38 [A(cm)/uterus(cm)], obtained with ethanolic maceration of the whole plant of Ceratotheca sesamoides Endl. (eth-Y). The traditional use of plants during childbirth could be linked to the antioxidant and/or uterotonic effects of phytoconstituents. These constitutes a scientific basis that could justify the use of these plants in the management of childbirth.

Antihyperglycemic potential of fermented Digitaria exilis polysaccharide partially substituted with Clendendrum volubile leaf extract

Digitaria exilis and Clendendrum volubile are underutilized food resources common in Africa. Clendendrum volubile leaf has a history of being used in traditional medicine to treat or manage hyperglycemia. Despite Clendendrum volubile nutritive and pharmaceutical significance, no scientific study has explored its application in functional food development. In this study, the inhibitory activities of Clendendrum volubile leaf extract (CVLE) against α-amylase and α-glucosidase was determined. Fermented Digitaria exilis polysaccharide (FDEP) was partially substituted with CVLE at different percentages (0.8 % and 1.2 %) and its antihyperglycemic effect was investigated in alloxan-induced diabetic rat models. Results showed that the IC50 (CVLE extract concentration causing 50 % enzyme inhibition) for α-amylase and α-glucosidase were 330 μg/mL and 120 μg/mL, respectively, compared to acarbose, a standard inhibitor of starch-digesting enzymes, which had IC50 values of 370 μg/mL and 170 μg/mL for α-amylase and α-glucosidase, respectively. The animal study showed that FDEP containing 0.8 % CVLE lowered the blood glucose level of diabetic rats by 45.31 % after 24 days. Increasing CVLE concentration in the FDEP to 1.2 % not only reduced blood glucose by 72.97 % after 24 days, comparable to metformin's 74.29 % reduction, but also alleviated body weight loss and improved liver function by lowering alanine transaminase, aspartate transaminase, and alkaline phosphatase.

Polygenic and transcriptional risk scores identify chronic obstructive pulmonary disease subtypes in the COPDGene and ECLIPSE cohort studies

Genetic variants and gene expression predict risk of chronic obstructive pulmonary disease (COPD), but their effect on COPD heterogeneity is unclear. We aimed to define high-risk COPD subtypes using genetics (polygenic risk score, PRS) and blood gene expression (transcriptional risk score, TRS) and assess differences in clinical and molecular characteristics. We defined high-risk groups based on PRS and TRS quantiles by maximising differences in protein biomarkers in a COPDGene training set and identified these groups in COPDGene and ECLIPSE test sets. We tested multivariable associations of subgroups with clinical outcomes and compared protein-protein interaction networks and drug repurposing analyses between high-risk groups. We examined two high-risk omics-defined groups in non-overlapping test sets (n=1133 NHW COPDGene, n=299 African American (AA) COPDGene, n=468 ECLIPSE). We defined "high activity" (low PRS, high TRS) and "severe risk" (high PRS, high TRS) subgroups. Participants in both subgroups had lower body-mass index (BMI), lower lung function, and alterations in metabolic, growth, and immune signalling processes compared to a low-risk (low PRS, low TRS) subgroup. "High activity" but not "severe risk" participants had greater prospective FEV1 decline (COPDGene:-51mL/year; ECLIPSE:-40mL/year) and proteomic profiles were enriched in gene sets perturbed by treatment with 5-lipoxygenase inhibitors and angiotensin-converting enzyme (ACE) inhibitors. Concomitant use of polygenic and transcriptional risk scores identified clinical and molecular heterogeneity amongst high-risk individuals. Proteomic and drug repurposing analysis identified subtype-specific enrichment for therapies and suggest prior drug repurposing failures may be explained by patient selection. National Institutes of Health.

Enrichment of polyphenols from Cinnamomum camphora seed kernel by macroporous adsorption resins and evaluation of its antioxidant and enzyme inhibitory activities

The Cinnamomum camphora seed kernel (CCSK) has potential as a natural source of bioactive phenolics. However, there is limited information on the recovery and characteristics of polyphenols from the by-product of CCSK after oil extraction. In this study, an efficient macroporous adsorption resin technology was established to enrich polyphenols from CCSK (CCSK-P). HJ-18 resin was found as the most appropriate adsorbent because of its highest adsorption/desorption capacity for CCSK-P. The pseudo-second-order kinetic and Freundlich isotherm models better described the whole adsorption process. The adsorption process was spontaneous, physical, and dominated by multilinear intraparticle diffusion. The optimum enrichment procedure of CCSK-P on HJ-18 resin was as follows: for adsorption, loading flow rate and sample volume were 1.5 BV/h, and 4.79 BV, respectively; for desorption, the eluent type, elution flow rate and volume were 80% ethanol, 3.0 BV/h and 8 BV, respectively. After one-step large-scale enrichment, the total polyphenol content of CCSK-P was increased 7.11-fold with a recovery of 81.07%. Moreover, enriched CCSK-P showed significantly higher scavenging ability against DPPH radical and ABTS radical and higher inhibitory activity against α-amylase and α-glucosidase. In conclusion, CCSK-P was well enriched by HJ-18 resin and exhibited good antioxidant and enzyme inhibition activity, which may be applied in the food, cosmetic and pharmacy industries. This study provides a meaningful guidance for the industrial enrichment of polyphenols from CCSK.

Antibacterial Potential of Tetrahydrocarbazoles (THCZ): A Review

: Antibiotic resistance has become a major public threat across the globe associated with human health. Some bacterial and fungal infections produce resistance, such as methicillinresistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus faecium (VRE) and multidrug-resistant (MDR) species Acinetobacter baumannii etc. Tetrahydrocarbazoles (THCz) are a sub-class of indole alkaloids profoundly present in natural products and biologically active compounds and have displayed potential biological activities in literature. THCz exhibit potential antibacterial activities through major bacterial pathways like cell wall synthesis inhibition and DNA gyrase enzyme inhibition with DNA sliding clamp inhibitors and MreB inhibitors. These THCZ also showed significant in vitro antibacterial activities against bacterial-resistant species, such as MRSA, VRE and Acinetobacter baumannii (MDR) in literature. MTDL (Multi Target Direct ligand) approach has been significantly used for the design of THC motif-based antibacterial agents. In this review article, we collected literature on THCz as a potential antibacterial agent from 2014 to date. The review study of THC core-based derivatives found excellent in vitro antibacterial profiles and revealed that they can play a significant role in drug discovery and the development of new antibiotics against various infectious diseases.

Cholesterol promotes IFNG mRNA expression in CD4+ effector/memory cells by SGK1 activation.

IFNγ-secreting T cells are central for the maintenance of immune surveillance within the central nervous system (CNS). It was previously reported in healthy donors that the T-cell environment in the CNS induces distinct signatures related to cytotoxic capacity, CNS trafficking, tissue adaptation, and lipid homeostasis. These findings suggested that the CNS milieu consisting predominantly of lipids mediated the metabolic conditions leading to IFNγ-secreting brain CD4 T cells. Here, we demonstrate that the supplementation of CD4+CD45RO+CXCR3+ cells with cholesterol modulates their function and increases IFNG expression. The heightened IFNG expression was mediated by the activation of the serum/glucocorticoid-regulated kinase (SGK1). Inhibition of SGK1 by a specific enzymatic inhibitor significantly reduces the expression of IFNG Our results confirm the crucial role of lipids in maintaining T-cell homeostasis and demonstrate a putative role of environmental factors to induce effector responses in CD4+ effector/memory cells. These findings offer potential avenues for further research targeting lipid pathways to modulate inflammatory conditions.

Kill two birds with one stone: Hapatologist’s approach to metabolic dysfunction-associated steatotic liver disease and heart failure

Heart failure (HF) is a major global public health concern, and one of the less commonly known risk factors for HF development is metabolic dysfunction-associated steatotic liver disease (MASLD), as they share a similar pathophysiological background. In this article, we evaluated a recently published review article by Arriola-Montenegro et al . This article briefly summarizes the common pathophysiology of HF and MASLD development and evaluates the available therapeutic options to treat both conditions. Clinical practice guidelines highlight the importance of initiating and titrating guideline-directed medication therapy (GDMT) for patients with HF with reduced ejection fraction. GDMT is comprised of the four pillars currently proposed in most clinical practice guidelines, namely angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), angiotensin receptor-neprilysin inhibitors, beta-blockers, mineralocorticoid receptor antagonists, and sodium-glucose co-transporter 2 inhibitors (SGLT-2i). Given the similarity of pathophysiology and risk factors, recent studies for GDMT regarding ACEIs, ARBs, mineralocorticoid receptor antagonists, and SGLT-2i have shown beneficial effects on MASLD. Nonetheless, other medications for both conditions and novel therapies require more robust data and well-designed clinical studies to demonstrate their efficacies in both conditions.

Oxidative Stress Mechanism by Gold Compounds: A Close Look at Total ROS Increase and the Inhibition of Antioxidant Enzymes.

The antitumor activity of various gold compounds is a promising field of investigation, attracting researchers seeking potential clinical candidates. To advance this research, they explore the complex mechanisms of action of these compounds. Since the discovery of the strong inhibition of thioredoxin reductase by auranofin, the primary mechanism explored has been the inhibition of this enzyme. This inhibition disrupts the redox balance in cells, promoting oxidative stress and triggering cell death. In this review, we analyzed studies from the past decade that measured cellular ROS increase and examined the coordination structures of gold compounds. We also correlate ROS increase with the inhibition of redox-regulating enzymes, thioredoxin reductase, and glutathione reductase, to elucidate the relationship between these cellular effects and chemical structures. Our data compilation reveals that different structures exhibit varying efficacy: some significantly increase ROS production and inhibit thioredoxin reductase or glutathione reductase, while others elevate ROS levels without affecting these target enzymes, suggesting alternative mechanisms of action. This review consolidates critical evidence, enhancing our understanding of the mechanisms by which these gold complexes act and providing valuable insights for developing new therapeutic strategies against tumor cells.

Depression, stress, and tryptophan metabolism through the kynurenine pathway: treatment strategies from the perspective of Chinese herbal medicine.

The pathogenesis of depression is complex, involving abnormalities in tryptophan (TRP) metabolism through the kynurenine pathway (KP). Moreover, depression is closely related to the hypothalamic-pituitary-adrenal (HPA) axis, the gut-brain axis, neuroinflammation, and stress. These factors collectively influence the multidimensional pathological mechanisms of depression. TRP, a fundamental amino acid, serves as a precursor for neuroactive metabolites vital to physiological functions. Central to TRP metabolism is the KP, and the imbalance between neurotoxic and neuroprotective metabolites is closely related to the onset and progression of depression. Therefore, maintaining the balance of KP metabolites is important. In this review, we have investigated the role of the KP in depression and explored the complexity of KP dysregulation and its therapeutic importance. Here, we highlight how a deeper understanding of the KP and its regulation can pave the way for new treatment strategies. Specifically, we have summarized the latest advances in elucidating the key mechanisms of rate-limiting enzyme inhibitors, providing insights into their potential therapeutic efficacy. In addition, we have explored the emerging field of Chinese herbal medicine, discussing its potential to regulate KP metabolites and alleviate depressive symptoms, thereby expanding the treatment options for depression. Our findings emphasize the multifaceted nature of depression and the necessity of interdisciplinary research to fully utilize KP regulation and Chinese herbal medicine as strategies to advance the treatment of depression.

UPLC-ESI/MSn metabolic profiling of Cedrela odorata L. and Toona ciliata M. Roem and in vitro investigation of their anti-diabetic activity supported with molecular docking studies

IntroductionThe genus Cedrela is one of the phytochemically rich genera of the family Meliaceae. In this study, two Cedrela species, namely, Cedrela odorata and Toona ciliata M. Roem (formerly Cedrela toona), were selected for in-depth phytochemical profiling with the aid of UPLC-ESI/MSn analysis followed by evaluation of their anti-diabetic potential through assessment of in vitro α-amylase and α-glucosidase inhibitory effects, alongside the molecular docking studies on these target enzymes.Materials and methodsUPLC-ESI/MSn technique was applied to tentatively identify the extracts. The anti-diabetic properties were assessed using BioVision α-amylase and α-glucosidase inhibitor screening kits. Further, the molecular docking studies utilized PyRx® and Discovery Studio software.Results and discussionThe UPLC-ESI/MSn analysis led to the identification and quantification of 55 metabolites with their fragmentation patterns for the first time for these two species. Flavonoids represented the main identified class, followed by phenylpropanoids, terpenes, tannins, and others. The two species showed potent enzyme inhibition, where C. odorata and C. toona significantly inhibited α-amylase (IC50 = 4.83 ± 0.01 and 3.50 ± 0.03 μg/mL) compared to pioglitazone (IC50 = 2.17 ± 0.23 μg/mL), while their α-glycosidase inhibitory properties were also potent with (IC50 = 7.17 ± 0.01 and 6.50 ± 0.69 μg/mL), respectively, compared to acarbose (IC50 = 4.83 ± 1.02 μg/mL). The enzyme inhibitory activities were further confirmed by in silico molecular docking of the main identified components with the respective binding sockets in both α-amylase and α-glycosidase enzymes.ConclusionThese promising results could pave the way for a novel discovery of natural phytoconstituents with potent anti-diabetic activity.

Aurora kinase as a putative target to tick control.

Aurora kinases (AURK) play a central role in controlling cell cycle in a wide range of organisms. They belong to the family of serine-threonine kinase proteins. Their role in the cell cycle includes, among others, the entry into mitosis, maturation of the centrosome and formation of the mitotic spindle. In mammals, 3 isoforms have been described: A, B and C, which are distinguished mainly by their function throughout the cell cycle. Two aurora kinase coding sequences have been identified in the transcriptome of the cattle tick Rhipicephalus microplus (Rm-AURKA and Rm-AURKB) containing the aurora kinase-specific domain. For both isoforms, the highest number of AURK coding transcripts is found in ovaries. Based on deduced amino acid sequences, it was possible to identify non-conserved threonine residues which are essential to AURK functions in vertebrates and which are not present in R. microplus sequences. A pan AURK inhibitor (CCT137690) caused cell viability decline in the BME26 tick embryonic cell line. In silico docking assay showed an interaction between Aurora kinase and CCT137690 with exclusive interaction sites in Rm-AURKA. The characterization of exclusive regions of the enzyme will enable new studies aimed at promoting species-specific enzymatic inhibition in ectoparasites.

Development of an Antiviral Medicinal Plant and Natural Product Database (avMpNp Database) from Biodiversity.

The construction of compound databases (DB) is a strategy for the rational search of bioactive compounds and drugs for new and old diseases. In order to bring greater impact to drug discovery, we propose the development of a DB of bioactive antiviral compounds. Several research groups have presented evidence of the antiviral activity of medicinal plants and compounds isolated from these plants. We believe that compiling these discoveries in a DB would benefit the scientific research community and increase the speed to discover new potential drugs and medicines. Thus, we present the Antiviral Medicinal Plant and Natural Product DB (avMpNp DB) as an important source for acquiring, organizing, and distributing knowledge related to natural products and antiviral drug discovery. The avMpNp DB contains a series of chemically diverse compounds with drug-like profiles. To test the potential of this DB, SARS-CoV-2 Mpro and PLpro enzymatic inhibition assays were performed for available compounds resulting in IC50 values ranging from 6.308±0.296 to 15.795±0.155 μM. As a perspective, artificial intelligence tools will be added to implement computational predictions, as well as other chemical functionalities that allow data validation.

Assessment of Pelargonium graveolens flower essential oil: Antimicrobial, antioxidant, enzyme inhibition and in vivo topical analgesic and anti-inflammatory efficacy as treatment for atopic dermatitis

Background Atopic dermatitis (AD) is a chronic inflammatory skin condition characterized by pruritus and skin barrier dysfunction. This study aims to evaluate the therapeutic potential of Pelargonium graveolens (Geraniaceae) in managing AD symptoms through its essential oil. Methods The chemical composition of Pelargonium graveolens flower essential oil (PFEO) was analyzed using gas chromatography-mass spectrometry (GC-MS). Its antimicrobial, antioxidant, and anti-inflammatory properties were assessed, along with the inhibitory effects of PFEO on key enzymes involved in skin repair: tyrosinase, elastase, and collagenase. An in vivo evaluation of a gel formulation containing PFEO was also conducted to assess its anti-inflammatory and analgesic efficacy. Results GC-MS analysis identified major compounds in PFEO, including Geraniol (22.83%), beta-citronellol (19.51%), naphthalenemethanol (15.36%), and Geranyl tiglate (9.38%), with minor constituents such as linalool (3.81%) and neryl formate (1.31%). PFEO exhibited bacteriostatic activity against various bacterial and fungal strains, including Pseudomonas aeruginosa, Staphylococcus aureus, Methicillin-Resistant Staphylococcus aureus (MRSA), Bacillus anthracis, Streptococcus pyogenes, Staphylococcus epidermidis, Candida albicans, and Malassezia spp. The essential oil also demonstrated significant antioxidant properties and inhibited key enzymes linked to skin alterations in AD. Conclusions PFEO shows promising therapeutic potential for managing symptoms of atopic dermatitis due to its antimicrobial, antioxidant, and anti-inflammatory properties, as well as its analgesic effects. The findings support further exploration of PFEO as a natural alternative in the treatment of AD.

Abstract B025: Redox reprogramming by SOD1 knockdown: A novel liposomal siRNA strategy to overcome platinum resistance in ovarian cancer

Abstract Platinum resistance remains a significant obstacle in the treatment of advanced-stage ovarian cancer, frequently leading to therapeutic failure. Our previous research identified Superoxide Dismutase 1 (SOD1) as a key antioxidant target for re-sensitizing platinum-resistant ovarian cancer cells to platinum-based therapies through both enzymatic inhibition and RNA interference (RNAi) utilizing a graphene-based siRNA delivery platform. Building on these findings, we have now developed a liposomal formulation of chemically modified siRNA targeting SOD1, which demonstrates potent knockdown efficiency and significantly enhances the sensitivity of resistant ovarian cancer cells to cisplatin in vivo. While SOD1 inhibition or knockdown via RNAi effectively re-sensitizes resistant cells to cisplatin, the underlying redox-sensitive signaling pathways remain largely unexplored in ovarian cancer. Our current study reveals that SOD1 knockdown acts as a redox switch, triggering cellular reprogramming in drug-resistant cells through post-translational cysteine modifications. This reprogramming leads to the rewiring of critical cancer hallmarks, culminating in the restoration of a cisplatin-sensitive phenotype. These findings suggest that a liposomal, chemically modified SOD1 siRNA formulation could serve as a promising therapeutic approach for reversing platinum resistance in ovarian cancer by exploiting redox-mediated reprogramming of cancer hallmarks. This study not only underscores the therapeutic potential of targeting SOD1 but also highlights the broader implications of redox signaling in the etiology of platinum resistance, providing a novel avenue for therapeutic intervention. Citation Format: Attila Szenasi, Sonia Rocha, Mu Wang. Redox reprogramming by SOD1 knockdown: A novel liposomal siRNA strategy to overcome platinum resistance in ovarian cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: RNAs as Drivers, Targets, and Therapeutics in Cancer; 2024 Nov 14-17; Bellevue, Washington. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(11_Suppl):Abstract nr B025.

Screening Inhibitors of α-Amylase in Polygala Radix Based on an Online Targeted Detection System and Molecular Docking.

Targeted screening of inhibitors of key enzymes in the progression of diabetes from natural products is one of the effective methods for the treatment of diabetes. Polygala has been proved to reduce glucose levels; however, the bioactive compounds in Polygalae Radix (PR) that have anti-diabetic properties are unknown. The purpose of this study was to explore the material basis of the anti-diabetic effect of PR by inhibiting α-amylase through an online detection system and molecular docking. An online analysis platform was established and optimized for the screening of potent enzyme inhibitors from complex mixtures based on ultra-performance liquid chromatography-photodiode array-quadrupole-time-of-flight-mass spectrometry-α-amylase-fluorescence detector (UHPLC-PDA-Q-TOF-MSn-α-amylase-FLD) detection system and molecular docking, which could efficiently separate extracts, quickly detect α-amylase inhibitors, and determine their structures. Molecular docking confirms the inhibition of these compounds. The molecular interaction between α-amylase and the active compound was evaluated. Among the 101 compounds identified, 28 compounds had a strong inhibitory effect on α-amylase. Molecular docking screening confirmed the inhibition of these compounds and evaluated the molecular interactions between α-amylase and 30 active compounds, which strongly supported the experimental results. Among the evaluated compounds, onjisaponin R (83) and polygalaxanthone III (11) have the strongest inhibitory activity to α-amylase (the binding energies were -9.639 and -8.972 kcal/mol, respectively) and are potential lead compounds against diabetes. This study proved the feasibility of using the existing platform to screen the active ingredients in PR extract, and provided a practical method for the rapid screening of potential anti-diabetic active ingredients in traditional Chinese medicine.

Development and Biological Evaluation of New Diphenyl Ether Formylhydrazide Compounds as Potent Inhibitors of Succinate Dehydrogenase.

Succinate dehydrogenase (SDH), also recognized as succinate ubiquinone oxidoreductase (SQR), is considered one of the most promising targets for fungicide development, garnering significant international interest. We have focused on the development of highly effective, broad-spectrum-targeted SDH inhibitors. Using an active scaffold combining strategy, we designed and synthesized a series of novel diphenyl ether formylhydrazine derivatives, and most compounds have demonstrated broad-spectrum antifungal activity. Notably, compound M8 exhibited antifungal activity of more than 93% against four tested pathogen types at a concentration of 10 μg/mL, with an EC50 value below 0.3 μg/mL for each pathogen, outperforming boscalid. Additionally, compound M8 exhibited a control efficacy of 83% against Sclerotinia sclerotiorum on rapeseed leaves at a concentration of 200 μg/mL and demonstrated an 87% efficacy in controlling Fusarium graminearum on wheat ears when applied at 400 μg/mL. Structure-activity relationship research suggested that para-substituted benzene rings are more effective, offering stronger and more extensive antifungal potency. Further investigation, including enzyme inhibition assays, mycelial morphology observations, and molecular docking studies, suggests that the antifungal potency of M8 is due to the inhibition of its SDH activity. Therefore, our research positions compound M8 as a highly promising lead compound with broad-spectrum antifungal properties, potentially introducing a new class of fungicide.

Benzocarbazoledinones as SARS-CoV-2 Replication Inhibitors: Synthesis, Cell-Based Studies, Enzyme Inhibition, Molecular Modeling, and Pharmacokinetics Insights

Endemic and pandemic viruses represent significant public health challenges, leading to substantial morbidity and mortality over time. The COVID-19 pandemic has underscored the urgent need for the development and discovery of new, potent antiviral agents. In this study, we present the synthesis and anti-SARS-CoV-2 activity of a series of benzocarbazoledinones, assessed using cell-based screening assays. Our results indicate that four compounds (4a, 4b, 4d, and 4i) exhibit EC50 values below 4 μM without cytotoxic effects in Calu-3 cells. Mechanistic investigations focused on the inhibition of the SARS-CoV-2 main protease (Mpro) and papain-like protease (PLpro) have used enzymatic assays. Notably, compounds 4a and 4b showed Mpro inhibition activity with IC50 values of 0.11 ± 0.05 and 0.37 ± 0.05 µM, respectively. Furthermore, in silico molecular docking, physicochemical, and pharmacokinetic studies were conducted to validate the mechanism and assess bioavailability. Compound 4a was selected for preliminary drug-likeness analysis and in vivo pharmacokinetics investigations, which yielded promising results and corroborated the in vitro and in silico findings, reinforcing its potential as an anti-SARS-CoV-2 lead compound.

Influence of pharmacotherapy on function of biotransformation of xenobiotics liver in patients with neuropsychiatric disorders

BACKGROUND: The mechanisms of drug interactions of psychotropic drugs are associated with the processes of drug biotransformation by enzymes of microsomal oxidation of cytochrome P-450 in the liver. Various drugs can increase or decrease the activity of enzymes of the cytochrome P450-dependent system. AIM: To evaluate the effect of pharmacotherapy with psychotropic drugs: alprazolam, bromazepam, lithium carbonate on the metabolic rate of the model substrate antipyrine in saliva in patients with neuropsychiatric disorders; the effect of the enzyme-inducing activity of the original anticonvulsant 1-[(3-chlorophenyl)(phenyl)methyl]urea on the pharmacokinetic parameters of antipyrine in healthy volunteers. MATERIALS AND METHODS: 34 male patients were divided into three groups according to the nosological forms of diseases according to ICD-10: Group 1 — heading F43.23 and F43.25; 2 — F06.61; 3 — F41.2. Patients in the group 1 were prescribed alprazolam, in the 2 — bromazepam, in the 3 — lithium carbonate, for a course of 21 days. The comparison group consisted of 10 healthy volunteers. The original anticonvulsant was prescribed to the volunteers. Determination of the pharmacokinetics of antipyrine parameters as a test witness of the processes of elimination from the body was carried out in saliva before and after the end of therapy at a dose of 10 mg/kg once. RESULTS: Alprazolam administration by patients of group 1 at a dose of 0.5–1.5 mg/day for 21 days did not significantly affect the pharmacokinetic parameters of antipyrine: T1/2, Clt, AUC. Alprazolam did not change the elimination of antipyrine from the saliva of patients. In patients of the group2, who received bromazepam at a dose of 6–12 mg / day,a background decrease in T1/2, an increase in Clt, a decrease in AUC due to concomitant therapy were noted. Comparison of the pharmacokinetic parameters of antipyrine under the influence of bromazepam with background values not reveal significant differences. Therapy with lithium carbonate at a dose of 500–1000 mg/day in patients of the group 3 did not change the parameters of antipyrine elimination. The obtained data indicate that the drugs do not affect the activity of liver microsomal oxidation in patients. The study of the effect of 1-[(3-chlorophenyl)(phenyl)methyl]urea on the pharmacokinetic parameters of antipyrine in volunteers revealed a diametrically opposite result: a significant decrease in T1/2 by 2 times, an increase in Clt and a decrease in AUC, which indicates accelerated elimination of antipyrine from the saliva of the subjects and indicates the induction of liver microsomal oxidation. CONCLUSIONS: Pharmacotherapy using the studied psychotropic drugs in patients is not associated with the induction or inhibition of liver enzymes, which indicates the absence of drug pharmacokinetic interference. The original anticonvulsant 1-[(3-chlorophenyl)(phenyl)methyl]urea stimulated the induction of liver microsomal oxidation in volunteers.

Exploring Moroccan Medicinal Plants for Anticancer Therapy Development Through In Silico Studies

Background: Angiogenesis is a crucial process in the growth and proliferation of cancer, enabling tumor growth through the formation of new vasculature and the supply of nutrients and oxygen to growing malignant cells. This disease-promoting process can be targeted through the inhibition of tyrosine kinase enzymes. Objectives: The objective of this study is to evaluate the anticancer potential of various Moroccan plants from different regions. While these plants have a rich history of traditional medicinal use, they have not been extensively investigated as anticancer therapies. Methods: This study employed a multifaceted approach to evaluate the anticancer potential of various Moroccan plants. Receptor–ligand docking and virtual screening were used to assess the binding affinity of phytocompounds to the EGFR and VEGFR2 receptors. Additionally, predictive pharmacokinetic analyses were conducted to evaluate the ADMET properties of the selected compounds, followed by molecular dynamics simulations to analyze the stability of the receptor–ligand complexes. Results: In our research, we identified three notable active compounds—catechin, 4-O-glucoside ferulic acid, and 3-glucoside resveratrol—in the Moroccan plant Ajuga iva L. These findings suggest that Ajuga iva L. may possess significant potential for cancer inhibition. Conclusions: This research highlights the potential of the Moroccan plant Ajuga iva L. as a source of active compounds with significant anticancer properties. Further investigation is essential to validate these findings and explore new therapeutic avenues based on these traditional resources.