Significant Inhibitory Activity Research Articles

Design, synthesis, and histone deacetylase inhibition study of novel 4-(2-aminoethyl) phenol derivatives.

Histone deacetylases (HDACs) have been identified as promising targets for anticancer treatment. The study demonstrates virtual screening, molecular docking, and synthesis of 4-(2-aminoethyl) phenol derivatives as HDAC inhibitors. The virtual screening and molecular docking analysis led to the identification of 10 representative compounds, which were evaluated based on their drug-like properties. The results demonstrated that these compounds effectively interacted with the active site pocket of HDAC 3 through π-stacking, Zn2+ coordination, hydrogen bonding, and hydrophobic interactions with catalytic residues. Furthermore, a series of 4-(2-aminoethyl) phenol derivatives were synthesized, and their HDAC inhibitory activity was evaluated. Compounds 18 and 20 showed significant HDAC inhibitory activity of 64.94 ± 1.17% and 52.45 ± 1.45%, respectively, compared to the solvent control. The promising results of this study encourage further research on 4-(2-aminoethyl) phenol derivatives and may provide significant insight into the design of novel small molecule HDAC inhibitors to fight against target-specific malignancies of chronic obstructive pulmonary disease and nonsmall cell lung cancer in the future.

Bioinspired total synthesis and biological activity of Pegaharine A.

Phytopathogens cause various diseases by parasitizing crops, reducing crop yield and resulting in substantial economic losses in agricultural production. A novel type isolated from the perennial herbaceous Peganum harmala L. seeds, β-carboline alkaloids pegaharine A (PA), has become a hot topic in developing plant-originated green pesticides owing to their significant physiological activities. A scalable bioinspired total synthesis of PA is accomplished in the present work. The systematical biological assay study showed that PA exhibited moderate inhibitory activity against nine tested plant pathogenic fungi and showed significant inhibitory activity in vitro against the three tested plant pathogenic bacteria. Most noteworthy is the inhibitory rates of PA on Xanthomonas oryzae pv. oryzae (Xoo), X. oryzae pv. oryzicola (Xoc) and X. axonopodis pv. citri (Xac) of 93.6%, 92.1% and 86.1%, respectively, which are better than the control drug, bismerthiazol (63.4%, 61.2% and 53.7% at 100 μg mL-1 concentration). Furthermore, the EC50 value of PA against Xoo, Xoc and Xac was 52.2, 60.0 and 65.1 μg mL-1 , respectively, superior to 72.9, 64.2 and 70.1 μg mL-1 of the control drug. Moreover, the anti-Xoo mechanistic studies revealed that PA exerted its antibacterial effects by increasing the permeability of the bacterial membrane, reducing the extracellular polysaccharide content and inducing morphological changes in bacterial cells. A novel β-carboline alkaloid, PA, was prepared by biomimetic total synthesis. Its significant antibacterial activity was closely related to the permeation of bacterial cell membranes, which was confirmed by anti-Xoo mechanistic studies. More importantly, the structure could be regarded as a model for developing novel bactericides. © 2023 Society of Chemical Industry.

Salazinic Acid and Norlobaridone from the Lichen Hypotrachyna cirrhata: Antioxidant Activity, α-Glucosidase Inhibitory and Molecular Docking Studies

The present study was intended for the identification of secondary metabolites in acetone extract of the lichen Hypotrachyna cirrhata using UPLC-ESI-QToF-MS/MS and the detection of bioactive compounds. This study led to the identification of 22 metabolites based on their MS/MS spectra, accurate molecular masses, molecular formula from a comparison of the literature database (DNP), and fragmentation patterns. In addition, potent antioxidant and α-glucosidase inhibitory potentials of acetone extract of H. cirrhata motivated us to isolate 10 metabolites, which were characterized as salazinic acid (11), norlobaridone (12), atranorin (13), lecanoric acid (14), lichesterinic acid (15), protolichesterinic acid (16), methyl hematommate (17), iso-rhizonic acid (18), atranol (19), and methylatratate (20) based on their spectral data. All these isolates were assessed for their free radicals scavenging, radical-induced DNA damage, and intestinal α-glucosidase inhibitory activities. The results indicated that norlobaridone (12), lecanoric acid (14), methyl hematommate (17), and atranol (19) showed potent antioxidant activity, while depsidones (salazinic acid (11), norlobaridone (12)) and a monophenolic compound (iso-rhizonic acid, (18)) displayed significant intestinal α-glucosidase inhibitory activities (p < 0.001), which is comparable to standard acarbose. These results were further correlated with molecular docking studies, which indicated that the alkyl chain of norlobaridione (12) is hooked into the finger-like cavity of the allosteric pocket; moreover, it also established Van der Waals interactions with hydrophobic residues of the allosteric pocket. Thus, the potency of norlobaridone to inhibit α-glucosidase enzyme might be associated with its allosteric binding. Also, MM-GBSA (Molecular Mechanics-Generalized Born Surface Area) binding free energies of salazinic acid (11) and norlobaridone (12) were superior to acarbose and may have contributed to their high activity compared to acarbose.

Antibacterial Activity of Paracetamol, Trimethoprim/sulfamethoxazole, Azithromycin, and Ciprofloxacin

Paracetamol have indirect antibiotic activity and are commonly coadministered with antimicrobial therapy. This study aimed to assess the synergistic effect of Paracetamol to with Azithromycin, Trimethoprim/sulfamethoxazole and Ciprofloxacin against salmonella and Escherichia coli. In this study, Ciprofloxacin, Trimethoprim/sulfamethoxazole and Azithromycin was mixed paracetamol against salmonella and Escherichia coli. The results showed that the interaction between Paracetamol and Azithromycin, Trimethoprim/sulfamethoxazole and ciprofloxacin exhibited more in inhibitory potency against on Gram-negative salmonella and Escherichia coli. The combinations of Paracetamol with the Azithromycin and Trimethoprim/sulfamethoxazole showed significant inhibitory activity on the salmonella and Escherichia coli comparing to the inhibition activity showed from the tested antibiotics alone.

Polymethoxyflavone from Citrus depressa as an inhibitor against various variants of SARS-CoV-2 spike protein

Ethnopharmacological relevanceIn traditional Taiwanese medicine, Citrus depressa Hayata serves as the raw material of Chen-Pi which has been widely used to treat respiratory ailments. Scientific investigations have validated the attributes of C. depressa, elucidating its valuable properties, including antioxidative, anti-inflammatory, anticancer, neuroprotion, hepatoprotection, and hypolipidemic effects. Aim of the studyThis study aims to isolate a universal inhibitor of the SARS-CoV-2 spike protein from C. depressa and confirm the mechanism by which these inhibitors disrupt the binding of the spike protein to hACE2. Materials and methodsThe whole fruit of C. depressa was subjected to ethanol extraction, following by partitioning to obtain water, butanol, and ethyl acetate fractions. To identify the inhibitory components in citrus fruits, we performed both the SPR assay and the SARS-CoV-2 pseudo-virus assays. Subsequently, we employed a bioassay-guided approach to efficiently isolate and characterize the bioactive constituents that hindered the interaction between the SARS-CoV-2 spike protein and hACE2, using a combination of MPLC and Semi-preparative HPLC for compound isolation. ELISA based spike protein binding assay evaluate the inhibitory activities of the extract and potential constituents against multiple spike protein variants. To further shed light on the inhibitory mechanism, candidate inhibitors were validated through the SPR assay and molecular docking. ResultsThe crude extract and ethyl acetate layer derived from C. depressa showed significant inhibitory activity on SARS-CoV-2 Omicron BA.4/5, with IC50 of 77.4 μg/mL and 100 μg/mL, respectively. Ten potential compounds from C. depressa have been identified with inhibitory activity against various SARS-CoV-2 spike proteins. 2′-hydroxy-4,4′,5′,6′-tetramethoxychalcone (Cd3) and 5-hydroxy-3′,4′,6,7,8-pentamethoxyflavone (Cd8) also showed good inhibitory activity to the spike protein, with KD of 0.79 μM and 37.3 nM, respectively. These findings are in line with prior study, indicating Cd3 and Cd8 can bind to key amino acid residue, disrupting the formation of the spike protein and h-ACE2 complex. ConclusionThis study presents the initial evidence showcasing the inhibitory effect of polymethoxyflavones (PMFs) on the spike protein of SARS-CoV-2. Moreover, the inhibitory activity of C. depressa extracts indicates their potential to prevent infections of different SARS-CoV-2 variants.

Synthesis, biological evaluation, and computational studies of N-benzyl pyridinium–curcumin derivatives as potent AChE inhibitors with antioxidant activity

A library of N-benzylpyridinium-based compounds, 7a-j and 8a-j, was designed and synthesised as potential acetylcholinesterase) AChE (inhibitors. An in vitro assay for the synthesised compounds showed that most compounds had significant AChE inhibitory activities at the nanomolar and submicromolar levels. The benzyl (8a) and fluoro (8b) derivatives were the most active, with IC50 values ≤56 nM. Compound 7f, which had a benzyl moiety, showed the highest potency among all the target compounds, with an IC50 value of 7.5 ± 0.19 nM against AChE, which was higher than that of the activities of tacrine (IC50 = 30 ± 0.2 nM) and donepezil (IC50 = 14 ± 0.12 nM). Compounds with vanillin moieties exhibited antioxidant activity. Among the tested compounds, four derivatives (7f, 7 g, 8f, and 8 g) exhibited superior AChE inhibitory activity, with K i values of 6–16 nM, which were potent in the same range as the approved drug, donepezil. These compounds showed moderate antioxidant activities, as indicated by the results of the ABTS assay.

Highly oxygenated guaiane-type sesquiterpene lactones from Artemisia sacrorum and their antihepatoma activity

The ethanol and EtOAc extracts of Artemisia sacrorum exhibited inhibitory effect against HepG2, Huh7, and SK-Hep-1 cell lines with inhibitory ratios of 65.5%, 28.1%, 84.6%, and 93.5%, 82.0%, 89.0% at 200 μg/mL. Twenty-three undescribed guaiane-type sesquiterpene lactones, artemisacrolides A‒W, were isolated from A. sacrorum under the guidance of antihepatoma activity. Their structures were elucidated by spectral data (HRESIMS, IR, UV, 1D and 2D NMR), ECD calculations, and a single-crystal X-ray diffraction. Artemisacrolides A‒U were guaiane-type sesquiterpene lactones possessing α-methylene-γ-lactone and containing acetoxyl groups at C-8, and artemisacrolides V and W represented the first report from the genus Artemisia with a 1,10-rearranged guaiane-type sesquiterpene lactone. Antihepatoma assay suggested that artemisacrolides A‒U demonstrated better inhibitory activity in Huh7 and SK-Hep-1 cells than those of HepG2 cells. Among them, nine compounds exhibited significant inhibitory activity against Huh7 cells with IC50 values of 8.2–14.3 μM, superior or equal to that of sorafenib; seven compounds demonstrated obvious activity against SK-Hep-1 cells with IC50 values of 13.5–19.2 μM, which were equivalent to that of sorafenib. Artemisacrolides B and E were the most active ones in three human hepatoma cell lines with IC50 values of 21.9, 8.2, 16.9 and 22.6, 9.0, 17.3 μM.

Novel ligustilide derivatives target quorum sensing system LasR/LasB and relieve inflammatory response against Pseudomonas aeruginosa infection

The increasing antibiotic resistance driven by Pseudomonas aeruginosa typically leads to uncontrolled and persistent inflammatory damage, which is primarily attributed to the virulence and biofilms produced by the bacteria. Herein, we present a novel anti-infective drug strategy designed to inhibit the bacterial quorum sensing system, thereby attenuating P. aeruginosa virulence, and modulating inflammation from drug-resistant bacterial infections. We discovered new quorum sensing LasR/LasB inhibitors derived from the structural modification of a ligustilide derivative library. Of these compounds, 5f demonstrated significant inhibitory activity against LasB (LasB-gfp, IC50 = 8.7 μM) and a moderate inhibitory effect on P. aeruginosa biofilms (IC50 = 7.4 μM). Through live image analysis in a fluorescent protein–labeled zebrafish larva model, we observed that compound 5f significantly inhibited the migration of macrophages. Moreover, compound 5f effectively attenuated quorum sensing–mediated virulence factors and biofilm formation by P. aeruginosa. It also alleviated the inflammatory response by P. aeruginosa–infected macrophages through the downregulation of mitogen-activated protein kinase and NF-κB signal-transduction pathways. Notably, in vivo experiments, this compound demonstrated marked therapeutic effects in acute lung injury models induced by lipopolysaccharides from P. aeruginosa. These results indicate that compound 5f has the potential to be a novel anti-infective candidate against drug-resistant infections caused by P. aeruginosa.

Discovery of Novel 8-Hydroxyquinoline Derivatives with Potent In Vitro and In Vivo Antifungal Activity.

Fungal pathogens can cause life-threatening infections, yet current antifungals are inadequate at treating many of these, highlighting the importance of novel drug discovery. Here, we report hit compound L14, a novel 8-hydroxyquinoline derivative with potent and broad-spectrum antifungal activity. In vitro experiments exhibited that L14 had better activity and lower cytotoxicity than that of clioquinol and showed synergy in combination with fluconazole (FLC). In a Candida albicans-infected murine model, L14 at 2 mg/kg showed better in vivo efficacy than clioquinol at reducing fungal burden and extending the survival of C. albicans-infected mice. In addition, L14 alone or in combination with FLC had significant inhibitory activity against hypha and biofilm formation. Overall, our data indicated that 8-hydroxyquinoline derivative L14 has favorable pharmacokinetics and acceptable safety profiles and could be further investigated as a promising antifungal hit compound.

Aldose Reductase and Protein Glycation Inhibitory Activity of Dark Chocolate-Assisted Zinc Oxide Nanoparticles.

Introduction One of the most common health issues that the global population is dealing with is the associated complications of diabetes, which encompasses cataracts, peripheral neuropathy, vascular damage, impaired wound healing, retinal issues, and arterial wall stiffening. The present study is aimed to evaluate the effect of dark chocolate and its assisted zinc oxide nanoparticles against diabetes-associated complications. Materials and methods Zinc oxide nanoparticles were synthesized using commercially dark chocolate (DC-ZnO NP). The synthesized DC-ZnO NPs were evaluated against recombinant aldose reductase (AR) activity and the formation of advanced glycation end products (AGEs). Aminoguanidine and gallic acid were used as reference standards for AGE assay and sorbitol accumulation inhibition, respectively. Results The results of the present study showed that green synthesized DC-ZnO NP had a significant dose-dependent inhibitory activity on both AR and AGEs. The inhibitory activity was compared to that of quercetin and aminoguanidine, respectively. Conclusion Targeting the endogenous antioxidant systems like AGEs and AR enzymes seems to provide a promising therapeutic approach, thus concluding that ZnO-NP could be a promising agent for treating diabetes-related complications such as diabetic retinopathy, diabetic nephropathy, and diabetic neuropathy that provide grounds for further clinical investigations and trials.

Phenolic Acid Derivatives from Ficus esquiroliana Levl. and Their Anti-Inflammatory Effects.

One new mesomer, ficusnaph A (1), two new phenolic acid derivatives, ficusnaphs B and C (2 and 3) together with three known biogenetically related polysubstituted naphthalene derivatives (4-6) were isolated from the stems of Ficus esquiroliana Levl. The structures of these compounds were elucidated using comprehensive spectroscopic methods. Compounds 1-6 were evaluated the inhibitory activities against the nitric oxide (NO) production induced by lipopolysaccharide (LPS) in mouse macrophage RAW264.7 cells in vitro. Compounds 1 and 2 showed significant inhibitory activity with the IC50 value of 3.12±0.14 and 7.66±0.18 μM, respectively.

New dammarane-type triterpenoids from hydrolyzate of total Gynostemma pentaphyllum saponins with protein tyrosine phosphatase 1B inhibitory activity

Protein tyrosine phosphatase 1B (PTP1B) is a key factor and regulator of glucose, lipid metabolism throughout the body, and a promising target for treatment of type 2 diabetes mellitus (T2DM). Gynostemma pentaphyllum is a famous oriental traditional medicinal herbal plant and functional food, which has shown many beneficial effects on glucose and lipid metabolism. The aim of the present study is to assess the inhibitory activity of five new and four known dammarane triterpenoids isolated from the hydrolysate product of total G. pentaphyllum saponins. The bioassay data showed that all the compounds exhibited significant inhibitory activity against PTP1B. The structure-activity relationship showed that the strength of PTP1B inhibitory activity was mainly related to the electron-donating group on its side chain. Molecular docking analysis suggested that its mechanism may be due to the formation of competitive hydrogen bonding between the electron-donating moiety and the Asp48 amino acid residues on the PTP1B protein.

Synthesis, in-silico studies, and biological evaluation of some novel 3-thiazolyl-indoles as CDK2–inhibitors

The essential enzyme cyclin-dependent kinase 2 (CDK2) is a promising target for anticancer drug development due to its pivotal role in regulating the cell cycle. This study aimed to synthesize novel 3-thiazolyl-indole derivatives and assess their ability to inhibit CDK2 using molecular docking analyses. A series of these compounds was synthesized through a multistep approach, and various techniques, including NMR, IR, and mass spectrometry, were used for structural characterization. Prolonged molecular dynamics (MD) simulations were conducted to explore pharmacokinetics, toxicity profiles, binding interactions, and structural dynamics. Additionally, nine newly synthesized compounds were evaluated for in vitro cytotoxicity against three human cancer cell lines (HepG2, MCF-7, and HCT-116) in comparison to cisplatin. The results revealed that compounds 5c, 5b, and 10b displayed favorable activities when compared to the reference drug. Furthermore, the inhibitory activity of the most potent compounds (5a-c) was tested in an in vitro enzyme assay against CDK2. The findings indicated that several 3-thiazolyl-indole derivatives exhibited significant inhibitory activity against CDK2, with compound 5c being the most potent (IC50 value of 0.35 ± 1.07 µM compared to roscovitine's 0.39 ± 0.47 µM). Molecular docking revealed the compounds' binding modes in the CDK2 site. This research highlights the potential of 3-thiazolyl-indoles in anticancer drug development.

A Perusal of Phenolics Within Polar Peel Fractions of Malus domestica var Maharaji via Hyphenated Techniques Cum Anti-microbial with REMA and Tyrosinase Inhibitory Potential thereof

This study aims to scrutinize the phenolic secondary metabolites in the polar peel decocture of Malus domestica var Maharaji via hyphenated techniques along with the study of the antibacterial, anti-candida, and tyrosinase inhibitory potential of bioactive compound-rich fractions. Preliminary phenolics go over was performed together with thin layer chromatography before the polar decocture was subjected to hyphenated techniques. FTIR investigation revealed the C-O bonds as in phenols, O-H bond stretch, and vibrations of alcohols and carboxylic acids as well as portrayed the C-H and >C=O stretches among other functional groups all of which are representative of phenolic and polyphenolic compounds. GC-MS perusal demonstrated the presence of bioactive compounds like Quercetin (13.04%), Ascorbic acid (6.48%), p-Coumaric acid (6.17%), Caffeic acid (5.69 %), Mallic acid (5.44%), Apigenin (5.28%), Citric acid (5.15%), Gallic acid (4.38%), Cyanidin (3.52%), and Ferulic acid (3.51%). Kirby-Bauer method followed by the resazurin microtiter assay technique (REMA) for MIC/MBC against six MTCC bacterial strains and one yeast, all producing stubborn opportunistic infection in humans, was used to assess the antibacterial property of all the bioactive rich fractions. Some fractions comparatively revealed a good activity index (AI) against tested microbes. MIC concentrations for bacteria ranged from 15-24 mg/ml while a lower MBC value recorded was 18 mg/ml. Methanol fraction revealed significant tyrosinase inhibitory activity by revealing IC50 of 980.98 µg/ml when L-Tyrosine was substrate and IC50 of 830.68 µg/ml when L-DOPA was substrate when juxtaposed to standard kojic acid that revealed IC50 of 128.822 µg/ml when L-Tyrosine was substrate and IC50 of 149.43 µg/ml when L-DOPA was substrate. The bioactive compounds possessed by the fractions, may be synergistically, turned out to be more effective in the diphenolase reaction and kojic acid acts more effectively in the monophenolase one. It was inferred that peel phenolics of this malus variety have a lot of therapeutic potential in the context of bacterial infections and pigmentation disorders.

Antagonistic potential of Bacillus amyloliquefaciens and B. velezensis as biocontrol agents against Lasiodiplodia theobromae

ABSTRACT Various fungi are known to cause important plant diseases leading to significant losses in agricultural products. To prevent crop diseases, biocontrol of these phytopathogenic fungi is necessary, most importantly by replacing the application of harmful pesticides from environmentally friendly management practices. The aim of this study was to isolate bacterial strains from soil and longan fruit with the capacity to inhibit Lasiodiplodia theobromae, a cosmopolitan fungal pathogen. Of 114, only four bacterial strains (3.51%) displayed significant inhibitory activity against L. theobromae by dual culture method. Strains CMU2 and RS5 were the most prominent isolates in controlling the tested pathogen and based on 16S rRNA gene sequence, they were identified as Bacillus velezensis and B. amyloliquefaciens, respectively. Cell-free supernatants (CFSs) of both antagonistic bacteria were prepared and found to be active against all tested L. theobromae strains. The optimum pH and temperature for antifungal activity of both CFSs were 7 and 30°C. In addition, conducted experiments on UV exposure and proteinase treatments did not affect the CFS’s antifungal activity. Characterisation of the chemical constituents using gas chromatography-mass spectrometry revealed the presence of various metabolites exhibiting antifungal activity. Furthermore, the in vivo bioassays also exhibited a significant impact on the banana rot lesion size, although it should be noted that the disease inhibition depends on the application procedure. In this study, the reduction of the disease development in bananas was most efficient when the antagonistic bacteria were applied before and/or at the same time with the fungal inoculation, emphasising the preventive measure. Our results demonstrated the effectiveness of B. amyloliquefaciens (CMU2) and B. velezensis (RS5) as the biological control agents. These findings would be useful in developing and implementing the management of L. theobromae pathogen.

Synthesis of Tetracyclic Spirooxindolepyrrolidine-Engrafted Hydantoin Scaffolds: Crystallographic Analysis, Molecular Docking Studies and Evaluation of Their Antimicrobial, Anti-Inflammatory and Analgesic Activities

In a sustained search for novel potential drug candidates with multispectrum therapeutic application, a series of novel spirooxindoles was designed and synthesized via regioselective three-component reaction between isatin derivatives, 2-phenylglycine and diverse arylidene-imidazolidine-2,4-diones (Hydantoins). The suggested stereochemistry was ascertained by an X-ray diffraction study and NMR spectroscopy. The resulting tetracyclic heterocycles were screened for their in vitro and in vivo anti-inflammatory and analgesic activity and for their in vitro antimicrobial potency. In vitro antibacterial screening revealed that several derivatives exhibited remarkable growth inhibition against different targeted microorganisms. All tested compounds showed excellent activity against the Micrococccus luteus strain (93.75 µg/mL ≤ MIC ≤ 375 µg/mL) as compared to the reference drug tetracycline (MIC = 500 µg/mL). Compound 4e bearing a p-chlorophenyl group on the pyrrolidine ring exhibited the greatest antifungal potential toward Candida albicans and Candida krusei (MIC values of 23.43 µg/mL and 46.87 µg/mL, respectively) as compared to Amphotericin B (MIC = 31.25 and 62.50 µg/mL, respectively). The target compounds were also tested in vitro against the lipoxygenase-5 (LOX-5) enzyme. Compounds 4i and 4l showed significant inhibitory activity with IC50 = 1.09 mg/mL and IC50 = 1.01 mg/mL, respectively, more potent than the parent drug, diclofenac sodium (IC50 = 1.19 mg/mL). In addition, in vivo evaluation of anti-inflammatory and analgesic activity of these spirooxindoles were assessed through carrageenan-induced paw edema and acetic acid-induced writhing assays, respectively, revealing promising results. In silico molecular docking and predictive ADMET studies for the more active spirocompounds were also carried out.

Inhibitory Effects of B-, C-, and E-Ring-Truncated Deguelin Derivatives Against A549, HCT116, and MCF-7 Cancer Cells.

Deguelin has been extensively studied for its anticancer properties; however, its clinical application has been hindered by concerns about in vivo toxicity. Structural modifications of deguelin including ring truncation have been explored to enhance its pharmacological properties. In this study, the design and straightforward synthesis of a series of B, C, and E (BCE)-ring-truncated deguelin analogues with deoxybenzoin backbone were described. The structure-activity relationships (SARs) were established by evaluation of their inhibitory activities against three cancer cell lines, A549 (adenocarcinomic human alveolar basal epithelial cells), HCT116 (human colorectal cancer cells), and MCF-7 (breast cancer cells). Six derivatives demonstrated significant and selective inhibitory activities. The ketone derivative 3a showed potency against A549 (IC50 = 6.62 μM) while the oxime analogue 6a and D-ring-benzylated ketone analogue 8d exhibited activity against HCT116 (IC50 = 3.43 and 6.96 μM, respectively). Moreover, the D-ring alkylated derivatives 8c and 8e-f were active against MCF-7 cells (IC50 < 10 μM). The potential suitability of the BCE-ring-truncated deguelin derivatives for drug development was further supported by the favorable in silico prediction of their physicochemical properties, druglikeness, and toxicity. This study could provide valuable insights for the further development of novel anticancer agents.

Inhibitory activities and rules of plant gallotannins with different numbers of galloyl moieties on sucrase, maltase and α-amylase in vitro and in vivo.

α-Glucosidase inhibitors could effectively reduce postprandial blood glucose (PBG) levels and control the occurrence of complications of diabetes. Gallotannins (GTs) in plants have attracted much attention due to their significant α-glucosidase inhibitory activities in vitro. However, there is still a lack of systematic comparative studies to further elucidate inhibitory activities in vivo and in vitro of these compounds against α-glucosidase, especially for mammalian sucrase and maltase, and analyze their structure-activity relationship. Determine the in vitro and in vivo inhibitory activities of five GTs with different number of galloyl moieties (GMs) on sucrase, maltase and α-amylase, and elucidate the relationship between α-glucosidase inhibitory activities and the number and connection mode of GMs. Molecular docking and dynamics were used to study the binding mode and binding ability of five GTs against sucrase, maltase and α-amylase. Then, the inhibitory activities and inhibitory mechanisms of these compounds on sucrase, maltase and α-amylase in vitro were studied using inhibitory assay and enzyme inhibition kinetics. Further, the hypoglycemic effects in vivo of these compounds were demonstrated by three polysaccharides tolerance experiments on diabetes model mice. The results of molecular docking showed that these compounds could bind to enzymes through hydrogen bonds, hydrophobic interactions, etc. In addition, the α-glucosidase inhibition comparative studies in vitro and in vivo demonstrated that the inhibitory activities of these compounds on all three sucrase, maltase and α-amylase were ranked as TA ≈ PGG > TeGG > TGG > 1GG, and their inhibitory activities increases with the increase in the number of GMs. Moreover, the hypoglycemic effects of 1,2,3,4,6-pentagalloylglucose (PGG) and tannic acid (TA) in vitro and in vivo were also confirmed to be equivalent to or even stronger than that of acarbose. α-Glucosidase inhibitory activities in vitro and in vivo of GTs were positively correlated with the number of GTs, and the more the number, the stronger the activity. However, PGG with five GTs and TA with ten GTs showed almost identical α-glucosidase inhibitory activities, possibly due to the reduced binding force with the enzyme caused by spatial hindrance.

Integration of Deep Learning and Sequential Metabolism to Rapidly Screen Dipeptidyl Peptidase (DPP)-IV Inhibitors from Gardenia jasminoides Ellis.

Traditional Chinese medicine (TCM) possesses unique advantages in the management of blood glucose and lipids. However, there is still a significant gap in the exploration of its pharmacologically active components. Integrated strategies encompassing deep-learning prediction models and active validation based on absorbable ingredients can greatly improve the identification rate and screening efficiency in TCM. In this study, the affinity prediction of 11,549 compounds from the traditional Chinese medicine system's pharmacology database (TCMSP) with dipeptidyl peptidase-IV (DPP-IV) based on a deep-learning model was firstly conducted. With the results, Gardenia jasminoides Ellis (GJE), a food medicine with homologous properties, was selected as a model drug. The absorbed components of GJE were subsequently identified through in vivo intestinal perfusion and oral administration. As a result, a total of 38 prototypical absorbed components of GJE were identified. These components were analyzed to determine their absorption patterns after intestinal, hepatic, and systemic metabolism. Virtual docking and DPP-IV enzyme activity experiments were further conducted to validate the inhibitory effects and potential binding sites of the common constituents of deep learning and sequential metabolism. The results showed a significant DPP-IV inhibitory activity (IC50 53 ± 0.63 μg/mL) of the iridoid glycosides' potent fractions, which is a novel finding. Genipin 1-gentiobioside was screened as a promising new DPP-IV inhibitor in GJE. These findings highlight the potential of this innovative approach for the rapid screening of active ingredients in TCM and provide insights into the molecular mechanisms underlying the anti-diabetic activity of GJE.

Antimicrobial Efficacy of Allium cepa and Zingiber officinale Against the Milk-Borne Pathogen Listeria monocytogenes.

Listeria monocytogenes is an important food-borne pathogen that causes listeriosis and has a high case fatality rate despite its low incidence. Medicinal plants and their secondary metabolites have been identified as potential antibacterial substances, serving as replacements for synthetic chemical compounds. The present studies emphasize two significant medicinal plants, Allium cepa and Zingiber officinale, and their efficacy against L. monocytogenes. Firstly, a bacterial isolate was obtained from milk and identified through morphology and biochemical reactions. The species of the isolate were further confirmed through 16S rRNA analysis. Furthermore, polar solvents such as methanol and ethanol were used for the extraction of secondary metabolites from A. cepa and Z. officinale. Crude phytochemical components were identified using phytochemical tests, FTIR, and GC-MS. Moreover, the antibacterial activity of the crude extract and its various concentrations were tested against L. monocytogenes. Among all, A. cepa in methanolic extracts showed significant inhibitory activity. Since, the A. cepa for methanolic crude extract was used to perform autography to assess its bactericidal activity. Subsequently, molecular docking was performed to determine the specific compound inhibition. The docking results revealed that four compounds displayed strong binding affinity with the virulence factor Listeriolysin-O of L. monocytogenes. Based on the above results, it can be concluded that the medicinal plant A. cepa has potential antibacterial effects against L. monocytogenes, particularly targeting its virulence.