Inhibitory Potential Research Articles

Human IL-22 receptor-targeted small protein antagonist suppress murine DSS-induced colitis

BackgroundHuman interleukin-22 (IL-22) is known as a “dual function” cytokine that acts as a master regulator to maintain homeostasis, structural integrity of the intestinal epithelial barrier, and shielding against bacterial pathogens. On the other hand, the overexpression of IL-22 is associated with hyper-proliferation and recruitment of pathologic effector cells, leading to tissue damage and chronic inflammation in specific diseases including inflammatory bowel disease (IBD). To study a role of IL-22-mediated signaling axis during intestinal inflammation, we generated a set of small protein blockers of IL-22R1 and verified their inhibitory potential on murine model of colitis.MethodsWe used directed evolution of proteins to identify binders of human IL-22 receptor alpha (IL-22R1), designated as ABR ligands. This approach combines the assembly of a highly complex combinatorial protein library derived from small albumin-binding domain scaffold and selection of promising protein variants using ribosome display followed by large-scale ELISA screening. The binding affinity and specificity of ABR variants were analyzed on transfected HEK293T cells by flow cytometry and LigandTracer. Inhibitory function was further verified by competition ELISA, HEK-Blue IL-22 reporter cells, and murine dextran sulfate sodium (DSS)-induced colitis.ResultsWe demonstrate that ABR specifically recognizes transgenic IL-22R1 expressed on HEK293T cells and IL-22R1 on TNFα/IFNγ-activated HaCaT cells. Moreover, some ABR binders compete with the IL-22 cytokine and function as IL-22R1 antagonists in HEK-Blue IL22 reporter cells. In a murine model of DSS-induced acute intestinal inflammation, daily intraperitoneal administration of the best IL-22R1 antagonist, ABR167, suppressed the development of clinical and histological markers of colitis including prevention of mucosal inflammation and architecture deterioration. In addition, ABR167 reduces the DSS-induced increase in mRNA transcript levels of inflammatory cytokines such as IL-1β, IL-6, IL-10, and IL-17A.ConclusionsWe developed small anti-human IL-22R1 blockers with antagonistic properties that ascertain a substantial role of IL-22-mediated signaling in the development of intestinal inflammation. The developed ABR blockers can be useful as a molecular clue for further IBD drug development.

Ultrasound Assisted Extraction of Bioactive Compounds Rich Extract from Immature Dropped Kinnow Fruit

Ultrasound-assisted extraction process parameters of bioactive compounds extraction from immature dropped kinnow fruit were optimized using response surface methodology. Box–Behnken design of the experiments was used to optimize the independent extraction variables: amplitude (30% to 70%), extraction time (3 to 9 min), and pulse cycle (2 to 6 s) for maximizing extraction of bioactive (total phenolics, total flavonoids, antioxidant activity such as 2, 2-diphenyl-1-picrylhydrazyl (DPPH) inhibition and ferric reduction activity potential (FRAP) activity) compounds from immature dropped kinnow fruits. Optimized conditions for ultrasonication bioactive extraction using 45.80% amplitude, 6.63 min extraction time and 4.24 s pulse cycle yielded 5.02 g GAE 100g-1 total phenolics, 9.41 g QE 100g-1 flavonoid content, 302.88 mg AAE 100g-1 DPPH, 6.95 g TE 100g-1 FRAP activity, 0.76 g DE 100g-1 saponins and 6.29 mg AE 100g-1 alkaloids. These optimized conditions could be used for pilot scale extraction of bioactive compounds from immature dropped kinnow fruits.

Evaluation of chemical constituents in Norantea guianensis Aubl. extracts, embryotoxicity, and acetylcholinesterase inhibitory potential in Danio rerio.

Norantea guianensis Aubl., commonly referred to as the parrot flower or macaw-tail vine, is a plant species found in the Brazilian Amazon, Caatinga, and Cerrado biomes. It is used in folk medicine for its anxiolytic properties, as well as its ability to alleviate headaches and reduce fever. Nevertheless, despite its therapeutic benefits, the impact on embryonic development has yet to be fully explained. The objective of this study was to evaluate chemical constituents by HPLC-DAD, UV-visible and classical phytochemistry and the LC50 of ethanolic extracts from the stem and leaves of N. guianensis in Danio rerio after 96 hours and to investigate their effect on developmental morphology. The findings were then related to both Acetylcholinesterase (AChE) activity and the plant's chemical composition. Zebrafish embryos were exposed to 0, 20, 40, 60, 80 and 100 mg/L concentrations of stem and leaves extracts. Phytochemical analysis revealed that the stem extract contained predominantly phenolic compounds, tannins, and anthraquinones, while the leaf extract contained alkaloids and flavonoids. The LC50 values for the stem and leaf extracts were 64.55 mg/L and 7.16 mg/L, respectively, being the stem extract was more toxic than the leaf extract. Induced malformations and alterations in the zebrafish development in different concentrations for both extract including pericardial edema, increased heart rate, spinal malformation and equilibrium disruption. Unlike to stem extract, the leaf extract delayed larval hatching and inhibited AChE activity. The findings indicate that the leaf extract possesses higher embryotoxicity and its use should be avoided during pregnancy.

Exploring the chemical composition and biological effects of four Salvia hybrids: an innovative perspective on functional yields

AbstractGenus Salvia is considered one of the largest genera of family Lamiaceae with many recorded species and hybrids of valuable biological importance. This study involved the phytochemical characterization of four Salvia hybrids (KNM23 (S. fructicosa × S. officinalis), KNM101 (S. aramiensis × S. officinalis), KNM5 (S. aramiensis × S. officinalis) and KNM12 (S. fructicosa × S. officinalis)) through measuring their total phenolic content (TPC) and total flavonoid content (TFC) together with profiling through UPLC/MSn analysis followed by investigation of their antioxidant activities and enzyme inhibitory potential through different techniques. Hybrid KNM23 presented significantly high concentration of both phenolic and flavonoid, displaying a TPC of 92.10 mg GAE/g and a TFC of 50.85 mg RE/g. The UPLC/MSn profiling resulted in the tentative identification of one hundred eighty components from different phytochemical classes mainly flavonoids, phenolic acids, phenyl propanoids, tannins and many others. The antioxidant assay showed that hybrid KNM23, a hybrid of S. fruticosa and S. officinalis, exhibited the highest antioxidant activity in the DPPH, ABTS, and PBD assays, measuring 436.38 mmol TE/g, 543.65 mmol TE/g, and 3.20 mmol TE/g, respectively. KNM23 and KNM12 showed no inhibition of AChE and α‐glucosidase. However, KMN12 demonstrated highest BChE and tyrosinase 2.57 mg GALAE/g and 12.91 mg KAE/g, respectively. Our results suggest that the Salvia hybrids can be considered as natural sources of bioactive compounds in the development of health‐promoting applications.

Investigating Sortase A inhibitory potential of herbal compounds using integrated computational and biochemical approaches

Multi-drug resistance in bacteria is emerging as a major global health challenge, causing substantial harm in terms of mortality, morbidity, and financial strain on healthcare systems. These bacteria are constantly acquiring new virulence factors and drug-resistance mechanisms, which highlights the critical need for innovative antimicrobial medicines and identification of new therapeutic targets, such as Sortase A (EfSrtAΔN59). EfSrtAΔN59, a transpeptidase significant for the adhesion and virulence of Enterococcus faecalis (E. faecalis), presents an attractive target for disrupting biofilm formation—a key factor in persistent infections. This study investigates the inhibitory effects of two natural flavonoids- Rutin Trihydrate and Quercetin, on EfSrtAΔN59 and biofilm formation in E. faecalis. With in vitro enzymatic assays and biofilm quantification techniques, we demonstrate that both compounds significantly attenuate EfSrtAΔN59 activity, thereby hindering bacterial biofilm formation. Rutin Trihydrate and Quercetin exhibited strong binding affinities to the EfSrtAΔN59 enzyme, as confirmed by molecular docking and MD simulation studies. This was further substantiated by a notable reduction in biofilm biomass in bacterial cultures treated with these compounds. These findings highlight the potential of Rutin Trihydrate and Quercetin as promising candidates for the development of novel anti-virulence therapies aimed at mitigating E. faecalis infections, thereby offering a compelling alternative to traditional antibiotics.

Exploring Benzo[b][1,4]Thiazine Derivatives: Multitarget Inhibition, Structure–Activity Relationship, Molecular Docking, and ADMET Analysis

AbstractA series of benzothiazine derivatives (1–17) were synthesized via an intermolecular cyclocondensation reaction involving 2‐aminothiophenol (i) and substituted phenacyl bromide (ii). Structural elucidation of these synthetic derivatives utilized EI–MS, HR‐EIMS, 1H NMR, and 13C NMR spectroscopic techniques. The synthesized analogs were evaluated against key enzyme targets (acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and α‐glucosidase (α‐Glu)) and tested for cytotoxicity against various cancer cell lines. Six compounds were selected based on their inhibition profiles, exhibiting significant inhibitory potential against enzymes. In silico studies corroborated the observed inhibitory activities, aligning closely with experimental outcomes. Additionally, an ADME/T study provided insights into pharmacokinetic and safety profiles, identifying promising candidates for future drug development efforts.

Exploration of thiazine Schiff bases as promising urease inhibitors: Design, synthesis, enzyme inhibition, kinetic analysis, ADME/T evaluation, and molecular docking studies

Urease catalyzes the hydrolysis of urea, leading to an increase in stomach pH and supporting Helicobacter pylori survival, which is linked to several gastrointestinal disorders. In this study, thiazine-based Schiff bases were explored as promising urease inhibitors. Various spectroscopic techniques characterized the synthetic library of thiazine Schiff bases 2–36 and also evaluated for their inhibitory activities against urease. The derivatives demonstrated significant inhibitory potential with IC50 values ranging from 0.14 ± 0.08 to 3.66 ± 0.21 μM, outperforming the standard inhibitor thiourea (IC50 = 19.43 ± 0.18 μM). Structure-activity relationship (SAR) studies revealed that specific substitutions (type and positions) on the aryl ring significantly affect the inhibition potential. The most potent derivative, compound 7, possessed 2-methoxy-5-trifluoromethyl substitutions and exhibited an IC50 of 0.14 ± 0.08 μM. Enzyme kinetics studies revealed that the most potent derivatives function as competitive inhibitors. Additionally, molecular docking studies provided insights into the binding interactions between the molecule and the urease active site, highlighting key residues involved in inhibitor binding. These findings highlight the therapeutic potential of thiazine-based Schiff bases as urease inhibitors and provide insights for the development of new anti-ulcer agents.

Unraveling the Antidiabetic Effect of Alternantera brasiliana (L.) Kuntze: A Combined in Vitro and in Vivo Approach

Background of the study This study established the antidiabetic efficacy of Alternantera brasiliana in vitro and in vivo, identified the most active fraction and profiled the chemical constituents of the most active fraction. Methodology The leaf of A. brasiliana was air-dried, pulverized and extracted with methanol and evaluated for its α-amylase activity at different concentrations using in vitro method. The in vivo antidiabetic activity of the extract and glibenclamide was evaluated in glucose loaded and streptozotocin-induced diabetic rats using various doses, while the most active partitioned fraction was identified using glucose loaded method followed by identification of its chemical constituents through GC-MS analysis. Results The extract elicited good α-amylase inhibitory potential with IC50 = 0.45 mg/mL. Also, the 50 mg/kg dose demonstrated the highest percentage blood glucose level reduction and significantly ( P > 0.05) comparable to glibenclamide (5 mg/kg) from 0.5 to 4 h. The streptozotocin-induced antidiabetic assay showed that the 50 mg/kg demonstrated better activity than glibenclamide (5 mg/kg) and was significantly comparable on days 10 and 14. The aqueous methanol fraction was the most active fraction with 53% blood glucose level reduction at 4 h. The secondary metabolite profiling identified 30 chemical compounds whereby 1H-Indole-2-carboxylic acid, 6-(4-ethoxyphenyl)-3-methyl-4-oxo-4,5,6,7-tetrahydro-, isopropyl ester, Benzo[h]quinoline, 2,4-dimethyl-, thymol and 13,5-trioxane as the major constituents. Conclusion The antidiabetic activity demonstrated by the A. brasiliana extract established its antidiabetic efficacy

Novel 1,2,3-triazole derivatives containing benzoxazinone scaffold: Synthesis, docking study, DFT analysis and biological evaluation

In order to address the drastic demand for novel broad-spectrum antibacterial and anticancer medicines with enhanced activity, computer modelling was utilized to rationally develop newer anticancer triazole based drugs. A unique series of benzo[d][1,3]oxazin-4-one linked 1,2,3-triazoles was synthesised in five steps, with good yields and an assessment of their antibacterial and anticancer activities. IR spectroscopy, 1H NMR, 13C NMR, and mass spectrometry were used to characterize the synthesis of triazole compounds. From antibacterial screening, the prepared derivatives namely, 8a, 8e, 8h and 8k showed excellent inhibitory potential against S. aureus with ZI of 28 ± 0.48, 30 ± 0.42, 30 ± 0.11, 35 ± 0.23 mm respectively, compared to moxifloxacin (33 ± 0.15 mm). Compared to doxorubicin (IC50 = 2.45 ± 0.14 μM), compounds 8h and 8k demonstrated superior and exceptional cytotoxicity against the A549 cell line (IC50 = 2.30 ± 0.26 and 1.90 ± 0.30 μM, respectively). Latter All the derivatives were further subjected to in silico docking studies against human lung (PDB: 2P85), VEGFR2 kinase domain (PDB: 3CP9) and could serve as ideal leads for additional modification in the field of anticancer research. Based on docking results, 8e showed that the amino acids Arg373(A), Gly113(A), Glu103(A), Asp108(A), Ser119(A), Asn375(A), Val374(A), Lys387(A), and Asn120(A) exhibited highly stable binding to cytochrome P4502A13 receptor of lung cancer. Furthermore, Density Functional Theory (DFT) calculations are performed to support the molecular docking studies. Compounds 8e, 8h, and 8k were discovered to have estimated energy gaps (eV) of 3.181, 4.034, and 3.539 eV, respectively. Triazole 8h exhibited the lowest chemical hardness (1.962 eV) and the highest chemical softness (0.252 eV), which also suggests that it is more reactive than all the other compounds under study. Moreover, these scaffolds physicochemical characteristics, filtration molecular properties, assessment of toxicity, and bioactivity scores were assessed in relation to ADME (absorption, distribution, metabolism, and excretion). In conclusion, we discovered a novel benzoxazinone linked 1,2,3-triazoles with promising antimicrobial and anticancer activity and a favorable pharmacokinetic profile.

The Inhibitory Potentials of the Root Extract and Fractions of Brenania brieyi (De Wild) (Rubiaceae) on Lactate Dehydrogenase, Phospholipase A2, and α- Amylase in Plasmodium falciparum - Infected Persons

Medicinal plants have been used as an alternative in malaria chemotherapy. This study aimed to determine the in vitro inhibitory potentials of the extract and fractions of Brenania brieyi on Lactate Dehydrogenase (LdH), Phospholipase A2 (PLA2), and α-Amylase enzyme extracted from Plasmodium falciparum. Cold maceration and Liquid-Liquid partitioning were used to obtain the extract and fractions respectively, using different solvent of varying polarity. Phytochemical analysis was done using Gas Chromatography-Flame Ionization detector (GCFID) method to identify and quantify different phytoconstituents. In vitro enzyme assay (α-Amylase, LdH and PLA2) were performed using standard procedure. The extract contained Alkaloids such as Spartein (5.05 µg/ml), Dihydrocytisine (23.12 µg/ml), Aphyllidine (5.25 µg/ml), Ribalinidine (2.65 µg/ml), Epihedrine (1.91 µg/ml), Saponins such as sapogenin (5.70 µg/ml), Tannins (16.25 µg/ml), Flavonoids such as Kaempferol (4.59 µg/ml), Catechin (5.50 µg/ml), Proanthocyanidin (9.81 µg/ml), Anthocyanin (3.22 µg/ml), Narigenin (3.62 µg/ml), Flavonones (8.73 µg/ml), Steroids (8.58 µg/ml), Polyphenols such as Reservatrol (20.68 µg/ml) and Glycosides such as cardiac glycoside (4.42 µg/ml), Cyanogenic glycosides (17.72 µg/ml) while Terpenoids are absent. The percentage inhibition of the enzyme (PLA2, LdH and α-amylase) at 100 mg/ml of extract showed the highest inhibition (37 %, 0 % and 38.33 %) when compared to controls, while ethyl acetate fraction has the highest inhibition (98 %, 34 % and 92 %) at P ˂ 0.05 at 100 mg/kg respectively. This study justifies the use of ethnomedicinal remedies (B. brieyi) in treating malaria in infected individuals. The study also suggests that the extract and fractions may act through the inhibition of plasmodial enzymes in infected persons.

In silico DFT and molecular modeling of novel pyrazine-bearing thiazolidinone hybrids derivatives: elucidating invitro anti-cancer and urease inhibitors.

In the present work, one of the leading health issues i.e.cancer was targeted by synthesizing and biologically investigating the potential of pyrazine-based thiazolidinone derivatives (1-13). The basic structure of the synthesized compounds was determined using a variety of spectroscopic techniques, including 1H NMR, 13C NMR, and HREI-MS. These scaffolds were studied for their biological profiles as anti-cancer as well as anti-urease agents. The biological effectiveness of these compounds was compared using the reference tetrandrine (IC50=4.50±0.20 µM) and thiourea (IC50=5.10±0.10 µM), respectively. Among novel compounds, scaffold 3, 6, 7 and 10 demonstrated an excellent potency with highest inhibitory potential (IC50=1.70±0.10 and 1.30±0.20 µM), (IC50=4.20±0.10 and 5.10±0.30 µM), (IC50=2.10±0.10 and 3.20±0.20 µM) and (IC50=2.70±0.20 and 4.20±0.20 µM), respectively, out of which scaffold 3 emerged as the leading compound due to the presence of highly reactive-CF3 moiety which interacts via hydrogen bonding. Molecular docking investigations of the potent compounds was also carried out which revealed the binding interactions of ligands with the active sites of enzyme. Moreover, the electronic properties, nucleophilic and electrophilic sited of the lead compounds were also studied under density functional theory (DFT).

Inhibition of starch hydrolysis during in vitro co-digestion of pasta with phenolic compound-rich vegetable foods

The ability of phenolic compounds to inhibit amylolytic enzymes activities has been investigated, suggesting their possible role in type-2 diabetes management. However, these studies have been carried out with purified enzymes and synthetic substrates and are distant from simulating a real physiological situation. The objective of the present research was to evaluate the ability of phenolic-rich vegetable foods to inhibit starch hydrolysis during in vitro co-digestion with pasta resulting in a potential anti-diabetic effect and mimicking as closely as possible a real scenario. Some tested vegetable foods, such as capers, red-skinned onion, red radish, and olives, determined a decrease in starch hydrolysis by 21.5%–31.7% during in vitro co-digestion with pasta. The quali-quantitative phenolic profiles of in vitro co-digested samples were elucidated and selected standard compounds were tested for their ability to inhibit porcine pancreatic α-amylase and mammalian α-glucosidase. The inhibitory potential of these compounds, especially against α-glucosidase, explained the effect observed during co-digestion experiments. The most active phenolic compounds against α-glucosidase were quercetin-4’-O-glucoside, quercetin-3-O-rutinoside, luteolin-7-O-glucoside and quercetin-3-O-glucoside-4’-O-glucoside with IC50 values of 20.67, 52.23, 68.84 and 87.58 μmol/L, respectively. This is the first report suggesting that these compounds are potent inhibitors of mammalian α-glucosidase. This study indicates that consuming starchy foods (i.e., pasta) with phenolic-rich vegetable foods may result in an inhibition of starch digestion possibly reducing the post-prandial glucose levels.

Antioxidant, antibacterial, and α-glucosidase inhibition potential of three Allium species (Amaryllidaceae) from Iran

Introduction: Wild species of the genus Allium have high potential for use as medicine due to their essential secondary metabolites with antioxidant activity. This study explored the antioxidant, antibacterial, and α-glucosidase inhibition activities of three Allium species: Allium tripedale, Allium hooshidaryae, and Allium stipitatum. Methods: The antioxidant potentials of the plant methanol extracts were evaluated using the ferric reducing antioxidant power (FRAP) and the 2,2-diphenyl-1picrylhydrazil (DPPH) radical scavenging test. Total phenolic content (TPC), total flavonoid content (TFC) and α-glucosidase inhibition were also evaluated. Antibacterial assessments were done employing disk diffusion and microdilution methods to determine inhibition zone and minimum inhibitory concentration (MIC), respectively against Staphylococcus aureus, Bacillus subtilis, Escherichia coli, and Pseudomonas aeruginosa. Results: Allium hooshidaryae displayed high TPC (70.24 ± 0.0039 mg gallic acid equivalent/g extract), while A. tripedale had the highest TFC (87 ± 0.013 mg Quercetin equivalent/g extract). A. hooshidaryae showed superior antioxidant capacity (DPPH IC50: 724.4 ± 0.31 µg/mL; FRAP: 36.87 mg ascorbic acid equivalent/g extract) and stronger α-glucosidase inhibition (IC50 = 2.59 mg/mL vs. 4.33 mg/mL for A. tripedale and 6.41 mg/mL for A. stipitatum). Qualitative tests confirmed phenolic, flavonoid, and glycoside compounds in all three species. A. stipitatum uniquely contained saponin and tannin. A. hooshidaryae and A. stipitatum inhibited the bacterial strains effectively, especially at the higher concentration (400 µg/mL). A. stipitatum showed inhibition against all strains, particularly against S. aureus (MIC: 12.5 µg/mL). Conclusion: This study highlights the antidiabetic and antibacterial potential of three Allium species, emphasizing their values as rich sources of bioactive compounds.

Novel 3,5‐Dimethylpyrazole‐Linked 1,2,4‐Triazole‐3‐thiols as Potent Antihyperglycemic Agents: Synthesis, Biological Evaluation, and In Silico Molecular Modelling Investigations

AbstractIn this work, a series of pyrazole‐linked 1,2,4‐triazole‐3‐thiol derivatives (3a–i) were prepared and identified by 13C NMR, 1H NMR, and mass spectrometry (ESI‐MS) data. The newly synthesized molecules were also evaluated in vitro for their α‐amylase and α‐glucosidase inhibitory potential. All newly synthesized compounds exhibited potent α‐glucosidase inhibition activity with IC50 in the range of 1.016 ± 0.70 to 24.40 ± 0.02 µM and good α‐amylase inhibitory with IC50 in the range of 49.91 ± 0.32 to 500 µM, as compared to acarbose. The most potent compound among this series is derivative 3e, with IC50 value of 1.016 ± 0.70 µM, which is many folds more than that of acarbose. In addition, in docking studies, both compounds exhibited good interactions at the active region of target proteins. Therefore, this study may lead via structural modifications to the discovery of new potent α‐amylase and α‐glucosidase inhibitors useful in the diabetes treatment.

Inhibitory impact of a mesoporous silica nanoparticle-based drug delivery system on Porphyromonas gingivalis-induced bone resorption

Controlling and reducing plaque formation plays a pivotal role in preventing and treating periodontal disease, often utilizing antibacterial drugs to enhance therapeutic outcomes. Mesoporous silica nanoparticles (MSN), an FDA-approved inorganic nanomaterial, possess robust physical and chemical properties, such as adjustable pore size and pore capacity, easy surface modification, and high biosafety. Numerous studies have exploited MSN to regulate drug release and facilitate targeted delivery. This study aimed to synthesize an MSN-tetracycline (MSN-TC) complex and investigate its inhibitory potential on Porphyromonas gingivalis (P. gingivalis)-induced bone resorption. The antibacterial efficacy of MSN-TC was evaluated through bacterial culture experiments. A P. gingivalis-induced bone resorption model was constructed by subcutaneously injecting P. gingivalis around the cranial bone of rats. Micro-computed tomography was employed to assess the inhibitory impact of MSN and MSN-TC on bone resorption. Furthermore, the influence of MSN and MSN-TC on osteoclast differentiation was examined in vitro. The MSN exhibited optimal pore size and particle dimensions for effective loading and gradual release of TC. MSN-TC demonstrated significant bacteriostatic activity against P. gingivalis. MSN-TC-treated rats showed significantly reduced cranial bone tissue destruction compared to MSN or TC-treated rats. Additionally, both MSN and MSN-TC exhibited inhibitory effects on the receptor activator of nuclear factor kappa-Β ligand-mediated osteoclast differentiation. The MSN-TC complex synthesized in this study demonstrated dual efficacy by exerting antibacterial effects on P. gingivalis and by resisting osteoclast differentiation, thereby mitigating bone resorption induced by P. gingivalis.Graphical

Synthesis, Anticholinesterase and Antioxidant Activity of Thiosemicarbazone Derivatives

In this research, we report the synthesis and evaluation of novel thiosemicarbazones as anti-Alzheimer’s agents. The structural clarification of the newly synthesized compounds was carried out by 1H NMR, 13C NMR, and MS analyses. According to the in vitro cholinesterase inhibition assay, compounds showed more inhibitory potential against AChE than BuChE. The in vitro antioxidant activity of the synthesized compounds was measured via two different methods. According to ferrous ion-chelating assay compound 2b demonstrated 5.26% activity when compared to BHT (2.57%). DPPH radical scavenging activity assay revealed that compound 2b showed the most potent antioxidant activity with an IC50 value of 43.91 ± 0.021μM. Among the synthesized compounds, compound 2b was found as the most potent antioxidant agent.

In-Silico ADMET Prediction, Structure-Based Drug Design and Molecular Docking Studies of Quinazoline Derivatives as Novel EGFR Inhibitors

This Present research provides valuable insights and implications for the development of quinazoline derivatives as novel EGFR inhibitors. The in-silico ADMET predictions indicate that the quinazoline derivatives possess promising drug-like properties, suggesting their potential for further development as oral drugs. The low risk of toxicity and favorable metabolic and excretion profiles enhance their suitability for therapeutic applications Molecular docking studies revealed strong binding interactions between the quinazoline derivatives and the EGFR kinase domain. These interactions suggest that these compound shave the potential to effectively inhibit EGFR activity, making them promising candidates for anti- cancer drug development to progress from in-silico findings to clinical applications, further research is essential. Future work should encompass in vitro and in vivo experiments to validate the inhibitory potential of these compounds against EGFR. Additionally, pharmacokinetic studies are warranted to confirm their ADMET properties. Structural optimization through medicinal chemistry approaches may further enhance their binding affinities and specificity for EGFR. It represents a pivotal step in the exploration of quinazoline derivatives as novel EGFR inhibitors. The combined efforts in ADMET prediction, structure-based drug design, and molecular docking have provided a strong foundation for the development of innovative anti-cancer therapies. The potential of these compounds to target EGFR, a crucial player in various cancers, holds great promise for improving the treatment options available to patients and advancing the field of oncology.

Assessing the Inhibitory Potential of Pregnenolone Sulfate on Pentraxin 3 in Diabetic Kidney Disease: A Molecular Docking and Simulation Study.

Diabetic Kidney Disease (DKD), a frequent consequence of diabetes, has substantial implications for both morbidity and mortality rates, prompting the exploration of new metabolic biomarkers due to limitations in current methods like creatinine and albumin measurements. Pentraxin 3 (PTX3) shows promise for assessing renal inflammation in DKD. This study investigates how DKD metabolites could influence PTX3 expression through molecular docking, ADMET profiling, and dynamic simulation. Network and pathway analyses were conducted to explore metabolite interactions with DKD genes and their contributions to DKD pathogenesis. Thirty-three DKD-associated metabolites were screened, using pentoxifylline (PEN) as a reference. The pharmacokinetic properties of these compounds were evaluated through molecular docking and ADMET profiling. Molecular dynamics simulations over 200 ns assessed the stability of PTX3 (apo), the PRE-PTX3 complex, and PEN-PTX3 across multiple parameters. Cytoscape identified 1082 nodes and 1381 edges linking metabolites with DKD genes. KEGG pathway analysis underscored PTX3's role in inflammation. Molecular docking revealed pregnenolone sulfate (PRE) with the highest binding affinity (-6.25 kcal/mol), followed by hydrocortisone (-6.03 kcal/mol) and 2-arachidonoylglycerol (-5.92 kcal/mol), compared to PEN (-5.35 kcal/mol). ADMET profiling selected PRE for dynamic simulation alongside PEN. Analysis of RMSD, RMSF, RG, SASA, H-bond, PCA, FEL, and MM-PBSA indicated stable complex behavior over time. Our findings suggest that increasing PRE levels could be beneficial in managing DKD, potentially through isolating PRE from fungal sources, synthesizing it as dietary supplements, or enhancing endogenous PRE synthesis within the body.

Design and synthesis of new coumarin-1,2,3-triazole hybrids as new antidiabetic agents: In vitro α-amylase, α-glucosidase inhibition, anti-inflammatory, and docking study

The current study focuses on the synthesis of coumarin-triazole hybrids (7i-t) starting from 4-hydroxy benzaldehyde or 4-hydroxyacetophenone (1a-b) and propargyl bromide. On the other hand, coumarin derivatives (5c-h) were prepared by Pechmann cyclization and treated with sodium azide to give the corresponding 3-azido methyl coumarins (6c-h). Finally, 1,3-dipolar cycloaddition between compounds 6c-h and terminal alkyne 2a-b produces coumarin-triazole hybrids (7i-t) utilizing click chemistry approaches that are high yielding, wide in scope and simple to perform. The structural proofs of the newly synthesized coumarin-triazole hybrids (7i-t) are proved by various spectroscopic techniques, including IR, 1H NMR, 13C NMR, and LC-MS. The synthesized new coumarin triazole hybrids (7i-t) were explored for their antihyperglycemic potential and therefore evaluated for α-glucosidase and α-amylase inhibitory activities along with anti-inflammatory. The results suggest that among the series, compound 7l showed excellent activity with an IC50 value of 0.67±0.014 mg/mL and 0.72±0.012 mg/mL for α-amylase, and α-glucosidase inhibitory potential while compound 7o showed promising anti-inflammatory activity with IC50 value of 0.54±0.003 mg/mL. To support the above findings, molecular docking studies were performed, which confirmed the interaction of the synthesized molecules 7i-t with an effective binding energy of -9.0 to -10.6 kcal/mol at the active site of the enzyme human pancreatic α-amylase (PDB ID: 1B2Y). Therefore, these scaffolds have the potential to function as lead candidates for antidiabetic and anti-inflammatory activities.

Design, synthesis, in vitro and in silico studies of novel piperidine derived thiosemicarbazones as inhibitors of dihydrofolate reductase.

Dihydrofolate reductase (DHFR), an essential enzyme in folate metabolism, presents a promising target for drug development against various diseases, including cancer and tuberculosis. Herein, we present an integrated approach combining in vitro biochemical assays with in silico molecular docking analysis to evaluate the inhibitory potential of 4-piperidine-based thiosemicarbazones 5(a-s) against DHFR. In our in vitro study, a novel series of 4-piperidine-based thiosemicarbazones 5(a-s) were assessed for their inhibitory activity against DHFR enzyme. The synthesized compounds 5(a-s) exhibited potent inhibition with IC50 values in the range of 13.70 ± 0.25 µM to 47.30 ± 0.86 µM. Among all the derivatives 5p displayed highest inhibitory activity. Simultaneously, in silico analysis were performed and compared with standard drug (Methotrexate) to predict the binding affinity and interaction pattern of synthesized compounds with DHFR active site. SAR analysis was done to elucidate how structural modifications impact compound's biological activity, guiding the rational design of potent and selective drug candidates for targeted diseases. These findings may provide a comprehensive assessment of 4-piperdine-based thiosemicarbazones as DHFR inhibitors and contribute to the development of novel therapeutics targeting DHFR-associated diseases.