Inhibitory Potency Research Articles

Discovery of novel thiosemicarbazone-acridine targeting butyrylcholinesterase with antioxidant, metal complexing and neuroprotector abilities as potential treatment of Alzheimer's disease: In vitro, in vivo, and in silico studies

Inhibition of cholinesterases, combined with antioxidant activity, metal-chelating capacity, and neuroprotection, is recognized as an effective multitarget therapy for the treatment of Alzheimer's disease (AD). Based on our in-house thiosemicarbazone-acridine compounds, this study recognized these derivatives as possible multi-target-directed ligand (MTDL). Initial screening against cholinesterases identified CL-01, which exhibited a promising IC50 value of 0.71 μM against butyrylcholinesterase (BChE). Twelve new derivatives were designed based on CL-01 aiming to retain the BChE inhibitory activity while incorporating a MTDL profile, including antioxidant properties and metal-complexing abilities. Among the new derivatives, CL-13 maintained a good BChE inhibition (IC50 = 1.15 μM) with improved selective index against acetylcholinesterase (SI = 9.2). The acridine nucleus was important for the activity, as its saturated tetrahydroacridine analogue (TA-01) showed a decrease in cholinesterases inhibition potencies and altered the mode of inhibition, revealing for the first time distinct functional roles for the two nuclei. Moreover, CL-13 emerged as a promising lead compound, demonstrating interesting antioxidant activity (DPPH EC50 = 47.01 μM), chelating capacity of biometals involved in Aβ aggregation and/or oxidative stress, and a lack of neurotoxicity at 50 μM in SH-SY5Y cells. It also exhibited neuroprotective effects in an in vitro oxidative stress model induced by H2O2. Finally, in vivo experiments confirmed that CL-13 effectively reversed scopolamine-induced cognitive impairment, without affecting locomotor activity in the mice.

Ameliorative effect of rutecarpine supplementation against cisplatin-induced nephrotoxicity in rats via inhibition of monocyte chemoattractant protein-1, intercellular adhesion molecule-1, high-mobility group box 1, and nuclear factor kappa B.

Cisplatin, the pioneering heavy metal compound, stands out as a potent drug for the treatment of various solid tumors. However, its clinical utility is hampered by notable toxicity and adverse effects, particularly nephrotoxicity. The potency of rutecarpine, a phytochemical, in mitigating cisplatin-induced nephrotoxicity was assessed in the present study. In this experimental setup, healthy male Wistar rats were grouped into four and Group I rats served as the control group, receiving only vehicle control. Group II rats were subjected to cisplatin treatment alone, administered intraperitoneally at a dosage of 7mg/kg body weight on the 19th, 20th, and 21st days. Group III and IV rats were orally administered with rutecarpine at doses of 10 and 20mg/kg body weight, respectively, starting from Day 1 and continuing daily for 21 days. Additionally, they were injected intraperitoneally with cisplatin at the same dosage and schedule as Group II. Relative kidney weight and renal biochemical markers blood urea nitrogen, lactate dehydrogenase, serum urea, and creatinine were measured to assess rutecarpine inhibitory potency against cisplatin toxicity. Markers of oxidative damage and antioxidants levels were quantified in the ruteacarpine- and cisplatin-treated rats. The study investigated the anti-inflammatory property of rutecarpine in cisplatin-induced nephrotoxicity by analyzing inflammatory cytokines. Renal tissue levels of monocyte chemoattractant protein-1, intercellular adhesion molecule-1, high-mobility group box 1, and nuclear factor kappa B, key markers of nephrotoxicity, were quantified to assess rutecarpine's potential to mitigate cisplatin-triggered damage. Histopathological examinations were performed to confirm the impact of rutecarpine against cisplatin-induced nephrotoxicity. Treatment with rutecarpine notably reduced renal biochemical markers, prevented renal edema, and attenuated oxidative stress-induced damage in cisplatin-treated rats. Both inflammatory and nephrotoxicity markers showed significant decreases in rats treated with rutecarpine along with cisplatin. Histological analysis affirmed that rutecarpine pretreatment effectively prevented cisplatin-induced nephrotoxicity. The study findings demonstrate that rutecarpine ameliorates cisplatin-triggered nephrotoxicity through its antioxidant and anti-inflammatory properties, suggesting that rutecarpine supplementation alongside cisplatin treatment could potentially reduce nephrotoxicity in cancer patients.

Targeting N-methyl-lysine histone demethylase KDM4 in cancer: natural products inhibitors as a driving force for epigenetic drug discovery.

KDM4A-F enzymes are a subfamily of histone demethylases containing the Jumonji C domain (JmjC) using Fe(II) and 2-oxoglutarate for their catalytic function. KDM4 enzymes are overexpressed or deregulated in cancer, thus leading to alteration in chromatin structure and transcriptional defects. As KDM4 enzymes have been associated with malignancy, they may represent novel targets for developing innovative therapeutic tools to treat different solid and blood tumors, of note, KDM4A is the isozyme most frequently associated with aggressive phenotypes of these tumors. To this aim, industrial and academic medicinal chemistry efforts have identified different KDM4 inhibitors. In most cases, these are pan-KDM4 inhibitors, with low selectivity against other Jumonji family members. The pharmacophoric features of the inhibitors frequently include a chelating group capable of coordinating the catalytic iron within the active site of the KDM4 enzyme. Nonetheless, non-chelating compounds have also demonstrated promising inhibitory activity, suggesting potential flexibility in the drug design. Several natural products, containing monovalent or bivalent chelators, have been identified as KDM4 inhibitors, albeit with a micromolar inhibition potency. This highlights the potential for leveraging them as templates for the design and synthesis of new derivatives, exploiting nature's chemical diversity to pursue more potent and selective KDM4 inhibitors.

FREE FATTY ACIDS INHIBIT AN ION-COUPLED MEMBRANE TRANSPORTER BY DISSIPATING THE ION GRADIENT

Glutamate is the main excitatory transmitter in the mammalian central nervous system; glutamate transporters keep the synaptic glutamate concentrations at bay for normal brain function. Arachidonic acid (AA), docosahexaenoic acid (DHA), and other unsaturated fatty acids modulate glutamate transporters in cell- and tissue slices-based studies. Here, we investigated their effect and mechanism using a purified archaeal glutamate transporter homolog reconstituted into the lipid membranes. AA, DHA, and related fatty acids irreversibly inhibited the sodium-dependent concentrative substrate uptake into lipid vesicles within the physiologically relevant concentration range. In contrast, AA did not inhibit amino acid exchange across the membrane. The length and unsaturation of the aliphatic tail affect inhibition, and the free carboxylic headgroup is necessary. The inhibition potency did not correlate with the fatty acid effects on the bilayer deformation energies. AA does not affect the conformational dynamics of the protein, suggesting it does not inhibit structural transitions necessary for transport. Single-transporter and membrane voltage assays showed that AA and related fatty acids mediate cation leak, dissipating the driving sodium gradient. Thus, such fatty acids can act as cation ionophores, suggesting a general modulatory mechanism of membrane channels and ion-coupled transporters.

Synthesis and structure-activity relationship of boronic acid bioisosteres of combretastatin A-4 as anticancer agents

The boronic acid group plays an important role in drug discovery. Following our discovery of a boronic acid analog of combretastatin A-4 (CA-4), a series of analogs featuring a boronic acid group on the C phenyl ring of CA-4 was synthesized and evaluated for cytotoxicity, as well as for their ability to inhibit tubulin polymerization, inhibit the binding of [3H]colchicine to tubulin and cause depolymerization of cellular microtubules. Modifications on the C ring of CA-4, either eliminating the methoxy group or replacing the C phenyl ring with a pyridine ring, resulted in a reduced potency for inhibiting tubulin polymerization, colchicine binding and cytotoxic activities as compared to CA-4. Replacing the phenol group with a boronic acid group on the C ring of phenstatin led to a slight increase in cytotoxic potency but a decreased potency for inhibition of tubulin assembly and colchicine binding. Moreover, there was a significant decrease in activity by replacing the C phenyl ring with a pyridine ring. Our results indicate the critical importance of the methoxy group on the C ring as well as the importance of the C phenyl ring compared to a pyridine ring, despite the latter providing a nitrogen atom as a hydrogen bond donor/acceptor, which was predicted by molecular modeling to enhance interaction with the target. The decreased activities of our modified CA-4 boronic analogs may be attributed to weakened hydrogen bonding in our docking model based on the crystal structure of colchicine bound to αβ-tubulin. Notably, even though their effectiveness in inhibiting tubulin polymerization and colchicine binding and causing microtubule depolymerization in cells, the majority of these boronic acid analogs exhibited substantial cytotoxicity. This suggests that they may have additional cellular targets that contribute to their cytotoxicity, and this warrants further evaluation of these unique boronic acid compounds as potential anticancer agents.

Ionic liquid promoted facile one-pot synthesis of phenothiazine-thiazolidin-4-ones as potent antitubercular agents via mycobacterial ATP synthase inhibition

The mycobacterial ATP synthase is responsible for the optimal growth, metabolism and viability of mycobacteria, establishing it as a validated target for the development of anti-TB therapeutics. Herein, we report the facile and efficient one-pot three component synthesis of 2-(10H-phenothiazin-3-yl)-3-substituted thiazolidin-4-one derivatives by using ionic liquid, 1-butyl-3-methylimidazolium bromide [Bmim]Br and their inhibitory potency against mycobacterium tuberculosis H37Rv strain (ATCC-27294). Compound T27 exhibited the highest inhibition activity with an MIC of 0.78 μg/mL, which is twofold and fourfold superior (in terms of the MIC values) to the standard first-line TB drugs isoniazid (MIC: 1.56 μg/mL) and pyrazinamide (MIC: 3.12 μg/mL) respectively. Two other compounds (T25 and T30) are equipotent as the isoniazid. The SAR studies revealed that insertion of 1,2,3-traizole and thiozolidine-2-one rings enhance the anti-TB activity in most of the tested compounds. Also, compound T27 was screened for mycobacterial ATP synthase inhibition activity and it exhibited an IC50 of 0.735 µM in M. smegmatis IMVs. Further, toxicity evaluation against VERO cell lines confirmed null cytotoxicity (selectivity index > 70) of the potent analogues. The title compounds are highly specific towards to the M. tb strain, i.e., most of the compounds exhibited moderate inhibitory potency against the tested bacterial strains (MIC ≥ 6.25 μg/mL). In addition, molecular docking was employed against the active site of the ATP synthase enzyme to validate the binding mechanism and in vitro activity profile of the phenothiazine derivatives. Furthermore, in silico ADME and pharmacokinetic parameters’ prediction indicated good oral bioavailability.

Dithiocarbamate fungicides suppress aromatase activity in human and rat aromatase activity depending on structures: 3D-QSAR analysis and molecular simulation

ABSTRACT Dithiocarbamate fungicides have been widely used in agricultural practices due to their effective control of fungal diseases, thereby contributing to global food security and agricultural productivity. In this study, the inhibitory potency of eight compounds on human and rat aromatase (CYP19A1) activity was evaluated. The results revealed that zineb exhibited the highest inhibitory potency on human CYP19A1 (IC50, 2.79 μM). Maneb (IC50, 3.09 μM), thiram (IC50, 4.76 μM), and ferbam (IC50, 6.04 μM) also demonstrated potent inhibition on human CYP19A1. For the rat CYP19A1, disulfiram (IC50, 1.90 μM) displayed the strongest inhibition followed by maneb (2.16 μM), zineb (2.54 μM), and thiram (6.99 μM). These dithiocarbamates acted as mixed/non-competitive inhibitors of human and rat CYP19A1. Dithiothreitol (DTT), a reducing agent, partially rescued thiram-mediated inhibition when incubated at the same. Moreover, positive correlations were observed between log P, topological polar surface area, molecular weight, and heavy atoms and IC50 values. 3D-QSAR analysis revealed the hydrogen bond acceptor and donor play critical roles in the binding of dithiocarbamates to human CYP19A1. In silico analysis showed that dithiocarbamates bind to the haem binding site, containing Cys437 residues. In conclusion, some dithiocarbamates potently inhibit human and rat CYP19A1 via interacting with haem-binding Cys437 residues.

Examining the inhibitory potency of metal polyphenolic network–coated silver nanoparticles against amyloid fibrillogenesis of lysozyme

There are currently over forty degenerative diseases that are correlated with abnormal accumulation of peptide/protein aggregates in the human body, such as Alzheimer’s disease. Due to their unique physiochemical properties (e.g., small size, large surface-to-volume ratio, and facile surface modification), silver nanoparticles (AgNPs) have been considered potential substrates for designing inhibitors against amyloid fibrillogenesis. Metal polyphenolic network (MPN) that combines the characteristics of organic and inorganic components has been used to suppress amyloid fibril formation. This study is aimed at investigating the effects of MPN–coated AgNPs (MPN–AgNPs) on the in vitro amyloid fibrillogenesis of hen lysozyme (HEWL). The two types of MPN–AgNPs (Zn/MPN–AgNPs and Co/MPN–AgNPs) were synthesized through chemical reduction and metal chelation, and their particle sizes were determined to be in the range of 40–60 nm. The characterization of MPN–AgNPs by ζ–potential and transmission electron microscopy showed that the MPN–AgNPs had negative surface charge and spherical-shaped morphology. Furthermore, the elemental analysis demonstrated that the MPN was uniformly coated on the surface of AgNPs. The thioflavin T fluorescence results revealed that the Co/MPN–AgNPs showed a better percent of inhibition compared to Zn/MPN–AgNPs and TA–AgNPs. The kinetics data of amyloid fibril formation in the presence of MPN–AgNPs were analyzed using the sigmoidal curve, showing that the MPN–AgNPs reduced fibril growth rate and prolonged lag time. Our findings also demonstrated that MPN–AgNPs could effectively suppress HEWL aggregation upon binding to aggregation-prone regions. The quenching of intrinsic fluorescence of HEWL by MPN–AgNPs was found to be a static type. Moreover, the fluorescence quenching data were analyzed using the modified Stern-Volmer equation to determine the number of binding sites. Notably, our findings indicated that the binding between HEWL and MPN–AgNPs was mainly governed by hydrophobic interaction. This work offers an excellent example of utilizing MPN–based materials as anti-aggregating/anti-fibrillogenic nano-drugs for the treatment of amyloidosis.

Quinoline-Piperazine Derivatives as Potential α-Glucosidase Inhibitors: Synthesis, Biological Evaluation, and In Silico Studies

α-Glucosidase inhibitors are crucial therapeutic agents for managing postprandial hyperglycemia in type 2 diabetes mellitus (T2DM). This study focuses on designing, synthesizing, and evaluating a new series of quinoline-piperazine-acetamide derivatives as potential α-glucosidase inhibitors. These derivatives introduce a unique combination of a quinoline core with a flexible piperazine linker, as new scaffold for α-glucosidase inhibition. This structural modification is hypothesized to enhance enzyme interaction. The synthesized derivatives were tested in vitro for their inhibitory activity, with compounds 6m (benzyl) and 6f (2-nitrophenyl) showing significant inhibition, having IC50 values of 280.0 µM and 546.2 µM, respectively, compared to the standard drug acarbose (IC50 = 750.7 µM). Molecular docking studies revealed crucial pi-pi stacking and pi-cation interactions with key residues such as His239 and Phe231, along with hydrogen bonding with Lys155, Pro309, and Thr215, which enhanced the inhibitory potency of the active compounds. Furthermore, molecular dynamics simulations confirmed that 6m consistently maintained stability within the active site of α-glucosidase throughout the simulation. These findings suggest that the synthesized compounds hold promise as α-glucosidase inhibitors for adjusting blood sugar control and metabolic health.

Study on the effects of endogenous polyphenols on the structure, physicochemical properties and in vitro digestive characteristics of Euryales Semen starch based on multi-spectroscopies, enzyme kinetics, molecular docking and molecular dynamics simulation

Euryales Semen (ES) is a highly nutritious food with low digestibility, which is closely associated with its endogenous phenolic compounds. In this study, five phenolic compounds (naringenin, isoquercitrin, gallic acid, epicatechin and quercetin) with high concentrations in ES were selected to prepare starch-polyphenol complexes. Subsequently, the effects of endogenous polyphenols on the structure, physicochemical properties and digestion characteristics of ES starch were studied using multiple techniques. The addition of phenolic compounds markedly reduced the in vitro digestibility, swelling power, gelatinization enthalpy, while increased the solubility of ES starch. Fourier-transform infrared spectroscopy and X-ray diffraction analysis showed that phenolic compounds interacted with the starch through non-covalent bonds. Five phenolic compounds inhibited α-amylase activity through a mixed competitive inhibition mechanism, with the inhibition potency ranked as follows: quercetin > epicatechin > gallic acid > isoquercitrin > naringenin. The spectroscopic analysis and molecular dynamics simulations confirmed that five phenolic compounds interacted with the amino acid residues of α-amylase through hydrogen bonding and hydrophobic interactions, caused α-amylase static fluorescence quenching, and altered its conformation and microenvironment. This study provides a better understanding of the interaction mechanisms between ES starch and polyphenols, and supports the development of ES as a food that lowers sugar levels.

Targeting c-Met in Cancer Therapy: Unravelling Structure-Activity Relationships and Docking Insights for Enhanced Anticancer Drug Design.

The c-Met receptor, a pivotal player in oncogenesis and tumor progression, has become a compelling target for anticancer drug development. This review explores the intricate landscape of Structure-Activity Relationship [SAR] studies and molecular binding analyses performed on c-Met inhibitors. Through a comprehensive examination of various chemical scaffolds and modifications, SAR investigations have elucidated critical molecular features essential for the potent inhibition of c-Met activity. Additionally, molecular docking studies have provided invaluable insights into how c-Met inhibitors interact with their target receptor, facilitating the rational design of novel compounds with enhanced efficacy and selectivity. This review highlights key findings from recent SAR and docking studies, particularly focusing on the structural determinants that govern inhibition potency and selectivity. Furthermore, the integration of computational methodologies with experimental approaches has accelerated the discovery and optimization of c-Met inhibitors, fostering the advancement of promising candidates for clinical applications. Overall, this review underscores the pivotal role of SAR and molecular docking studies in advancing our understanding of c-Met inhibition and guiding the rational design of next-generation anticancer agents targeting this pathway.

Discovery and evaluation of HW161023 as a potent and orally active AAK1 inhibitor

AAK1, also known as AP2-associated protein kinase 1, is an enzyme that belongs to the family of serine/threonine protein kinases. It regulates the assembly and disassembly of clathrin-coated pits and thereby protein endocytosis, by phosphorylating the μ2 subunit of the AP2 complex, which is a key component of clathrin-coated vesicles. LX9211 is currently the only selective small molecule AAK1 inhibitor at the clinical trial stage for diabetic peripheral neuropathic pain, which was found to be safe and well tolerated in healthy participants in phase I clinical trials. The present manuscript described a series of fused-ring derivatives as a novel class of potent AAK1 inhibitors, resulting in the discovery of compound 5, namely HW161023, which showed high inhibitory potency against AAK1 enzyme and satisfactory oral pharmacokinetic profile with weaker HepG2 cell toxicity and hERG inhibition than LX9211.

Ameliorative Potency of Iridoid Glucoside Compound Catalpol on Inhibiting NF-κB-mediated Inflammation in Allergic Rhinitis-induced Mice

Background Over time, the prevalence of allergic rhinitis (AR) has surged due to various risk factors, notably attributed to global urbanization, rendering heightened levels of pollutants, including traffic-related emissions and particulate matter. About 25% of the global children population and 40% of the adult population were reported with AR. Even though AR is recognized as a systemic inflammatory disease, it often results in diverse other comorbidities, such as dermatitis, sinusitis, conjunctivitis, and otitis, requiring extensive and expensive treatment. Purpose We assessed the effectiveness of iridoid glucoside catalpol against AR in a mouse model. Catalpol is recommended in traditional Chinese medicine to treat diverse acute and chronic diseases. Methods AR was induced in mice with an ovalbumin-sensitized AR model and treated with 10 and 20 mg of catalpol. Nasal severity scoring was performed to confirm the AR induction in mice. Allergic mediators immunoglobulin E (IgE) and histamine were quantified in the serum to assess the anti-allergic response of catalpol. In nasal lavage fluid (NALF), the inflammatory mediators IgE Ab, prostaglandin D2, leukotriene C4, eosinophil cationic protein (ECP), and pro-inflammatory cytokines were measured to analyze the anti-inflammatory potency of catalpol. The binding capacity of nuclear factor-kappa B (NF-κB) to DNA was evaluated to assess the catalpol inhibitory potency against NF-κB-mediated inflammation in AR mice. To confirm the ameliorative potency of catalpol in AR mice, a histopathological analysis of nasal mucosa was performed. Results Catalpol treatment significantly decreased the nasal symptoms and reduced the allergic mediators in the serum of experimental animals. It effectively inhibited the synthesis of inflammatory mediators, ECP, and pro-inflammatory cytokines in the NALF, and also suppressed the NF-κB DNA-binding activity in AR mice. The decrease in ciliary loss, goblet cells, eosinophil infiltration, and vascular congestion observed with our nasal mucosa histopathological analysis confirmed the ameliorative potency of catalpol. Conclusion Our findings have proven catalpol inhibits NF-κB-mediated inflammatory response in AR mice. With further analysis, a potent natural compound, catalpol, can be formulated as a drug to treat AR.

The effect of cancer-associated mutations on ligand binding and receptor function – A case for the 5-HT2C receptor

The serotonin 5-HT2C receptor is a G protein-coupled receptor (GPCR) mainly expressed in the central nervous system. Besides regulating mood, appetite, and reproductive behavior, it has been identified as a potential target for cancer treatment. In this study, we aimed to investigate the effects of cancer patient-derived 5-HT2C receptor mutations on ligand binding and receptor functionality. By filtering the sequencing data from the Genomic Data Commons data portal (GDC), we selected 12 mutations from multiple cancer types. We found that the affinity of the endogenous agonist serotonin (5-HT) and inverse agonist mesulergine were both drastically decreased by mutations L209HECL2 and F328S6.52, which are located in the orthosteric binding pocket. In the calcium-flux assay, the potency of 5-HT was decreased at F328S6.52, while a trend of increased efficacy was observed. In contrast, 5-HT displayed higher affinity at E306K6.30 and E306A6.30, while a trend of decreased efficacy was observed. These two mutations may disrupt the conserved ionic interaction between E6.30 and R3.50, and thus increase the constitutive activity of the receptor. The inhibitory potency of mesulergine was increased at E306A6.30 but not E306K6.30. Lastly, P365H7.50 decreased the expression level of the receptor by more than ten-fold, which prevented further functional analyses. This study shows that cancer-associated mutations of 5-HT2C receptor have diverse effects on ligand binding and function. Such mutations may affect serotonin-mediated signaling in tumor cells as well as treatment strategies targeting this receptor.

Sulcardine, an investigational multichannel blocker for atrial fibrillation with uniquely intense JTp inhibition to enhance safety

Abstract Background Sulcardine is a multi-ion channel blocker for treating atrial fibrillation (AF) with similar inhibitory potency on peak/late sodium, L-type calcium, and rapidly activating delayed-rectifier potassium (IKr) currents. The therapeutic effect of inhibiting IKr includes QT prolongation (accompanied by a proportional J to T peak [JTp] interval prolongation), which, when excessive, may cause malignant arrhythmias. As previously reported, sulcardine strongly mitigates the JTp increase that may contribute to excessive QT prolongation by inhibiting late sodium and L-type calcium currents, an intrinsic mechanism to protect from excessive IKr block. Purpose We explored the JTp mechanism, pharmacokinetics (PK), electrocardiogram (ECG) changes, safety, and drug-drug interaction (DDI) of a single sulcardine (as HBI-3000) intravenous (IV) infusion in healthy subjects. Methods An open-label Phase 1 study evaluated the PK interaction between sulcardine, dosed as a 350 mg 30-minute infusion of the sulfate salt HBI-3000, and a cytochrome P450 CYP2D6 enzyme inhibitor (paroxetine). Triplicate ECGs were extracted from continuous 12-lead Holter ECG recordings at baseline and 10 time points thereafter. Mean baseline-subtracted and heart rate-corrected QTcF (dQTcF), JTpc (dJTpc), and other ECG changes were calculated at each time point. Left ventricular ejection fraction (LVEF) was assessed at baseline, 30-, and 120-minutes post-infusion start by transthoracic echocardiography (TTE). Results 39 subjects received HBI-3000, 33 in the paired PK population. Expected ECG parameter changes proportional to sulcardine plasma concentrations were observed in the HBI-3000-alone portion of the study, including modest QTcF prolongation (Fig 1, blue slope, confidence band) and JTpc inhibition (Fig 1, red). The usual JTpc increase associated with IKr blockers, even those with mitigating channel block (such as the late sodium current), was not only reduced but actually reversed. We calculated the dQTcF change that would have been observed in the absence of JTpc reduction by sulcardine (Fig 1, green). Sulcardine reduced the QTcF increase that might have occurred by about 21 msec at the highest concentrations, and this mitigating effect was observed at all concentrations. No clinically significant safety findings or arrhythmias were observed. The most frequent TEAEs were nausea and headache (n=2 each [5.1%]). No LVEF changes were clinically significant. Sulcardine had minimal metabolic interactions. Conclusion Acute IV HBI-3000 administration resulted in no clinically significant safety findings, LVEF depression, or DDI with CYP2D6. Sulcardine facilitates QT prolongation, which has a therapeutic benefit in terminating AF, with simultaneous uncoupling and reversing of the JTpc interval increase, a potential mechanism for reducing proarrhythmic risk due to excessive QT prolongation.Figure 1.ECG Intervals vs Sulcardine Conc

Bioactivity-Guided Isolation of Secondary Metabolites from Camellia fascicularis: Antioxidative Antibacterial Activities and Anti-Inflammatory Hypoglycemic Molecular Docking

Camellia fascicularis is a valuable ornamental, edible, and medicinal plant with promising prospects for bioactivity development. We screened the bioactivity of eight fractions (Fr. A−I) obtained from the ethyl acetate phase of C. fascicularis via silica gel column chromatography. The results indicated that the anti-inflammatory, antioxidative, and antimicrobial active components were mainly found in Fr. B*, E, A, and H; Fr. A–G; and Fr. D–I, respectively. Bioactivity-guided isolation identified 18 secondary metabolites. Compounds 1, 3–5, 7, and 15–18 were isolated from the genus Camellia for the first time in this study, whereas the other compounds were also isolated from this plant for the first time. The structures of these compounds were elucidated through comprehensive spectroscopic techniques. Compounds 1, 9−11, 28, 30, and 31 demonstrated antioxidative activities comparable to those of ascorbic acid, whereas the remaining compounds exhibited diminished antioxidative activity. In terms of antimicrobial activity, compounds 7, 18, 22, and 27 exerted inhibitory potency against Pseudomonas aeruginosa, similar to tetracycline (MIC: 125 µg/mL). Other compounds showed moderate to weak inhibitory effects against Staphylococcus aureus and Escherichia coli (MIC: 250–500 µg/mL). Molecular docking revealed that compounds 2, 36, 41, and 65 showed strong binding affinity for 8ET0, whereas compounds 2, 36, 38, 40, 63, and 65 showed strong binding affinity for 3A4A. This research further increased the diversity of the secondary metabolites of C. fascicularis, laying a foundation for the subsequent development and utilization of this species.

Molecular docking, DFT and antiproliferative properties of 4-(3,4-dimethoxyphenyl)-3-(4-methoxyphenyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine as potent anticancer agent with CDK2 and PIM1 inhibition potency.

Due to the limited effeteness and safety concerns associated with current cancer treatments, there is a pressing need to develop novel therapeutic agents. 4-(3,4-Dimethoxyphenyl)-3-(4-methoxyphenyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine (3) was synthesized and Initially screened on 59 cancer cell lines showed promising anticancer activity, so, it was chosen for a 5-dose experiment by the NCI/USA. The GI50 values ranged from 1.04 to 8.02 μM on the entire nine panels (57 cell lines), with a GI50 of 2.70 μM for (MG-MID) panel, indicating an encouraging action. To further explore the molecular attributes of compound 3, we optimized its structure using DFT with the B3LYP/6-31 + + G(d,p) basis set. We have considered vibrational analysis, bond lengths and angles, FMOs, and MEP for the structure. Additionally, pharmacokinetic assessments were conducted using various in-silico platforms to evaluate the compound safety. A molecular modeling study created a kinase profile on 44 different kinases. This allowed us to study our compound's binding affinity to these kinases and compare it to the co-crystallized one. Our findings revealed compound 3 exhibited better binding for half of the tested kinases, suggesting its potential as a multi-kinase inhibitor. To further validate our computational results, we tested compound 3 for its inhibitory effects on CDK2 and PIM1. Compound 3 exhibited an IC50 of 0.30 µM for CDK2 inhibition, making it five times less active than Roscovitine, which has an IC50 of 0.06 µM. However, compound 3 demonstrated slightly better inhibition of PIM1 compared to Staurosporine. These findings suggest that compound 3 is a promising anticancer agent with the potential for further development into a highly active compound.

Ajuga orientalis L. Extract as a Green Corrosion Inhibitor of Aluminum in an Acidic Solution: An Experimental and DFT Study

The inhibitory effect of A. orientalis L. extract (AO) on aluminum corrosion in a 1.0 M HCl solution was investigated utilizing weight loss, electrochemical polarization, electrochemical impedance spectroscopy (EIS), and scanning electron microscopy (SEM). The results show that AO is a potent inhibitor in an acidic environment, and that the inhibition potency increases with concentration. Temperature investigations showed that, in an acidic medium, the efficiency decreased, increased, and then decreased as the temperature rose. Adsorption isotherms from Freundlich, Temkin, El Awady, and Redlich–Peterson (R-P) approximated the inhibitor’s adsorption properties. For the inhibitory behavior, a physical and chemical adsorption mechanism is proposed. The adsorption process’s thermodynamic parameters (Ea, ΔH*, and ΔS*) were determined and explained. The inhibitor, AO, was identified as a mixed-type (anodic and cathodic) inhibitor based on polarization studies. According to the SEM findings, the inhibitor partially covers the metal surface, providing it with a respectable level of protection. The weight loss, electrochemical polarization, EIS, scanning electron microscopy (SEM), and quantum chemical calculations show a strong agreement, indicating that the AO extract is a highly effective inhibitor of aluminum in an acidic solution.

Synthesis and Structure of Novel Hybrid Compounds Containing Phthalazin-1(2H)-imine and 4,5-Dihydro-1H-imidazole Cores and Their Sulfonyl Derivatives with Potential Biological Activities

A novel hybrid compound—2-(4,5-dihydro-1H-imidazol-2-yl)phthalazin-1(2H)-imine (5) was synthesized and converted into di-substituted sulfonamide derivatives 6a–o and phthalazine ring opening products—hydrazonomethylbenzonitriles 7a–m. The newly prepared compounds were characterized using elemental analyses, IR and NMR spectroscopy, as well as mass spectrometry. Single crystal X-ray diffraction data were collected for the representative compounds 5, 6c, 6e, 7g, and 7k. The antiproliferative activity of compound 5, sulfonyl derivatives 6a–o and benzonitriles 7a–m was evaluated on approximately sixty cell lines within nine tumor-type subpanels, including leukemia, lung, colon, CNS, melanoma, ovarian, renal, prostate, and breast. None of the tested compounds showed any activity against the cancer cell lines used. The antioxidant properties of all compounds were assessed using the DPPH, ABTS, and FRAP radical scavenging methods, as well as the β-carotene bleaching test. Antiradical tests revealed that among the investigated compounds, a moderate ABTS antiradical effect was observed for sulfonamide 6j (IC50 = 52.77 µg/mL). Benzonitrile 7i bearing two chlorine atoms on a phenyl ring system showed activity in a β-carotene bleaching test (IC50 = 86.21 µg/mL). Finally, the interaction AGE/RAGE in the presence of the selected phthalazinimines 6a, 6b, 6g, 6m, and hydrazonomethylbenzonitriles 7a, 7c–g, and 7i–k was determined by ELISA assay. A moderate inhibitory potency toward RAGE was found for hydrazonomethylbenzonitriles—7d with an electron-donating methoxy group (R = 3-CH3O-C6H4) and 7f, 7k with an electron-withdrawing substituent (7f, R = 2-Cl-C6H4; 7k, R = 4-NO2-C6H4).

Synthesis and Evaluation of Phenyltriazole-Deoxynojirimycin Hybrids as Potent α-Glucosidase Inhibitors

1-deoxynojirimycin (DNJ) is a well-known α-glucosidase inhibitor. A series of phenyltriazole-deoxynojirimycin hybrids containing C4 and C6 (4 and 6 methylenes, respectively) linkers were synthesized. These novel compounds were assessed for preliminary glucosidase inhibition and cytotoxicity tests in vitro. Among them, compounds 12–14 and 16–20 (IC50: 105 ± 9–11 ± 1 μM) were more active than deoxynojirimycin (DNJ, IC50 = 155 ± 15 μM). The kinetics of enzyme inhibition measured by using Lineweaver–Burk plots indicated that compounds 18 and 19 were competitive inhibitors. In addition, a molecular docking study of α-glucosidase revealed that the interaction modes and the orientations of compound 18 and DNJ were clearly different. Furthermore, in tissue culture, HL60 cell compounds showed no cytotoxicity at low concentrations. When the concentration reached 50 µM, only compound 20 exhibited cytotoxicity. The structure–activity relationships exhibit that the length of the linker and the nature of 4-position substituents on the phenyl have a significant effect on the inhibitory potency of glucosidases and cytotoxicity.