Promising Activity Research Articles

Promising anti-proliferative indolic benzenesulfonamides alter mechanisms with sulfonamide nitrogen substituents

Agents that cause apoptotic cell death by interfering with tubulin dynamics, such as vinblastine and paclitaxel, are an important class of chemotherapeutics. Unfortunately, these compounds are substrates for multidrug resistance (MDR) pumps, allowing cancer cells to gain resistance to these chemotherapeutics. The indolesulfonamide family of tubulin inhibitors are not excluded by MDR pumps and have a promising activity profile, although their high lipophilicity is a pharmacokinetic limitation for their clinical use. Here we present a new family of N-indolyl-3,4,5-trimethoxybenzenesulfonamide derivatives with modifications on the indole system at positions 1 and 3 and on the sulfonamide nitrogen. We synthesized and screened against HeLa cells 34 novel indolic benzenesulfonamides. The most potent derivatives (1.7–109 nM) were tested against a broad panel of cancer cell lines, which revealed that substituted benzenesulfonamides analogs had highest potency. Importantly, these compounds were only moderately toxic to non-tumorigenic cells, suggesting the presence of a therapeutic index. Consistent with known clinical anti-tubulin agents, these compounds arrested the cell cycle at G2/M phase. Mechanistically, they induced apoptosis via caspase 3/7 activation, which occurred during M arrest. The substituents on the sulfonamide nitrogen appeared to determine different mechanistic results and cell fates. These results suggest that the compounds act differently depending on the bridge substituents, thus making them very interesting as mechanistic probes as well as potential drugs for further development.

Lipopolysaccharide-binding protein in Crohn's disease patients: a promising noninvasive biomarker monitoring disease activity.

Following STRIDE-II recommendations, the discovery of novel noninvasive biomarkers, beyond the use of C-reactive protein (CRP) and fecal calprotectin, remains a medical need to further improve the monitoring of patients with inflammatory bowel disease (IBD). This study aims to evaluate the potential of serum lipopolysaccharide-binding protein (LBP) in monitoring IBD activity. This retrospective cross-sectional study included 69 IBD patients (43 Crohn's disease and 26 ulcerative colitis) and 82 controls. Serum LBP levels were measured by ELISA. Clinical, biological and endoscopic parameters were analyzed for IBD patients with no reports of missing data. Statistical tests, including nonparametric tests and receiver operating characteristic (ROC) curve analysis, were used to evaluate the diagnostic accuracy of LBP. IBD patients displayed a significantly higher LBP median [29.6 μg/ml (19.8-38.8) in Crohn's disease and 22.8 (13.7-38.8) in ulcerative colitis] than controls [5.8 (4.7-7.3), P < 0.001] with little overlapping distributions. In Crohn's disease patients, LBP levels gradually increased with endoscopic activity scores demonstrating a 1.7-fold rise in active patients compared to remitter patients (P = 0.02). LBP level exhibited a positive correlation with CRP (ρ = 0.75, P < 0.001) as well as fecal calprotectin (ρ = 0.42, P < 0.01), both of which further increased when excluding cases that did not match endoscopic activity. LBP might be a promising noninvasive biomarker for monitoring disease activity, especially in Crohn's disease patients. In clinical situations where current biomarkers lack sensitivity, LBP could be discriminative and help filling the gap for reliable therapeutic decisions.

Design, synthesis, and evaluation of 1,4-benzothiazine-3-one containing bisamide derivatives as dual inhibitors of Staphylococcus aureus with plausible application in a urinary catheter.

In this study, 1,4-benzothiazine-based bisamide derivatives, a new class of antibacterial agents targeting bacterial peptide deformylase (PDF), were designed and synthesized to combat Staphylococcus aureus infection. Molecular modeling of the designed molecules showed better docking scores compared to the natural product actinonin. Bioactivity assessment identified two derivatives with promising antibacterial activity in vitro. The stability of the most active molecule, 8bE, was assessed using molecular dynamics (MD) simulation. Significantly, compound 8bE could also inhibit the S. aureus biofilm at low concentrations. Furthermore, the capability of the synthesized molecule to inhibit S. aureus biofilm formation on medical devices like urinary catheters is also demonstrated.

Insecticidal Activity of Allium sativum Essential Oil-Based Nanoemulsion against Spodoptera littoralis

Spodoptera littoralis, commonly known as the Egyptian or African cotton leafworm, is a significant agricultural threat. It is widely distributed in Africa, Mediterranean Europe, and Middle Eastern countries. This polyphagous pest infests numerous crop plants across 44 families, including cotton, soybeans, alfalfa, sweet potato, pepper, eggplant, tomato, maize, lettuce, strawberry, wheat, and hibiscus. The damage caused by S. littoralis on different plant organs, such as young leaves, shoots, stalks, bolls, buds, and fruits, often determines substantial product losses. Current control strategies predominantly rely on synthetic insecticides, which, despite their efficacy, have notable drawbacks, including insecticide resistance, environmental contamination, consumer concerns, and adverse effects on non-target organisms and beneficial insects. In response to these challenges, in this study, we developed and evaluated a garlic EO-based nanoemulsion with a high EO concentration (15%) and low surfactant content to mitigate the possible negative impact on plants and to enhance efficacy against S. littoralis larvae. Laboratory bioassays demonstrated promising larvicidal activity and reduced larval feeding, although some phytotoxicity symptoms were observed. This study underscores the potential of botanical insecticides as sustainable alternatives to synthetic chemicals, emphasizing the importance of balancing efficacy with environmental and ecological considerations in pest management strategies.

FDA Approved Niraparib-based Virtual Screening and Molecular Docking Studies to Discover Novel 6NRF Protein Modulator for Ovarian Cancer

The abstract summarizes the findings of a comprehensive analysis of chemical compounds, focusing on their potential therapeutic relevance in ovarian cancer treatment. Utilizing data from the ChEMBL database, pharmacophore-based screening identified compounds with promising activity against ovarian cancer, with notable catching scores ranging from 0.556 to 1.000. Crystallographic refinement metrics highlighted improvements in structural accuracy and quality following PDB-REDO refinement, with reductions in R and R-free values and significant enhancements in bond length RMS Z-scores. Molecular docking studies revealed predicted binding affinities ranging from -9.6 to -8.4, indicating strong interactions with target proteins. ADME analysis of niraparib, a lead compound, demonstrated favorable physicochemical properties and pharmacokinetic profiles, with Lipinski, Ghose, Veber, and Egan’s rules for drug-likeness and bioavailability met. Toxicity prediction models identified potential organ toxicity endpoints, with neurotoxicity, respiratory toxicity, and immunotoxicity showing active involvement. These findings underscore the complexity of structure-activity relationships and the importance of predictive models in guiding drug discovery efforts and ensuring safety profiles. Overall, this study provides valuable insights into the landscape of PARP inhibitors and their potential in advancing personalized medicine approaches for ovarian cancer therapy.

Hydrogen-Bonding-Regulated Morphology Control and the Impact on the Antibacterial Activity of Cationic π-Amphiphiles.

This manuscript describes the synthesis, self-assembly, and antibacterial properties of naphthalene-diimide (NDI)-derived cationic π-amphiphiles. Three such asymmetric NDI derivatives with a nonionic hydrophilic wedge and a guanidine group in the two opposite sides of the NDI chromophore were considered. They differ by a single functional group (hydrazide, amide, and ester for NDI-1, NDI-2, and NDI-3, respectively), located in the linker between the NDI and the hydrophilic wedge. For NDI-1, the H-bonding among the hydrazides regulated unilateral stacking and a preferential direction of curvature of the resulting supramolecular polymer, producing an unsymmetric polymersome with the guanidinium groups displayed at the outer surface. NDI-3, lacking any H-bonding group, exhibits π-stacking without any preferential orientation and generates spherical particles with a relatively poor display of the guanidium groups. In sharp contrast to NDI-1, NDI-2 exhibits an entangled one-dimensional (1D) fibrillar morphology, indicating the prominent role of the H-bonding motif of the amide group and flexibility of the linker. The antibacterial activity of these assemblies was probed against Staphylococcus aureus (Gram-positive) and Escherichia coli (Gram-negative). NDI-1 showed the most promising antibacterial activity with a minimum inhibitory concentration (MIC) of ∼7.8 μg/mL against S. aureus and moderate activity (MIC ∼ 125 μg/mL) against E. coli. In sharp contrast, NDI-3 did not show any significant activity against the bacteria, suggesting a strong impact of the H-bonding-regulated directional assembly. NDI-2, forming a fibrillar network, showed moderate activity against S. aureus and negligible activity against E. coli, highlighting a significant impact of the morphology. All of these three molecules were found to be compatible with mammalian cells from the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl-tetrazolium bromide (MTT) and hemolysis assay. The mechanistic investigation by membrane polarization assay, live/dead fluorescence assay, and microscopy studies confirmed the membrane disruption mechanism of cell killing for the lead candidate NDI-1.

Exploring the Therapeutic Potential of Lepidagathis pungens Nees Extracts as Novel Therapy Options in Streptozotocin and Nicotinamide-Induced Diabetes in Albino Wistar Rats

Diabetes mellitus remains a global health concern, necessitating innovative therapeutic approaches. This study explores the antidiabetic potential of aqueous and methanol extracts from Lepidagathis pungens Nees in albino Wistar rats induced with diabetes. Diabetes induction involves the administration of streptozotocin (STZ) and nicotinamide (NIC), mimicking pathological conditions observed in human diabetes. The study employed aqueous and methanol extracts of L. pungens Nees alongside a standard drug, glibenclamide. Diabetes induction was achieved through intraperitoneal injection of STZ and NIC. Extracts and the standard drug were orally administered, and various parameters, including blood glucose levels, body weight changes, insulin and hemoglobin levels, as well as liver and lipid profiles, were monitored at specified intervals. Furthermore, liver and pancreas tissues were evaluated histopathologically. In comparison to the diabetic group, both aqueous and methanol extracts demonstrated significant antidiabetic activity (p &lt;0.001), with effects comparable to or better than the standard drug. A remarkable improvement in insulin and hemoglobin levels was observed, along with significant improvements in blood glucose levels and body weight changes. Furthermore, the extracts demonstrated positive effects on liver and lipid profiles, exhibiting potential to mitigate diabetes-induced complications. Histopathological studies revealed protective effects on liver and pancreas tissues, supporting the extracts’ therapeutic efficacy. In STZ- and NIC-induced diabetic rats, L. pungens Nees extracts show promising antidiabetic activity. The extracts demonstrated significant improvements in various physiological parameters, suggesting their potential as alternative or adjunctive therapies in the management of diabetes. Further research and clinical investigations are warranted to elucidate the underlying mechanisms and translate these findings into practical therapeutic applications.

Antimicrobial, Cytotoxic and Phytochemical Analysis of Chloroform Extracts of Andrographis paniculata Root (Burm.F) and Parquetina nigrescens (Afzel) Aerial Part

The menace of antibiotic resistance especially multi-drug resistant bacteria is increasing in the clinical setting. Therefore, the study investigated antimicrobial activity and phytochemical constituents of chloroform extracts of Andrographis paniculata root (Burm.F.) and Parquetina nigrescens (Afzel) aerial part. The extracts were screened for cytotoxic activity using brine shrimp (Artemia salina) lethality bioassay. The antimicrobial activity of the extracts was tested against Citrobacter diversus, Klebsiella pneumoniae, Proteus vulgaris and Shigella sonnei using tetrazolium microtitre-plate method. Analysis of chemical components of the extracts was done on Agilent Technologies 7890A gas chromatograph system s. GC-MS analysis of A. paniculata root extract and P. nigrescens aerial part extracts revealed a total of 32 and 22 compounds, respectively. The major components identified in these two extracts were fatty acid esters, alkaloids and terpenes. The lowest MIC observed with A. paniculata extract was 6.25 μg/ml for Citrobacter diversus and 12.5 μg/ml for Klebsiella pneumoniae. The lowest MIC recorded for Parquetina nigrescens extract was 3.125 μg/ml for Citrobacter diversus, Shigella sonnei and Proteus vulgaris while it was 12.5 μg/ml for Klebsiella pneumoniae. The susceptibility was compared with a clinical antibiotic (0.02 μg/ml) which served as the positive control. P. nigrescens with LC50 of 89.75 ± 0.18 μg/ml showed higher lethal toxicity than A. paniculata with LC50 of 167.5 ± 0.21 μg/ml. The observed toxicity might be due to presence of fatty acids and alkaloids in the extracts. The extract of the plants investigated in our study showed promising antimicrobial activity. Dhaka Univ. J. Pharm. Sci. 23(1): 43-51, 2024 (June)

Anti-Inflammatory and Antioxidant Properties of the Mucuna sanjappae Seeds in the Rat Model and In Vitro Assays

The Fabaceae (Leguminosae) plant family contains several species of the Mucuna Adans. genus possessing therapeutic potential and growing widely in tropical and sub-tropical regions. In this research, we investigated the anti-inflammatory and antioxidant properties of the extract from the Mucuna sanjappae Aitawade &amp; S.R.Yadav seeds. Initially, we conducted an in vitro anti-inflammatory activity test using the bovine serum albumin anti-denaturation assay and found promising dose-dependent activity. Subsequently, we performed an in vivo anti-inflammatory and antioxidant study on a rat paw edema model induced by carrageenan. Three different doses of M. sanjappae seed water extract (50, 100 and 200mg/kg B/W) were used for the study (Oral administration). Edema measurement was carried out at 0, 2, 4 and 6 hr intervals. Dose dependent inhibition in edema in the M. sanjappae seed extract treatment group was observed with maximum activity for 200mg/kg B/W dose at 4 hr (53.49%). Standard drug showed maximum edema inhibition (54.94%) at 6hr. Our results also showed that, M. sanjappae seed extract inhibited pro-inflammatory cytokine TNF-α and increases anti-inflammatory cytokine IL-10 with increased level of blood serum antioxidants. Phytochemical analysis for secondary metabolites including polyphenol, flavonoids, phytic acid, proanthocyanidin, tannin and saponin was also quantified which might be the responsible component for biological activities under study.

A phase 2 study of spartalizumab (PDR001) among patients with recurrent or metastatic esophageal squamous cell carcinoma (KCSG HN18-17, K-MASTER project 12)

ABSTRACT Spartalizumab (PDR001) is a humanized IgG4 monoclonal antibody targeting programmed cell death protein 1 (PD-1). We conducted a single-arm, phase 2 trial to investigate the efficacy and safety of spartalizumab in patients with refractory esophageal squamous cell carcinoma (ESCC). Patients with histologically confirmed ESCC who experienced disease progression after platinum-based chemotherapy received 300 mg of intravenous spartalizumab every three weeks until disease progression or occurrence of unacceptable toxicity. The primary endpoint was centrally assessed objective response according to the Response Evaluation Criteria in Solid Tumors, version 1.1. Adverse events were closely monitored throughout the study. From March 2020 through April 2021, 44 patients with ESCC were enrolled. Of the 44 patients, the objective response rate was 20.5% (95% confidence interval: 8.5–32.4). With a median follow-up of 10.9 months, median progression-free survival and overall survival were 3.2 months and 11.2 months, respectively. In addition, the median duration of response was 24.7 months. The most common grade 3 or 4 adverse event was grade 3 dysphagia (eight [18%] patients). Biomarker analyses explored programmed cell death ligand 1 and CD20 as potential predictive markers for PD-1 blockade. Spartalizumab showed promising activity with a manageable safety profile, indicating its potential as a new treatment option for patients with refractory ESCC. Trial registration The trial was registered at ClinicalTrials.gov under the identifier NCT03785496.

Fabrication, structural elucidation, and DFT calculation of some new hydrophilic metal chelates based on N N′‐(1‐methyl‐2‐oxoindolin‐3‐ylidene)benzohydrazide ligand: Pharmaceutical studies and molecular docking approach

Some novel FeIII, CuII, and PdII chelates incorporating N′‐(1‐methyl‐2‐oxoindolin‐3‐ylidene)benzohydrazide (MIBA) were fabricated. The tested compounds were investigated using thermogravimetric analysis (TGA), CHN, spectra analysis (IR, mass spectra, and NMR), melting point, magnetic moments, molar conductance, ultraviolet–visible spectroscopy, powder X‐ray diffraction, and computational studies. The conductance results showed that the tested FeIII, CuII, and PdII chelates are electrolytes. Magnetic and electronic spectra are applied to deduce the coordinating ability of the tested ligand, and the geometric structure of the studied chelates is found to be octahedral, distorted octahedral, and square planar for FeIII, CuII, and PdII chelates, respectively. The TGA study of these studied complexes displays that the hydrated H2O molecules, acetate, and nitrate are removed in the first and second degradation steps followed directly by degradation of the studied ligand leaving metal oxide as residue. The thermodynamic factors, like ΔS*, ΔH*, E*, A, and ΔG* are evaluated from the TGA curves and explained. The density functional theory (DFT)/B3LYP computation method was applied for the estimation of the molecular electrostatic potential (MEP; highest occupied molecular orbital [HOMO] and lowest unoccupied molecular orbital [LUMO]) energy for the studied compounds. In an in vitro study, the antimicrobial effects of the prepared compounds were screened on various strains of bacteria and fungi. It was found that tested compounds exposed a good biological efficacy through IC50 results close to reference drugs and antitumor potential against (MCF‐7, Hep‐G2, and HC‐T116) cell lines. The data obtained displayed that the studied chelates showed promising antitumor activity. The studied metal chelates were screened for in vitro antioxidant efficacy using DPPH assay. The studied compounds explained dynamic satisfying performance. Also, the crystal structures of breast cancer protein (PDB ID: 3HB5) and Escherichia coli (PDB ID: 2VF5) were performed by molecular docking simulation. Data of docking simulation suggestions are which tested compounds have biological behavior as well as have obvious benefit in the pharmaceutical business.

A Structure-Activity Investigation of the Fungal Metabolite (-)-TAN-2483B: Inhibition of Bruton's Tyrosine Kinase.

The natural product (-)-TAN-2483B is a fungal secondary metabolite which displays promising anti-cancer and immunomodulatory activity. Our previous syntheses of (-)-TAN-2483B and sidechain analogues uncovered inhibitory activity against Bruton's tyrosine kinase (Btk), an established drug target for various leukaemia and immunological diseases. A structure-based computational study using ensemble docking and molecular dynamics was performed to determine plausible binding modes for (-)-TAN-2483B and analogues in the Btk binding site. These hypotheses guided the design of new analogues which were synthesised and their inhibitory activities determined, providing insights into the structural determinants of the furopyranone scaffold that confer both activity and selectivity for Btk. These findings offer new perspectives for generating optimised (-)-TAN-2483B-based kinase inhibitors for the treatment of leukaemia and immunological diseases.

ETMR-18. ADVANCING ETMR RESEARCH: NOVELIN VITRO ANDIN VIVO PRECLINICAL MODELS FOR DEVELOPING MORE EFFECTIVE TREATMENTS

Abstract BACKGROUND Embryonal Tumor with Multilayered Rosettes (ETMR) is a rare and aggressive tumor that occurs mainly in infants under three years of age. Genetically, ETMRs are characterized by amplification and fusion of a microRNA cluster on chromosome 19 (C19MC) with TTYH1, present in ~90% of the tumors. ETMR patients still have a poor prognosis without any recent advances in treatment. A major limitation to develop more effective treatment strategies is the lack of sufficient preclinical models. METHODS Establishment of ETMR patient-derived xenograft (PDX) models and tumoroid lines, molecular characterization, high throughput in vitro drug screens, targeted drug treatments in vitro and in vivo. RESULTS We have established four new tumoroid and five new PDX ETMR models. These models faithfully recapitulate ETMR patients’ tumors based on their histological, transcriptomic, and methylome signatures. The in vitro models were derived from two patients and two PDX models and included three C19MC-amplified cell lines, of which two were a primary-relapse pair, and one a primary C19MC non-amplified model. In vivo we established the same models as PDX models subcutaneously plus an additional C19MC-amplified relapse model. High-throughput drug screening assays, using drug libraries with 225 clinically approved drugs and other small molecules, were conducted across the panel of in vitro models. Potential therapeutic candidates with promising activity in ETMR tumoroid lines identified from these screens include FGFR, XPO1, MTOR, MDM2 and topoisomerase inhibitors. CONCLUSIONS The establishment of novel preclinical models represents a significant advancement in ETMR research, offering a platform that captures the molecular complexity of the disease. The identification of several inhibitors shows the potential of these models for drug discovery and preclinical testing. Ongoing in vitro and in vivo experiments with these drugs and combinations aim to further validate their activity, moving towards the development of more effective therapies for ETMR patients.

LGG-53. RESULTS FROM THE PHASE 1 AND PHASE 1 EXPANSION COHORTS OF SJ901: A PHASE 1/2 TRIAL OF SINGLE-AGENT MIRDAMETINIB (PD-0325901) IN CHILDREN, ADOLESCENTS, AND YOUNG ADULTS WITH LOW-GRADE GLIOMA

Abstract BACKGROUND Mirdametinib is an investigational, oral, selective MEK1/2 inhibitor (MEKi) with high blood-brain-barrier penetration. We hypothesized mirdametinib would benefit patients with pediatric low-grade gliomas (pLGG) and launched SJ901 (NCT04923126) to determine the recommended Phase 2 dose (RP2D), safety, and efficacy. METHODS Phase 1 required patients to be &amp;gt;2 and &amp;lt;25 years-old, MEKi-naive, and have recurrent/progressive pLGG with biopsy-proven MAPK pathway activation (except BRAF V600). Three dose levels (DL1: 2 mg/m2/dose BID, DL2: 2.5mg/m2/dose BID, DL3: 3mg/m2/dose BID administered continuously in 28-day cycles) were evaluated with an expansion cohort planned to evaluate the highest tolerated dose level in a total of 12 patients. RP2D was defined as the dose causing ≤3 dose-limiting toxicities (DLTs) in 12 patients within the first cycle of therapy. RESULTS Between June 2021 and December 2023, 23 patients enrolled (DL1=5, DL2=6, and DL3=12). Median age was 8.4 years (2.5-21.9); 52% female. Alterations were seen in BRAF (n=12;52%), FGFR1 (n=5;22%), NF1 (n=3;13%), RAF1 (n=2;9%), MYB (n=1;4%). The median time of follow-up was 14.6 months (3.2-27.8). One DLT was observed (grade-3 thrombocytopenia). Seventeen (74%) patients completed or remain on therapy; 4 (17%) stopped for progression (2 FGFR1; 1 MYB; 1 BRAF); 2 discontinued for toxicities [1 grade-2 rash; 1 grade-4 creatine phosphokinase (CPK) elevation]. Dose modifying adverse events included weight gain, CPK elevations, and rash. No significant cardiac or retinal toxicity was observed. Twelve (63%) of 19 patients with measurable tumors achieved an objective response (1 major, 6 partial, 5 minor). The median time to ≥ minor response was 5.4 months (1.7-7.3). DL3 (3 mg/m2/dose BID) was declared the RP2D. CONCLUSIONS Mirdametinib is well-tolerated and has promising clinical activity in patients with recurrent/progressive pLGG. Phase 2 is ongoing to establish safety and efficacy in newly diagnosed, recurrent/refractory tumors, and in patients with prior exposure to MEKi.

Deciphering in-situ surface reconstruction in two-dimensional CdPS3 nanosheets for efficient biomass hydrogenation

Steering on the intrinsic active site of an electrode material is essential for efficient electrochemical biomass upgrading to valuable chemicals with high selectivity. Herein, we show that an in-situ surface reconstruction of a two-dimensional layered CdPS3 nanosheet electrocatalyst, triggered by electrolyte, facilitates efficient 5-hydroxymethylfurfural (HMF) hydrogenation to 2,5-bis(hydroxymethyl)furan (BHMF) under ambient condition. The in-situ Raman spectroscopy and comprehensive post-mortem catalyst characterizations evidence the construction of a surface-bounded CdS layer on CdPS3 to form CdPS3/CdS heterostructure. This electrocatalyst demonstrates promising catalytic activity, achieving a Faradaic efficiency for BHMF reaching 91.3 ± 2.3 % and a yield of 4.96 ± 0.16 mg/h at − 0.7 V versus reversible hydrogen electrode. Density functional theory calculations reveal that the in-situ generated CdPS3/CdS interface plays a pivotal role in optimizing the adsorption of HMF* and H* intermediate, thus facilitating the HMF hydrogenation process. Furthermore, the reconstructed CdPS3/CdS heterostructure cathode, when coupled with MnCo2O4.5 anode, enables simultaneous BHMF and formate synthesis from HMF and glycerol substrates with high efficiency.

Litchi (Litchi chinensis Sonn.): A comprehensive and critical review on cancer prevention and intervention

Litchi (Litchi chinensis Sonn.) is a tropical fruit with various health benefits. The objective of this study is to present a thorough analysis of the cancer preventive and anticancer therapeutic properties of litchi constituents and phytocompounds. The Preferred Reporting Items for Systematic Reviews and Meta-Analysis criteria were followed in this work. Various litchi extracts and constituents were studied for their anticancer effects. In vitro studies showed that litchi-derived components reduced cell proliferation, induced cytotoxicity, and promoted autophagy via increased cell cycle arrest and apoptosis. Based on in vivo studies, litchi flavonoids and other extracted constituents significantly reduced tumor size, number, volume, and metastasis. Major signaling pathways impacted by litchi constituents were shown to stimulate proapoptotic, antiproliferative, and antimetastatic activities. Despite promising antineoplastic activities, additional research, especially in vivo and clinical studies, is necessary before litchi-derived products and phytochemicals can be used for human cancer prevention and intervention.

Design, synthesis, antineoplastic activity of new pyrazolo[3,4-d]pyrimidine derivatives as dual CDK2/GSK3β kinase inhibitors; molecular docking study, and ADME prediction

In the current study, novel pyrazolo[3,4-d]pyrimidine derivatives 5a–h were designed and synthesized as targeted anti-cancer agents through dual CDK2/GSK-3β inhibition. The designed compounds demonstrated moderate to potent activity on the evaluated cancer cell lines (MCF-7 and T-47D). Compounds 5c and 5 g showed the most promising cytotoxic activity against the tested cell lines surpassing that of the used reference standard; staurosporine. On the other hand, both compounds showed good safety and tolerability on normal fibroblast cell line (MCR5). The final compounds 5c and 5 g showed a promising dual CDK2/GSK-3β inhibitory activity with IC50 of 0.244 and 0.128 μM, respectively, against CDK2, and IC50 of 0.317 and 0.160 μM, respectively, against GSK-3β. Investigating the effect of compounds 5c and 5 g on CDK2 and GSK-3β downstream cascades showed that they reduced the relative cellular content of phosphorylated RB1 and β-catenin compared to that in the untreated MCF-7 cells. Moreover, compounds 5c and 5 g showed a reasonable selective inhibition against the target kinases CDK2/GSK-3β in comparison to a set of seven off-target kinases. Furthermore, the most potent compound 5 g caused cell cycle arrest at the S phase in MCF-7 cells preventing the cells’ progression to G2/M phase inducing cell apoptosis. Molecular docking studies showed that the final pyrazolo[3,4-d]pyrimidine derivatives have analogous binding modes in the target kinases interacting with the hinge region key amino acids. Molecular dynamics simulations confirmed the predicted binding mode by molecular docking. Moreover, in silico predictions indicated their favorable physicochemical and pharmacokinetic properties in addition to their promising cytotoxic activity.

Magnetic carboxymethyl gond katira-grafted-poly(3-aminobenzoic acid) as an antibacterial biosorbent for purification of acetamiprid-contaminated water

The elimination of pesticides from polluted water is critical due to their harmful environmental and biological impacts. Recently, there has been interest in utilizing natural polymer-based adsorbents as an eco-friendly approach to eliminate or reduce the levels of water pollutants. In this work, we synthesized an antimicrobial and magnetic bionanocomposite consisting of carboxymethyl gond katira-grafted- poly(3-aminobenzoic acid) with iron oxide and zinc oxide NPs (CMT-g-P3ABA/ZnO/Fe3O4) through an in situ polymerization reaction and examined for its ability to adsorb the pesticide acetamiprid (AP). The bionanocomposite was characterized using several analytical techniques, including spectroscopy; XRD presented the crystalline structure of ZnO/Fe3O4 in the CMT-g-P3ABA amorphous matrix. The ZnO/Fe3O4 partially aggregated formation and exhibited polyhedral crystal shapes was depicted by electron microscopy images, vibrating sample magnetometer (45.06 emu/g), porosimetry (5.52 m2/g), and thermal (Chair yield of approximately 43.83 %) and elemental analyses. Under various conditions, including solution pH (4–9), adsorbent dosage (0.005–0.025 g), time of contact (10–30 min), and pesticide preliminary concentration (200–400 mg/L) in 10 mL of the solution. Based on this research, Adsorption data were perfectly fitted by the Freundlich isotherm model with RAP2= 0.99038, while the pseudo-second-order (PSO) model well-explained adsorption kinetics with RAP2= 0.99847. AP adsorption to the CMT-g-P3ABA/ZnO/Fe3O4 bionanocomposite was successful due to hydrophobic interactions, hydrogen bonding, and π-π stacking. Furthermore, adsorption-desorption experiments demonstrated that the bionanocomposite could be regenerated after three reuse cycles without considerable loss of pesticide removal performance. The bionanocomposite also exhibited promising antimicrobial activity in contradiction to test bacteria.

Metabolic profiling of Vitex Pubescens Vahl bark via UPLC-ESI-QTOF/MS/MS analysis and evaluation of its antioxidant and acetylcholinesterase inhibitory activities

BackgroundAlzheimer’s disease is a neurodegenerative age-related disease that primarily affects the elderly population leading to progressive memory impairments and neural deficits. It is counted as a major cause of geriatric dependency and disability. The pathogenesis of Alzheimer’s disease incidence is complex and involves various hypotheses, including the cholinergic hypothesis, deposition of β-amyloid plaques, neuroinflammation, oxidative stress, and apoptosis. Conventional treatments such as donepezil aim to delay the symptoms but do not affect the progression of the disease and may cause serious side effects like hepatoxicity. The use of natural candidates for Alzheimer’s disease treatment has drawn the attention of many researchers as it offers a multitargeted approach.MethodsThis current study investigates the metabolic profiles of total defatted methanolic extract of Vitex pubescens bark and its polar fractions, viz. ethyl acetate and n-butanol, using ultra-performance liquid chromatography-electrospray ionization-quadrupole time-of-flight tandem mass spectrometry(UPLC-ESI-QTOF/MS/MS) technique as well as evaluate the antioxidant using free radical scavenging assays, viz. DPPH and ABTS assays and in-vitro acetylcholinesterase inhibitory activities using Ellman’s microplate assay.ResultsMetabolic profiling revealed a total of 71, 43, and 55 metabolites tentatively identified in the defatted methanolic extract, ethyl acetate, and n-butanol fractions, respectively. Phenolic acids were the most abundant class, viz. benzoic acids, and acyl quinic acid derivatives followed by flavonoids exemplified mainly by luteolin-C-glycosides and apigenin-C-glycosides. Quantification of the total phenolic and flavonoid contents in the total defatted methanolic extract confirmed its enrichment with phenolics and flavonoids equivalent to 138.61 ± 9.39 µg gallic acid/mg extract and 119.63 ± 4.62 µg rutin/mg extract, respectively. Moreover, the total defatted methanolic extract exhibited promising antioxidant activity confirmed through DPPH and ABTS assays with a 50% inhibitory concentration (IC50) value equivalent to 52.79 ± 2.16 µg/mL and 10.02 ± µg/mL, respectively. The inhibitory activity of acetylcholine esterase (AchE) was assessed using in-vitro Ellman’s colorimetric assay, the total defatted methanolic extract, ethyl acetate, and n-butanol fractions exhibited IC50 values of 52.9, 15.1 and 108.8 µg/mL that they proved the significant inhibition of AchE activity.ConclusionThe results obtained herein unraveled the potential use of the total methanolic extract of Vitex pubescens bark and its polar fractions as natural candidates for controlling Alzheimer’s disease progression.

Aroylhydrazone‐based nickel(II) complexes: Synthesis and their structural, density functional theory (DFT), biological and catalytic studies

Nickel(II) complexes of tridentate NNO donor aroylhydrazones, viz., di‐2‐pyridyl ketone‐4‐methoxybenzhydrazone monohydrate (DKMBH·H2O) and 2‐acetylpyrazine‐4‐methoxybenzhydrazone monohydrate (APMBH·H2O), were synthesized and characterized using various methods, including spectral techniques (Fourier transform infrared [FT‐IR], UV–vis) and analytical methods (elemental and X‐ray diffraction [XRD] analysis). Single‐crystal XRD was used to elucidate the crystal structures of nickel(II) complexes 1 and 2. The XRD analysis revealed that the respective ligands coordinated to the Ni(II) center through the deprotonated iminolate form in complex 1 and the neutral amido form in complex 2, resulting in distorted octahedral geometries. The ground state electronic configurations of the complexes were studied using the B3LYP/UB3LYP levels of DFT. Using absorption spectral titration methods, the interactions of complexes with CT‐DNA and bovine serum albumin (BSA) protein were examined. The observed data demonstrate that the complexes adopt an intercalative binding mode to bind to CT‐DNA and BSA protein. Additionally, the antioxidant activity of the nickel(II) complexes and their ligands was determined using 1,1‐diphenyl‐2‐picrylhydrazyl (DPPH). Complex 2 demonstrated the highest radical scavenging activity of the compounds studied (IC50 = 3.81 mM). Furthermore, molecular docking studies were performed to understand how the complexes can interact with the SARS‐CoV‐2 main protease. The results revealed that complex 2 had the highest docking score (−8.18 kcal/mol) when compared with the other complexes under study. Aside from their biological properties, the nickel complexes heterogenized on functionalized SBA‐15 showed promising catalytic activity, achieving 98% yield in the reduction of nitrobenzene, forming exclusively aniline as the end product.