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We synthesized a novel compound library featuring a spirooxindole core structure combined with various heterocycles, including benzofuran, benzothiophene, and thiophene scaffolds. Evaluation using MTT assays against HepG2, 4T1, and MDA‐MB‐231 cells revealed the most potent candidate, spirooxindole hybrid 5c, with an IC50 of 5 ± 0.6 µM against HepG2, inducing G2/M phase cell cycle arrest, inhibition of the wound healing, and induction of ROS. Selected spirooxindole conjugates exhibited significant inhibitory potential against MDM2, with KD values ranging from 0.0531 to 16.8 µM. Notably, the salt of spirooxindole analogue 5q demonstrated the highest inhibitory activity at KD = 53.1 nM. Molecular docking studies revealed excellent accommodation of the designed compounds within the MDM2 receptor. All compounds displayed favorable ADME profiles, suggesting their potential as lead compounds for further optimization. [ABSTRACT FROM AUTHOR]

Passion fruit is widely cultivated in tropical, subtropical regions of the world. The attack of bacterial and fungal diseases, and environmental factors heavily affect the yield and productivity of the passion fruit. The CC-NBS-LRR (CNL) gene family being a subclass of R-genes protects the plant against the attack of pathogens and plays a major role in effector-triggered immunity (ETI). However, no information is available regarding this gene family in passion fruit. To address the underlying problem a total of 25 and 21 CNL genes have been identified in the genome of purple (Passiflora edulis Sims.) and yellow (Passiflora edulis f. flavicarpa) passion fruit respectively. Phylogenetic tree was divided into four groups with PeCNLs present in 3 groups only. Gene structure analysis revealed that number of exons ranged from 1 to 9 with 1 being most common. Most of the PeCNL genes were clustered at the chromosome 3 and underwent strong purifying selection, expanded through segmental (17 gene pairs) and tandem duplications (17 gene pairs). PeCNL genes contained ciselements involved in plant growth, hormones, and stress response. Transcriptome data indicated that PeCNL3, PeCNL13, and PeCNL14 were found to be differentially expressed under Cucumber mosaic virus and cold stress. Three genes were validated to be multi-stress responsive by applying Random Forest model of machine learning. To comprehend the biological functions of PeCNL proteins, their 3D structure and gene ontology (GO) enrichment analysis were done. Our research analyzed the CNL gene family in passion fruit to understand stress regulation and improve resilience. This study lays the groundwork for future investigations aimed at enhancing the genetic composition of passion fruit to ensure robust growth and productivity in challenging environments. [ABSTRACT FROM AUTHOR]

A series of spirooxindoles-based N-alkylated maleimide derivatives (AMIs) were synthesized and their inhibition profile also reported. Three component, one-pot [3 + 2] cycloaddition (32CA) reactions of isatin, amino acids and AMIs were found to proceed via syn-anti-azomethine ylides (AYs) to endo-addition of AMIs. These 32CA reactions present a very low activation enthalpy, 5.1 kcal·mol−1, as a consequence of the supernucleophilic character of AYs and the strong nucleophilic character of AMIs. The favorable electrostatic interactions taking place at the zwitterionic endo transition state structure are responsible for the endo stereoselectivity found in these polar 32CA reactions. The new hits of spirooxindoles-based AMIs were screened for their anticancer activity. Compounds 4e and 4f revealed the best anti-cancer activity against breast cancer cell line (MCF-7) that highly expressed human epidermal growth factor receptor (HER)-3 with the lowest IC50 < 6 µM. 4e and 4f were able to induce apoptosis by 47.26% and 55.36% with suppression of serine/threonine kinase (Akt). The latter is crucial mediator in the enhancement HER-3 which has essential function in HER-2-mediated tumor progression. Moreover, 4e and 4f were able to repress Akt-downstream genes (NF-kB and Bcl-2) expression and upregulating the expression of p21 in treated MCF-7 cells. Further, the newly synthesized spirooxindoles-based AMIs (4e and 4f) exhibited inhibitory potency for Akt and HER-2 that was supported by good binding affinity and docking interaction. Thus, 4e and 4f represent promising proapoptotic agents for breast cancer treatment. [ABSTRACT FROM AUTHOR]

The intent of this article was to explore the impact of Cognitive Behavior Therapy’s (CBT) distraction techniques on teenagers’ hope and resilience. The sample was selected from educational institutions around the Malakand division of Khyber Pakhtunkhwa, Pakistan by using a random sampling technique for an initial sample (N=300). Pre-test data was collected through standardized measures, 14 items Resilience Scale, and 40-item Hope Scale. Based on pretest findings adolescents having below-average hope and resilience were put into experimental (n=62) and control (n=50) groups using a stratified random sample technique. Correlation results showed a positive correlation between hope and resilience. Further, a significant difference was found in hope and resilience in terms of gender. The posttest study of teenagers in the experimental group highlighted a substantial increase in hope and resilience following the application of distraction strategies compared to those in the control group. Since the fast-paced, competitive atmosphere is overwhelming for adolescents, this study is incredibly important for bolstering hope and resilience among adolescents. These findings will benefit educational and clinical psychologists in handling such problems efficiently. [ABSTRACT FROM AUTHOR]

Currently, acetylcholinesterase (AChE) inhibiting drugs in clinical use, such as tacrine, donepezil, rivastigmine, and galanthamine, are associated with serious side effects and short half-lives. In recent years, numerous phytochemicals have been identified as inhibitors of cholinesterases with potential applications in the management of Alzheimer's disease (AD). In this study three natural coumarins, 2'-O-ethylmurrangatin (1), murranganone (2), and paniculatin (3) isolated previously by our group from the leaves of Murraya paniculata, were tested against the two cholinesterases (ChE) enzymes, AChE and butyrylcholinesterase (BChE) using in vitro assay. Molecular docking was performed to highlight the structural properties that contribute to the molecular recognition pattern in the inhibition of ChE and the structural differences resulting in the selectivity of these compounds toward AChE. Classical enzyme inhibition kinetics data suggested that compounds 2 and 3 were potent inhibitors of AChE and BChE, while 1 was found inactive against both enzymes. The findings from molecular docking studies revealed the competitive and non-competitive inhibition mechanisms of compounds 2 and 3 against both enzymes. Molecular docking and simulations have revealed that hydrogen bonding, mediated by ketone and hydroxyl functionalities in various positions, significantly contributes to the binding of the inhibitor to the receptor. According to MD simulation studies, the stability of the ligand-AChE complex for the most active compound (3) is found to be comparable to that of the widely used drug Tacrine. In addition, to evaluate the drug-likeness of compounds, in silico ADME evaluation was performed, and the compounds presented good ADME profiles. Data suggested that the coumarin nucleus having diverse side chains at the C-8 position can serve as a potential inhibitor of cholinesterases and can act as a lead to develop a new semisynthetic drug for the treatment of AD. [ABSTRACT FROM AUTHOR]

Background: Stachys schimperi Vatke has been previously reported for its analgesic, antipyretic, antioxidant, antimicrobial and cardioprotective properties. Objectives: Phytochemical analysis and assessment of anti-hepatitis B virus (anti-HBV) activity of S. schimperi. Materials and Methods: Surface extraction was performed to isolate the phytoconstituents using chromatographic techniques, including HPLC. The isolates were identified by a 1D and 2D NMR spectroscopic data. Further, the isolates were tested for cytotoxicity using an MTT assay. Non-cytotoxic doses of the isolates were assessed for their antiviral potential on cultured HepG2.2.15 cells. To rationalize the plausible mechanisms of the tested anti-HBV active compounds, molecular docking studies were carried out using HBV polymerase (Pol) enzyme. Results: The NMR data proved the structure of isolates as artemetin [5-hydroxy, 3' 3′,4′'6,7-penta methoxy flavone] (1), chrysosplenetin [5,4′-dihydroxy, 3'3′' 6,7-tetra methoxy flavone] (2) and calycopterin [5,4′-dihydroxy, 3' 6,7'8-tetra methoxy flavone] (3). Notably, this is the first report on the isolation of these three compounds from S. schimperi as well as artemetin and calycopterin from the genus Stachys. Further antiviral assessment of the non-cytotoxic dose showed marked inhibitions of HBV antigens (HBsAg/HBeAg) by artemetin (52.28%/46.52%) and calycopterin (61.24%/57.26%) in HepG2.2.15 cells. Chrysosplenetin, however, did not show any anti-HBV activity. Artemetin and calycopterin exhibited anti-HBV activity, possibly through inhibition of HBV-Pol as revealed by molecular docking. Conclusion: We report the identification of anti-HBV active flavones artemetin and Calycopterin from S. shimperi. Our data strongly warrant further molecular and pharmacological studies on artemetin and calycopterin toward developing potential anti-HBV therapeutics. [ABSTRACT FROM AUTHOR]