Quinolones have recently gained significant interest in oncology due to their structural versatility and broad pharmacological potential. Their modifiable scaffold makes them attractive candidates for anticancer drug development, enabling optimization of potency, selectivity, and pharmacokinetic properties. This review highlights recent advances in the synthesis of 2-quinolone and 4-quinolone derivatives, with an emphasis on emerging strategies such as metal-catalyzed reactions, photochemical approaches, base-mediated transformations, and metal-free methodologies. We summarize contemporary structure-activity relationship (SAR) studies that elucidate features governing anticancer activity in quinolone-based compounds. Additionally, we discuss mechanistic evidence demonstrating that quinolones exert antitumor effects through diverse molecular pathways, including topoisomerase inhibition, apoptosis induction, cell-cycle arrest, G-quadruplex stabilization, HDAC inhibition, modulation of miRNA processing, and regulation of key oncogenic signaling networks such as EGFR/PI3K/mTOR and S1P. The current landscape of quinolone-derived anticancer agents in preclinical and clinical development is also reviewed. Overall, this article provides a comprehensive and translational perspective on the synthetic advances, SAR insights, and mechanistic foundations supporting the development of 2- and 4-quinolone scaffolds as promising anticancer therapeutics.

P2Y14 receptor in the nervous system: Pharmacology, mechanisms, and therapeutic potential.

Glaucocalyxin D (GLD), an ent-kaurane diterpenoid isolated from Isodon species, exhibits extensive pharmacological potential; however, its mechanism of action against acute myeloid leukemia (AML) remains to be elucidated. The present study employed a combined network pharmacology and experimental approach to elucidate the anti-AML mechanisms of GLD. Potential targets were identified using database mining and a protein-protein interaction network was constructed. The Gene Ontology and the Kyoto Encyclopedia of Genes and Genomes enrichment analyses highlighted the JAK-STAT signaling pathway as central to action by GLD. Molecular docking predicted stable binding of GLD to core targets, including STAT3. Experimental validation in HEL and K562 AML cells demonstrated that GLD potently and dose-dependently inhibits cell proliferation, with efficacy similar to the standard chemotherapeutic agent doxorubicin. Mechanistically, GLD suppressed the phosphorylation of JAK2 and STAT3. GLD also induced mitochondrial apoptosis by modulating the Bcl-2/Bax ratio and triggered G2/M phase arrest by downregulating cyclin B1 and CDK1. These findings delineated a coherent mechanism whereby GLD exerts anti-leukemic effects by inhibiting the JAK-STAT pathway, supporting its potential as a novel lead compound for AML therapy in the future.

Multiscale computational modeling integrated with in vitro evaluation of green-synthesized 2,3-dihydroquinazolin-4(1 H)-ones targeting U87 glioblastoma cells.

A natural product-hybridization approach toward anticancer drug discovery: synthesis and antitumor evaluation of CTBC6, designed from sulforaphane and magnolol.

This study explores the biological and pharmacological potential of Inula aschersoniana Janka (I. aschersoniana) by utilizing both in silico computational and in vitro analyses, focusing on anticancer, antioxidant, and enzyme inhibitory activities. I. aschersoniana extracts were observed to have effective properties against breast cancer (MCF-7) and human colon adenocarcinoma (HT-29) cell lines compared to normal human umbilical vein endothelial (HUVEC) cell line. Also, effective antioxidant activity of the plant sample was determined by using several in vitro antioxidant methods. Furthermore, inhibitory effects of I. aschersoniana extracts against alpha-glucosidase (α-Gly) and glutathione S-transferase (GST) enzymes were evaluated. The IC50 value of I. aschersoniana ethyl acetate extract was determined as 4.05µg/mL for α-Gly and 1.67µg/mL for GST. Similarly, IC₅₀ value of the ethanol extract was measured as 3.74µg/mL for α-Gly and 2.71µg/mL for GST. Also, main organic compounds of I. aschersoniana were detected to be vanillic acid, rutin, and naringin by HPLC technique. Finally, integrated network pharmacology, molecular docking, and molecular dynamics simulations were performed to elucidate the potential interactions between the active components of I. aschersoniana and genes associated with breast and colon cancer. To ensure reliability, molecular docking results were validated using re-docking and comparison with reference inhibitors or co-crystallized ligands. RMSD and RMSF analyses revealed that naringin, the major compound of I. aschersoniana, exhibited dynamically stable binding within the active sites of AKT1, EGFR, and PPARG proteins, with AKT1@Naringin and PPARG@Naringin complexes displaying a more stable dynamic profile. In this network pharmacology study, forty-five common targets between the major compounds of I. aschersoniana with breast and colon cancers were identified.

Designer benzodiazepines (DBZDs) are a class of new psychoactive substances (NPS) designed as legal alternatives to prescription BZDs. Bromazolam has been the most prevalent DBZD detected on the recreational market around the world; however, a new DBZD, ethylbromazolam (8-bromo-1-ethyl-6-phenyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; also known as bromoethylazolam) has recently emerged. In this study, the emergence of ethylbromazolam in Canada, the UK, and Australia is reported based on analysis of samples from drug checking services and in Germany based on analysis of samples seized by customs and mail services. Since November 2024, ethylbromazolam has been increasingly detected with a concurrent decrease in bromazolam detections, suggesting that its emergence is likely in response to the international control of bromazolam on 3rd December 2024. Additionally, increased detections of other DBZDs, including desalkylgidazepam (bromonordiazepam) and clobromazolam (phenazolam) have been recently observed. The in vitro α1β2γ2 GABAA receptor activity of ethylbromazolam was determined using an automated patch clamp assay. Ethylbromazolam was found to have similar in vitro GABAA receptor activity as bromazolam (EC50 of 10.1 nM and 15.2 nM, respectively), indicating comparable pharmacological activity and potential for harm. The market should continue to be monitored closely as it continues to evolve in response to the control of bromazolam.

CFTR facilitates fluid secretion by ferret alveolar type 2 cells.

We report an efficient palladium-catalyzed synthesis of diverse enantioenriched benzofused nine- and ten-membered heterocycles featuring a stereogenic carbon as well as an axially chiral N-aryl sulfonamide motif. Such a structural scaffold has shown significant pharmacological potential in related heterocyclic compounds. This method utilizes readily accessible aza-ortho-quinone methide precursors and vinyl carbonates in formal [5 + 4] and [6 + 4] cycloadditions with excellent diastereo- and enantioselectivity. Furthermore, the ten-membered heterocycles can undergo sequential ring-contractive rearrangements, providing systematic access to highly functionalized nine- and eight-membered heterocycles with excellent stereocontrol.

Delphinium brunonianum Royle (Ranunculaceae) is medicinally important species that has a diverse phytochemical profile and pharmacological potential. This study aimed to investigate phytochemicals, green synthesis of nanoparticles, and in vitro biological activities of Delphinium brunonianum extracts. GC-MS study of n-hexane, ethyl acetate, and dichloromethane extracts verified the existence of various bioactive phytochemicals. Green synthesis of Ag, Cu, Fe, and Zn nanoparticles was determined using UV-Vis spectroscopy, XRD, FT-IR, and SEM. Biological analysis showed that ethyl acetate extract and Ag nanoparticles exhibited radical scavenging activity, showing 93.43% and 66.99% inhibition, respectively. Acetylcholinesterase inhibition was high in n-hexane extract with 57.56%, whereas lipase inhibition was predominant in Cu and Fe nanoparticles with 72.52% and 65.90% values, respectively. Inhibition of tyrosinase was high in Cu nanoparticles with a 78.18% value, but inhibitory effect of α-amylase was high in crude extract with 49.06%. Zone of inhibition of n-hexane extract was 21.66mm and Zn nanoparticles had 27.3mm in antibacterial and antifungal activities, respectively. The results suggest that D. brunonianum is a potential source of bioactive phytochemicals and an effective green matrix for the synthesis of nanoparticles to support its possible implication in medical-related fields in future.

Guggulsterone-Mediated Selective Modulation of Nuclear Receptors: Implications for FXR-PXR Signaling and Hepatic Metabolic Homeostasis.

Acute liver injury (ALI) is a severe public health problem closely associated with oxidative stress, inflammation, and hepatocyte injury, leading to high mortality. Fucoxanthin (Fx), a marine carotenoid found in brown seaweeds, has various beneficial effects against multiple diseases. However, the potential role of Fx on ALI remains unclear. This study aims to explore the pharmacological potential of Fx in lipopolysaccharide (LPS)/D-galactosamine (D-Gal)-induced ALI. The therapeutic effect of Fx on ALI was primarily evaluated using a mouse model induced by LPS/D-Gal, focusing on pathological changes, oxidative stress, inflammation, and pyroptosis. Additionally, the effects of Fx on cell pyroptosis and its molecular mechanisms were explored in an invitro pyroptosis model established by inducing macrophages with LPS/Nigericin. Fx significantly alleviated the LPS/D-Gal-induced histopathological progression and hepatocyte apoptosis, reducing plasma levels of ALT, AST, and LDH. It also obviously decreased hepatic MDA levels while increasing antioxidant enzyme activities and GSH concentration compared to LPS/D-Gal-treated mice. These antioxidant effects were linked to the upregulation of hepatic Nrf-2, HO-1, and GCLC expression. Furthermore, Fx treatment alleviated macrophage accumulation and downregulated the expression of pro-inflammatory factors in the liver. Importantly, Fx administration suppressed NLRP3 inflammasome-dependent canonical pyroptosis both in LPS/D-Gal-treated mice and LPS/Nigericin-stimulated macrophages, potentially mediated by the suppression of MAPKs and NF-κB pathways. These findings suggest that Fx could be an effective strategy to prevent ALI, particularly in cases associated with NLRP3 inflammasome-mediated pyroptosis.

The role of HIF-1α in innate immune mechanisms and autoimmunity: A double-edged sword.

Astrocytes containing alpha-synuclein (α-Syn) are a cytopathological finding in post-mortem samples of patients with Parkinson's disease (PD). Aminochrome, a subproduct of dopamine oxidation, can induce formation of neurotoxic α-Syn oligomers, astrocyte reactivity, and astrocyte cell death. Nicotine, on the other hand, has been shown to have a protective effect against aminochrome cytotoxicity in substantia nigra dopaminergic cells. However, whether nicotine can also protect against aminochrome toxicity in α-Syn-expressing astrocytes is not known. To address this question, we used the human glioblastoma U251 cells stably overexpressing mutant A53T/nYFP α-Syn, and the U251 wild-type cells as a negative control. The results showed that treatments with 10 µM nicotine, for 24 or 48 h, protected U251 cells containing mutant α-Syn against aminochrome-induced cytotoxicity. Cell viability was assessed by MTT, and cleaved Caspase-3 by immunofluorescence. The protective effect of nicotine was also associated with an increase in acidic organelles in U251 cells containing mutant α-Syn. Overall, the results of this study reinforce the pharmacological potential of nicotine as a protective agent against brain cell degeneration especially relevant to PD.

Recent advances in indole-thiazole hybrid scaffolds: synthesis, molecular hybridization, and pharmacological potential.

Pharmacological potential of gardoside in anxiety: Behavioral and molecular evidence.

This review provides a focused analysis of recent developments in the design, synthesis, and pharmacological evaluation of benzoxazole derivatives, emphasizing their emerging role as versatile therapeutic scaffolds. By systematically examining studies published across major scientific databases, the article highlights how structural modifications to the benzoxazole core translate into distinct bioactivities, particularly in antimicrobial, anticancer, antitubercular, anti-inflammatory, analgesic, and anthelmintic domains. Special emphasis is placed on Structure-Activity Relationship (SAR) trends, in which variations such as heteroatom substitutions, aryl linkages, and bulky substituents significantly influenced biological potency. Comparative cell line testing results are consolidated to illustrate how specific substitutions modulate cytotoxic responses across various cancer models. The novelty of this review lies in its integrated discussion of SAR findings alongside therapeutic applications, offering insights into how subtle functionalization patterns enhance pharmacological potential. Additionally, the review underscores critical gaps that remain in in-vivo validation and translational studies. Overall, it not only consolidates recent findings but also provides perspectives for future medicinal chemistry strategies aimed at advancing benzoxazole-based agents toward clinical utility.

Background The hypothalamic-pituitary-adrenal (HPA) axis is an important part of the stress response system that produces a biological reaction to stressful stimuli and can be activated by stressors such as atrazine. Atrazine (ATZ) is a common triazine herbicide used in the management of weeds in corn and sugarcane, and its persistence in the environment through runoff and leaching leads to frequent contamination of soil and water, with subsequent adverse health implications. Myricetin (MYR) is a biologically active compound with various pharmacological potentials against noxious agents. Objective and Methods This study evaluated the effects of MYR on the HPA axis of male Wistar rats sub-chronically exposed to atrazine (ATZ), gavaged with either atrazine (50 mg/kg), myricetin (20 mg/kg), or a combination of both for 45 consecutive days. Result Exposure to ATZ increased serum levels of adrenocorticotropin-releasing hormone (ACTH) and corticosterone, and significantly decreased the activities of hypothalamic and adrenal antioxidant enzymes (catalase, glutathione S-transferase, glutathione peroxidase, reduced glutathione), and hypothalamic acetylcholinesterase (AChE). More so, ATZ-challenged rats showed increased levels of reactive oxygen species and lipid peroxidation, Nitric oxide, tumor necrosis factor-α, interleukin-1β, and caspase-3 in both tissues. Conversely, treatment with myricetin significantly restored the serum levels of ACTH and corticosterone, enhanced the antioxidant enzyme activities, reduced the oxidative-inflammatory and apoptotic markers in both tissues, and increased the hypothalamic AChE activity of the treated animals. Myricetin also reversed the histological abnormalities that atrazine elicited in the treated animals. Conclusion Overall, MYR, through its antioxidant, anti-inflammatory, and anti-apoptotic properties, attenuated the ATZ-induced disruption of the HPA axis of rats.

The aggregation of alpha-synuclein (αSN) is a key pathological feature of Parkinson's disease (PD), leading to neural cell death via reactive oxygen species (ROS) overload and activation of downstream neurotoxic pathways. Betanin, a beetroot-derived small molecule, has exhibited antioxidant and neuroprotective properties. In this study, three betaxanthins-Bxn-A, Bxn-B, and Bxn-C-were chemically synthesized from betanin to enhance its therapeutic properties. Betaxanthin Bxn-A effectively reduced intracellular ROS levels without cytotoxicity, even at 500 µM. Additionally, betanin and its derivatives revealed neuroprotective effects, including significant reductions in apoptosis, preservation of mitochondrial membrane potential, modulated autophagy, and enhanced cell viability in PD-model cells. In terms of aggregation inhibition, betaxanthins Bxn-A and Bxn-B significantly reduced αSN aggregation compared to the control after 48 h of incubation. Betaxanthin Bxn-A also triggered disaggregation of existing aggregates and inhibited formation of large, insoluble species. Moreover, αSN aggregation and disaggregation products formed in the presence of betanin or its derivatives exhibited significantly lower cytotoxicity than those formed in their absence. Specifically, cells treated with aggregates formed in the presence of 50 µM betaxanthin Bxn-B showed 100% viability, while those treated with disaggregation products formed in the presence of 100 µM betaxanthin Bxn-A showed 20% greater viability than those treated with untreated disaggregates. Molecular docking revealed interactions between betaxanthins and key αSN residues, suggesting destabilization mechanisms. Docking analyses with five ROS-PPI network key proteins-C5, CDC42, BCL2, CDKN1A, and CDKN1B-indicated potential roles in inhibiting oxidative stress-related pathways. Drug-likeness predictions indicated that the derivatives enhanced pharmacological potential, making them promising candidates for PD treatment.

Polyherbal formulations are increasingly recognized for their multi-target therapeutic potential in managing complex conditions such as inflammation and pain; however, the mechanistic basis of phytochemical synergy remains inadequately understood. The present study was designed to evaluate a rationally developed polyherbal anti-inflammatory and analgesic formulation using a systems-based mechanistic approach integrated with in vivo validation. Phytochemical profiling and network pharmacology analysis were employed to identify key bioactive constituents and predict their molecular targets and pathways. The formulation was subsequently evaluated using established in vivo models, including carrageenan-induced paw edema for anti-inflammatory activity and standard nociceptive models for analgesic assessment. The results demonstrated a significant (p < 0.05) reduction in inflammatory response and pain perception compared to control groups, indicating potent pharmacological activity. Systems-level analysis revealed that major phytoconstituents, including flavonoids, phenolic acids, and terpenoids, collectively modulate multiple pro-inflammatory mediators such as cyclooxygenase-2 (COX-2), tumor necrosis factor-alpha (TNF-α), and interleukin-6 (IL-6), suggesting a synergistic multi-target mechanism of action. The convergence of in vivo findings with network-based predictions highlights the role of phytochemical interactions in enhancing therapeutic efficacy. Overall, this study provides robust mechanistic and experimental evidence supporting the synergistic pharmacological potential of the developed polyherbal formulation and underscores the utility of integrating systems pharmacology with conventional in vivo approaches for the scientific validation and optimization of polyherbal therapeutics.