The current study devised and synthesized a novel class of pyrazole derivatives based on indole as possible inhibitors of cyclin-dependent kinase-2 (CDK-2). [1]H NMR, [13]C NMR, NOESY, HMQC, and elemental analysis were used to confirm the structural integrity of the synthesized compounds. Promising CDK-2 inhibitory activity was observed in biological assays, and numerous compounds exhibited sub-micromolar IC50 values. Compound 5 d outperformed the reference inhibitor Roscovitine (IC50 = 0.716 µM) as the most potent inhibitor (IC50 = 0.536 µM), followed by compound 9 g (IC50 = 0.675 µM). SAR analysis showed that the observed activity was significantly influenced by the electronic nature of the added substituents as well as the orientation of the indole bond, with brominated derivatives exhibiting greater potency. The antiproliferative activity of the most potent compounds against the cancer cell lines HepG2, HCT-116, and MCF-7 was further assessed. In addition to having an enhanced selectivity index for normal MCF-10A cells (SI = 8.00 vs. 4.96 for Roscovitine), compound 5 d had the greatest activity against MCF-7 cells (IC50 = 6.78 µM), surpassing Roscovitine (IC50 = 8.11 µM). According to mechanistic investigations, compound 5 d significantly reduced the S-phase population, markedly promoted apoptosis, and caused G1 and G2/M cell-cycle arrest. Additionally, the consistent binding of compound 5 d within the ATP-binding pocket of CDK-2 was confirmed by molecular docking and molecular dynamics simulations, and attractive drug-like and pharmacokinetic features, similar to those of Roscovitine, were demonstrated by in silico ADMET predictions. All of these results point to compound 5 d as a promising lead scaffold for developing potent CDK-2-targeted anticancer agents.

Breast cancer is one of the leading causes of cancer-related deaths among women worldwide, with estrogen receptor-positive (ER+) breast cancer being the most common subtype. Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) have become a crucial therapeutic approach for this type of cancer. However, ER+ breast cancer frequently develops resistance to CDK4/6i, limiting therapeutic efficacy. Alternative splicing is a key post-transcriptional regulatory mechanism that may drive such resistance. In this review, we comprehensively analyzed the literature on the molecular mechanisms and key signaling pathways associated with CDK4/6i resistance in ER+ breast cancer and introduced the role of alternative splicing, with a particular focus on its function in tumor drug resistance. Available evidence suggests that splicing dysregulation may influence resistance through multiple pathways, including cell-cycle control, epithelial-mesenchymal transition, growth factor and RAS/MAPK signaling, and immune-related programs. Recent work has also suggested that reduced expression of the splicing regulator NSRP1 may be associated with CDK4/6i resistance through altered NSD2 splicing and activation of interferon signaling, although this mechanism currently requires further independent validation. Collectively, these findings support alternative splicing as a promising but still evolving area of investigation in CDK4/6i resistance. This work provides deeper insights into the role of alternative splicing in CDK4/6i resistance and offers a theoretical foundation for developing novel therapeutic approaches. Future research may focus on developing drugs that precisely modulate specific splicing events or combining CDK4/6i with splicing modulators to reverse or delay resistance.

A novel series of 5-chloro-N-alkyl-1',1″-dimethyl-4'-aryldispiro[indene-2,3'-pyrrolidine-2',3″-indoline]-1,2″(3H)-diones (4a-r) was rationally designed and synthesized via a one-pot multicomponent reaction of N-alkylated 5-chloroisatin derivatives, 2-(arylmethylidene)-2,3-dihydro-1H-inden-1-ones (2a-i), and sarcosine (3). To assess their potential therapeutic efficacy, the entire library of synthesized compounds was screened for its inhibitory profiles against both acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), where most derivatives exhibited moderate to potent cholinesterase inhibitory activity. Notably, derivatives 4b, 4f, and 4o emerged as the most effective dual inhibitors, displaying strong potent activity against AChE (IC50 = 0.91 ± 0.02, 0.89 ± 0.01, and 0.74 ± 0.01 µM, respectively; donepezil IC50 = 0.68 ± 0.005 µM) alongside significant BChE inhibition (IC50 = 10.19 ± 0.16, 9.59 ± 0.08, and 9.11 ± 0.01 µM, respectively; donepezil IC50 = 2.97 ± 0.01 µM). The structure of the most active derivatives (4b, 4f, and 4o) was further confirmed by X-ray crystallographic analysis. In addition, antioxidant evaluation of compounds 4b, 4f, and 4o demonstrated that derivative 4f possessed the most superior radical scavenging profile (IC50 = 23.18 ± 0.33 µM), representing approximately a 5.5-fold enhancement in potency relative to ascorbic acid (IC50 = 128.20 ± 0.82 µM). Molecular docking studies revealed favorable binding interactions of the lead derivatives within the catalytic binding pockets of both AChE and BChE, with docking scores comparable to those of the standard inhibitor. Furthermore, in silico ADME profiling demonstrated promising pharmacokinetic behavior, characterized by robust gastrointestinal absorption and excellent predicted blood-brain barrier penetration, supporting the potential of these derivatives as promising multifunctional candidates for the development of anti-Alzheimer agents.

Non-small cell lung cancer (NSCLC) exhibits stem-like characteristics that drive tumor aggressiveness and treatment resistance. The molecular chaperone Glucose-Regulated Protein 78 (GRP78) is substantially elevated in NSCLC compared to normal tissues and cell lines. In clinical samples, GRP78 protein levels correlated with advanced tumor stage and lymph node metastasis. Pharmacological inhibition of GRP78 using BAPTA-AM and GRP78-IN-3 significantly suppressed NSCLC cell viability while promoting apoptosis. The inhibitors effectively attenuated cell migration by downregulating matrix metalloproteinases and reversed epithelial-mesenchymal transition by modulating key cadherin expression profiles. Importantly, GRP78 inhibition substantially reduced cancer stem cell markers and impaired spheroid formation capability. Genetic knockdown of GRP78 in A549 and H1975 cells recapitulated the effects of pharmacological inhibition, reducing cell migration, reversing EMT, attenuating stemness, and suppressing β-catenin signaling. Conversely, GRP78 overexpression in A549 and H1975 cells induced opposite effects, promoting mesenchymal markers, enhancing stemness proteins, and increasing spheroid size. Mechanistic studies revealed that this anti-tumor activity operates through suppression of β-catenin signaling mediated by SIX1, as evidenced by SIX1-overexpression rescue experiments. These findings demonstrate that GRP78 acts as a key regulator of NSCLC stemness and metastatic potential by coordinating epithelial plasticity and stemness pathways, positioning it as a promising therapeutic target for NSCLC treatment.

Nanotechnology has emerged as a promising avenue for producing nanomedicines as alternatives to conventional drugs. Many organic nanoparticles, such as liposomes used in formulations like Doxil, Onivyde, and Marqibo, are approved by the Food and Drug Administration (FDA) and instrumental in treating various types of cancers. However, due to the many challenges associated with these formulations, alternative delivery systems have been explored, particularly those derived from inorganic sources. In particular, bioinorganic nano-based delivery systems (BNDSs) such as gold, silver, platinum, silicon-based, metal oxide and hybrid nanoparticles have been found to be useful in treating cancer and infectious and noncommunicable diseases. This review presents the most commonly used BNDSs, providing an in-depth discussion on their use as therapeutic and imaging agents, the challenges associated with their use and current trends and future perspectives in their development for enhancing efficacy.

A common cause of multidrug-resistant (MDR) cancer is imbalanced redox signaling, which reduces the effectiveness of chemotherapy and promotes regrowth of cancer cells. Amplification of thioredoxin reductase (TrxR) and activation of the Keap1-Nrf2-FOXO3 pathway may contribute to enhanced drug efflux, strengthens antioxidant defenses, and resistance to oxidative stress-induced apoptosis in certain tumors. Redox-based drug repurposing offers a promising strategy to overcome MDR by targeting these shortcomings. Repurposing drugs including metformin, auranofin, brusatol, and natural polyphenols increase reactive oxygen species (ROS) and make MDR cells more sensitive to chemotherapy via modulation and inhibiting Nrf2 or TrxR. Nanotechnology advancements and combination of repurposed drugs with anticancer drugs, ferroptosis inducers may improve tumor selectivity while lowering systemic toxicity. Preclinical experiments show effectiveness by suppressing antioxidant pathways, inhibiting efflux pump function, and delivering drugs in a redox-responsive manner. Next-generation tumor-selective delivery systems, adaptive clinical trial designs, and biomarker-driven patient classification based on TrxR expression or Keap1/Nrf2 mutations are the main areas of focus. Translation into clinical practice could be accelerated by combining specific redox profiling, nanocarrier technologies, and pharmacokinetics. For MDR cancer, redox-targeted drug repurposing is an effective, precision-based strategy for recovering chemosensitivity and enhancing treatment outcomes.

Anonymous, "Reprogramming the Tumor Microenvironment: Calebin A as a Polyphenolic Paradigm Shift in Controlling Inflammation, Stemness, and Resistance in Colorectal Cancer," Drug Development Research 87, no. 2 (2026): e70230, https://doi.org/10.1002/ddr.70230. The above article, published online on 28 January 2026 in Wiley Online Library (onlinelibrary.wiley.com), has been retracted by agreement between the Editor-in-Chief, Steven Fletcher; and Wiley Periodicals LLC. An investigation by the publisher found that the paper was submitted by a fraudulent third-party who used a fake email address to impersonate the corresponding author. The named authors did not consent to the submission or publication of the article. Therefore, a decision has been made to retract this article. Since the authors were listed without their consent and under false pretenses, their names have been removed from the article's author list.

Drug-resistant bacteria such as Methicillin-resistant Staphylococcus aureus (MRSA) and Quinolone-resistant S. aureus (QRSA), are a growing problem, creating a need for the development of novel antimicrobial agents. In this study, we designed and synthesized two novel 1,4-naphthoquinone derivatives, LHN-1034 and LHN-1035, and evaluated their antibacterial efficacy. Both compounds exhibited great antimicrobial activity against a group of Gram-positive bacteria, including MRSA and QRSA, with Minimum Inhibitory Concentrations (MICs) ranging from 50 to 100 µM. Mechanism studies revealed that the antibacterial effect is oxygen-dependent. The compounds act as redox-cycling agents that induce intracellular reactive oxygen species (ROS), which disrupts cell membrane integrity and leads to cell lysis. In silico assessments predict low intestinal absorption and skin permeability, suggesting these compounds are suited for topical application. In conclusion, LHN-1034 and LHN-1035 are candidates for developing topical agents against resistant Gram-positive infections.

A focused library of 19 donepezil-linked chalcones (DLCs) was efficiently synthesised through microwave-assisted Claisen-Schmidt condensation and subsequently profiled for their inhibitory activities against cholinesterases (AChE and BuChE) as well as monoamine oxidases (MAO-A and MAO-B). The DLCs exhibited potent and selective inhibition of MAO-B, with IC50 values ranging from 0.019 to 18.98 μM, whereas activity toward MAO-A was moderate to low (IC50 = 0.81 to > 20 μM). Among the tested DLCs, DLC9 and DLC14 showed the highest MAO-B inhibitory potential with IC50 values of 0.054 ± 0.004 μM and 0.019 ± 0.0015 μM, respectively, and high selectivity indexes (> 370 and > 1052, respectively), whereas DLC12 displayed notable MAO-A inhibition (IC50 = 0.81 ± 0.035 μM). Kinetic and reversibility studies revealed that the selected two lead DLCs (DLC9 and DLC14) acted as mixed-type reversible MAO-B inhibitors, with Kᵢ values of 20.0 ± 2.83 nM and 10.0 ± 2.82 nM, respectively. Furthermore, IC50 values of AChE inhibitory activities ranged from 5.40 to > 40 µM, whereas those of BuChE inhibitory activity range from 4.30 to > 40 µM. DLC6 showed the best AChE inhibitory potential with IC50 values of 5.40 ± 0.29 µM, while DLC13 revealed effective BuChE inhibitory potential with an IC50 value of 4.30 ± 0.89 µM. Molecular docking studies performed on hMAO-A and hMAO-B revealed that DLC14 establishes favourable π-π stacking within the aromatic cage of hMAO-B and maintains complementary hydrophobic contacts along the substrate cavity, whereas DLC6 lacks this key interaction due to steric interference of the ethoxy substituent. Among the three most potent MAO-B inhibitors (DLC2, DLC9, and DLC14), DLC2 exhibited the most favourable microsomal stability with the longest half-life and lowest intrinsic clearance, whereas DLC14 showed comparable metabolic profiles in rat and human liver microsomes. Experimental BBB permeability assays were hindered by compound-membrane interactions; however, in silico predictions indicated satisfactory oral bioavailability and brain penetration for all three candidates. In the MPTP-induced rat model of parkinsonism, the selective MAO-B inhibitor DLC14 and the non-selective inhibitor DLC6 significantly improved motor deficits and behavioural impairments across open field, pole, bar, rotarod, and forced swim tests, with progressive improvements observed up to Day 28. Notably, DLC14 consistently outperformed DLC6 and demonstrated an efficacy profile comparable to that of Selegiline, highlighting its therapeutic potential as an antiparkinsonian agent. These results indicate that DLC14 is potent and selective MAO-B inhibitor and could serve as promising candidate for the treatment of neurodegenerative disorders, such as Parkinson's disease.

Accumulation of amyloid-β (Aβ) plaques is an important cause of Alzheimer's disease (AD) pathogenesis. In this study, we evaluated Aβ aggregation inhibitory activity of synthesized naphthoquinone derivatives as well as improvement in cognitive functions and metabolite profiling of brain tissues using scopolamine (SCO)-induced mice. Compound 888 (2-(4-(2,3,4-trimethoxybenzyl)piperazin-1-yl)naphthalene-1,4-dione, [TPN]) showed the highest Aβ aggregation inhibitory activity (IC50 = 0.14 μM), and was more potent than the reference compound curcumin (IC50 = 1.63 μM). Compound TPN showed effective monoamine oxidase (MAO)-A, MAO-B, acetylcholinesterase, and butyrylcholinesterase inhibitions at 10 μM, likely as candidates for multitarget-directed ligands. TPN was permeable through the blood-brain barrier, and non-toxic to MDCK and SH-SY5Y cells. TPN displayed prolonged and stable interactions with Aβ42 during molecular dynamics simulations, in contrast to the short-lived contacts observed for curcumin. Cognitive impairment was significantly improved by TPN-treatment in behavioral tests. TPN treatment attenuated Aβ-related protein expression, inflammatory responses, oxidative stress-related changes, and apoptosis-related alterations, while preserving hippocampal pyramidal neurons and their typical morphology. In metabolite profiling, TPN modulated a narrower set of pathways mainly related to amino acid and kynurenine metabolism, whereas donepezil induced broader adjustments involving amino acid, mitochondrial/energy, and lipid-related pathways compared to those in the serum and cortex of the SCO group, in contrast to those in the hippocampus. Collectively, a potent Aβ aggregation inhibitor TPN showed significant cognitive improvement, accompanying by neuroprotective effects, decreasing inflammation, and retaining neuron structures, exhibiting changed metabolic profiles compared to the control treatments. These findings suggest that TPN has cognitive-protective and neuroprotective potential under scopolamine-induced impairment conditions and warrants further validation in AD-relevant models.

Proprotein convertase subtilisin/kexin 9 (PCSK9) mediating the degradation of the hepatic low-density lipoprotein receptor (LDLR), has emerged as a novel therapeutic target for the treatment of hyperlipidemia. Herein, to disrupt the protein-protein interactions (PPIs) between PCSK9 and LDLR, a total of 43 compounds were designed and synthesized by structural modification of previous derived PCSK9 inhibitors. In the PCSK9-LDLR PPI interfering test, compounds B7, B23, and B27 showed inhibitory potency with IC50 values of 8.86 μM, 3.95 μM, and 5.02 μM, respectively, compared with the positive control SBC-115,337 (IC50 value of 11.36 μM). Molecular docking predicted binding mode of compound B27 on the PCSK9-LDLR interaction interface, and hydrophobic interactions play an important role in the binding of B27 to PCSK9. Moreover, compounds B7, B23, and especially B27 restored the expression of LDLR and increased LDL uptake of HepG2 cell in the presence of PCSK9. Collectively, lead compounds with lipid-lowering potential were developed for further design of PCSK9-LDLR PPI inhibitors.

Mutations in, or misregulation of, Tp53 are found in approximately 50% of all cancers. p53 functions by ensuring that cells with irretrievably damaged DNA undergo apoptosis. Tp53 mutations often induce conformational changes that inhibit activity; however, small-molecule chaperones could theoretically restore conformation and activity. COTI-2, a thiosemicarbazone with orphan-drug status for ovarian cancer, has proven an effective cytotoxic agent against various cancer cell lines in vitro, exhibited efficacy in vivo, and has demonstrated a good safety profile in Phase 1b human clinical trials. The proposed mechanism, direct engagement and refolding of mutant p53, has been supported by a combination of cell-based assays and transcriptomics data. Through a combination of experimental and computational approaches, we demonstrate that this is an unlikely mechanism of action, and that COTI-2 instead likely acts as a selective, well-tolerated, zinc chaperone to replace zinc ions lost to p53 mutants' deficient zinc-binding.

The global escalation of antimicrobial resistance poses a critical threat to public health, emphasizing the need for innovative therapeutic scaffolds with novel mechanisms of action. Among various heterocyclic frameworks, the indole nucleus has attracted significant attention due to its structural versatility and extensive pharmacological profile. The discussion systematically examines diverse biological targets, including bacterial cell wall biosynthesis, FtsZ-mediated cytokinesis, DNA gyrase, dihydrofolate reductase, glutathione S-transferase, and CYP51 enzymes. For each target, recent synthetic analogs, their mechanistic implications, and structure-activity relationships are examined to highlight the molecular determinants responsible for enhanced efficacy and selectivity. Classical and contemporary synthetic strategies, such as the Fischer, Bartoli, and Madelung methods, as well as metal-catalyzed cyclisation methods, are outlined to provide a foundation for rational drug design. Furthermore, molecular docking and structure-based drug design studies are reviewed to correlate binding affinities with observed bioactivities. The inclusion of FDA-approved indole-containing drugs and ongoing clinical evaluations underscores the translational relevance of this scaffold. Overall, this review accentuates the versatility of the indole core as a privileged pharmacophore and its promise in the development of next-generation antimicrobial agents capable of overcoming multidrug resistance. Continued efforts to optimize indole hybrids and elucidate their mechanistic pathways are anticipated to yield potent, safe, and clinically viable therapeutics.

Hypoxia-inducible factor-1 α (HIF-1α) is a key transcription factor for tumor cells to sense and adapt to the hypoxic microenvironment, regulate tumor progression such as tumor glycolysis, and is an important target for the development of anti-tumor drugs. YC-1 (1-benzyl-3-(5'-hydroxymethyl-2'-furyl)indazole), as a classic inhibitor of HIF-1α, has received extensive attention in multiple anti-tumor studies. Some derivatives that replace YC-1 indazole with the benzimidazole skeleton have shown certain HIF-1α inhibitory and anti-tumor potential. In this study, a series of substituted benzimidazole derivatives were designed and synthesized, and their HIF-1α inhibitory and anti-tumor effects were screened and investigated. In vitro anti-proliferation and dual-luciferase reports showed that compound 9o had superior in vitro anti-tumor (IC50 = 33.85 μM) and HIF-1α transcriptional inhibitory activity (79.59% inhibition rate) compared with the positive control YC-1. Meanwhile, compound 9o can also significantly inhibit the colony formation and survival rate of HCT-116 cells. In addition, Western blotting, real-time PCR and and lactic acid content experiments verified its inhibitory effect on HIF-1α and downstream glycolysis. In addition, compound 9o was found to reduce platelet aggregation more than YC-1, and the molecular docking results suggested that compound 9o weakened its interaction with soluble guanylate cyclase (sGC), which is beneficial for avoiding the bleeding risk during tumor treatment. In vivo studies have shown that compound 9o can inhibit tumor growth and reduce the levels of HIF-1α and glycolysis rate-limiting enzyme HK2 in HCT-116 tumor-bearing mice. The acute toxicity results also demonstrated the safety of compound 9o in vivo. Finally, we also explored its pharmacokinetic properties in rats, suggesting its potential for subsequent intravenous administration. These findings provide a basis for the further discovery of anti-tumor candidate compounds based on HIF-1α inhibitors.

Poly(ADP-ribose) polymerase-1 (PARP-1) plays a central role in the repair of DNA single-strand breaks and represents an established therapeutic target in cancer treatment. In this study, a series of novel oxadiazole-morpholine hybrid compounds was designed and synthesized using a structure-based drug design approach to target the catalytic domain of PARP-1. The synthesized compounds were evaluated for their cytotoxic activity against breast and ovarian cancer cells, PARP-1 inhibitory potency, and apoptosis-inducing effects. Among the tested compounds, 12a exhibited potent cytotoxic activity against MDA-MB-231 cells (IC50 = 1.23 μM), surpassing the reference drug olaparib (IC50 = 3.45 μM). Compound 12a also demonstrated strong PARP-1 inhibitory activity (IC50 = 0.034 μM), comparable to olaparib (IC50 = 0.012 μM). Flow cytometric analyses revealed that compound 12a significantly induced apoptotic cell death and altered cell cycle progression. Molecular docking studies suggested plausible binding interactions within the PARP-1 catalytic site, supporting the observed biological activity. These findings identify oxadiazole-morpholine hybrids as promising scaffolds for further optimization as PARP-1 inhibitors.