Plant-parasitic nematodes impose a severe risk to crops, affecting their yield and quality. To discover new nematicides, a series of natural juglone derivatives containing amide fragments, sulfonyl or ester groups were designed and synthesized with the activity-oriented strategy. Bioassays showed that most compounds exhibit good nematicidal activity against Bursaphelenchus xylophilus, Aphelenchoides besseyi, and Ditylenchus destructor. Especially, compound 4r exhibited outstanding nematicidal activity against B. xylophilus with an LC50 value of 9.4 ± 0.3 μg/mL at 48 h, outperforming juglone (LC50 = 15.7 ± 0.3 μg/mL) and fosthiazate (LC50 > 400 μg/mL). The preliminary results of the mechanism study revealed that compound 4r can not only disrupt structure but also affect the behavior, feeding, reproduction, and eggs hatching of B. xylophilus. Especially, compound 4r can promote the production of reactive oxygen species and lipofuscin and lipids within nematodes, leading to elevated malondialdehyde levels and reduced activity of antioxidant enzymes like superoxide dismutase, glutathione-S-transferase, and catalase, thereby exacerbating oxidative damage in nematodes. These findings indicate that natural juglone skeleton is a valuable template for discovering new nematicides, with compound 4r being a promising nematicides candidate.

Epilepsy is a common neurological disorder frequently complicated by drug resistance, underscoring the urgent need for novel therapeutic agents. Using a pharmacophore hybridization strategy, we designed and synthesized two series of novel hybrid compounds by conjugating memantine (an NMDA receptor antagonist) with levetiracetam (a modulator of synaptic vesicle glycoprotein 2 A, SV2A) and lacosamide (a sodium channel blocker), respectively. Cytotoxicity screening against four human cell lines at 100 μM identified 11 compounds with >70% cell viability. Among them, compound 11a-d lacosamide-memantine hybrid linked by a flexible alkyl chain-was selected as the most promising candidate based on in silico ADME profiling and safety evaluation. In mice, 11a exhibited no overt toxicity or neurotoxicity at doses up to 200 mg/kg. In the pentylenetetrazole (PTZ)-induced seizure model, administration of 11a at 50 mg/kg significantly prolonged the latency to first clonic seizure by 57% (from 76.3 s in the vehicle group to 179.0 s) and reduced the Racine score by 40% (from 5.25 to 3.13), achieving anticonvulsant efficacy comparable to lacosamide and levetiracetam. CETSA and DARTS assays confirmed that 11a simultaneously binds to voltage-gated sodium channels (Nav) and N-methyl-d-aspartate receptors (NMDAR), supporting its dual-target mechanism of action. Although passive blood-brain barrier permeability was predicted to be low, the potent central anticonvulsant activity of 11a suggests sufficient brain exposure, likely via active uptake transporters. Collectively, this study validates the dual-target hybridization strategy and identifies 11a as a promising lead for antiepileptic drug development.

Objective:This study aimed to to evaluate the efficacy and safety of hydrodissection in refractory painful peripheral neuropathy over six months, and to explore whether the DCEC ultrasound scoring system predicts treatment response. Methods:The study included 57 patients diagnosed with intractable painful peripheral neuropathy confirmed by neuroelectrophysiology who visited the outpatient or inpatient departments of the Affiliated Hospital of Guizhou Medical University from March 2023 to June 2024. All patients underwent nerve ultrasound examination and were scored using the DCEC ultrasound scoring system, as well as neurological function assessments (including the Michigan Neuropathy Screening Tool, Toronto Clinical Scoring Scale, and Short-Form McGill Pain Questionnaire). All patients were divided into two groups: the first group consisted of 18 patients with diabetic painful peripheral neuropathy, and the second group consisted of 39 patients with non-diabetic painful peripheral neuropathy. The adverse reactions and complications of both groups after nerve hydrodissection treatment were recorded. The correlation between nerve ultrasound DCEC scores, Michigan and Toronto scores, and visual analog scale (VAS) and Short-Form McGill scores before and after treatment was analyzed. Results:The VAS scores and SF-MPQ scores of both patient groups showed significant improvement at 1, 2, 3, and 6 months after treatment compared to before treatment (P<0.001), but there was no significant difference between the two groups. At 3 and 6 months, the percentage of patients with ≥50% improvement both in VAS scores and SF-MPQ scores were higher in the DPPN group compared to the NDPPN group (P=0.004, P=0.021, P=0.001, P=0.016). The clarity score of nerve ultrasound in the affected limb is correlated with pain improvement after treatment (P=0.015). Conclusion:Ultrasound-guided nerve hydrodissection may provide pain relief for patients with intractable painful peripheral neuropathy and has good safety. Further controlled studies are needed to confirm its efficacy.

This study presents a a straightforward synthetic approach to the specific pentacyclic bisindole structures related to fascaplysin alkaloids. The key transformation is an acid-promoted cascade involving a C-N bond formation/Mannich-type cyclization/dehydrogenation sequence. Nineteen novel bisindole derivatives bearing a wide range of functional groups were prepared by this method.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by hallmark pathological changes such as amyloid β (Aβ) plaques, neurofibrillary tangles (NFTs) due to tau hyperphosphorylation, and neuroinflammation. Current therapeutic approaches focusing on single-target strategies exhibit limited efficacy, necessitating the exploration of novel multi-target approaches. Histone deacetylase 6 (HDAC6) and SIRT2, as two types of cytosolic histone deacetylases, have emerged as promising targets for AD treatment. HDAC6 plays a role in tau protein phosphorylation, while SIRT2 is involved in Aβ production. Both enzymes regulate microtubule proteins, impacting the formation of NFTs and Aβ plaques. Inhibition of HDAC6 reduces tau hyperphosphorylation, improves microtubule stability, and mitigates neuroinflammation, whereas SIRT2 inhibition attenuates Aβ accumulation and neuroinflammation. Recent studies indicate that dual-targeted inhibition of HDAC6 and SIRT2 may exhibit synergistic effects, suggesting it as a promising strategy for AD treatment. This review summarizes the biological roles of HDAC6 and SIRT2 in AD pathology and examines the development of dual-target inhibitors. It also discusses the challenges, including selectivity and toxicity, emphasizing that the development of combined HDAC6 and SIRT2 inhibitors represents a new direction for future AD treatment.

Maintaining protein homeostasis is vital for multiple myeloma (MM) cell survival. Indirubin- 3-monoxime (I3MO), a potential MM therapeutic, inhibits proteasome activity, while histone deacetylase 6 (HDAC6) regulates autophagy. We developed I3MV- 8b, an I3MO derivative, integrating an HDAC6 inhibitor moiety to enhance dual inhibition of proteasome and autophagy pathways. The anti-MM effects of I3MV- 8b were tested in vitro and in vivo. To identify downstream targets, RNA-seq and dual-luciferase reporter assays were performed. Additionally, ChIP-seq and IP-MS techniques were employed to elucidate the underlying molecular mechanism. I3MV- 8b significantly suppressed MM cell proliferation and induced apoptosis. Combined with proteasome inhibitors, I3MV- 8b enhanced cytotoxicity by concurrently inhibiting proteasome and autophagy pathways. It reduced TRIM28 transcription, correlating with lower expression of proteasome subunits and autophagy-related genes. ChIP-seq revealed that TRIM28 binds to proteasome gene promoters, and its knockdown decreased proteasome subunit expression and activity. TRIM28 knockdown also impaired autophagosome formation. IP-MS and Co-IP assays showed TRIM28 interacted with 14–3 - 3ζ, a negative regulator of autophagy, promoting its ubiquitination and degradation. This interaction reduced autophagy regulation, further sensitizing cells to treatment. I3MV- 8b offers a novel dual inhibition strategy targeting proteasome and autophagy, presenting a promising therapeutic option for MM.

Epilepsy is a chronic neurological disorder characterized by abnormal neuronal discharge, leading to recurrent and unpredictable disruptions in brain function. Despite over 30 antiepileptic drugs (AEDs), 30% of patients develop drug-resistant epilepsy, requiring combination therapy. This review explores epilepsy’s pathogenesis, including neuronal hyperexcitability, neurotransmitter imbalances, and ion channel dysfunction, alongside genetic, inflammatory, immune, and oxidative stress factors. AEDs are classified by mechanisms like voltage-gated ion channel modulation and GABA/glutamate regulation, tracing their evolution from traditional (e.g., phenobarbital) to modern therapies (e.g., lamotrigine). Combination therapy, using complementary mechanisms (e.g., lacosamide with levetiracetam), enhances efficacy but poses risks like drug interactions and cognitive impairment. Integrating molecular biology and pharmacology advances, this review highlights the need for rational drug selection and individualized strategies to improve epilepsy treatment outcomes and patient quality of life. Future directions include personalized treatments, optimized dosage forms, novel drug targets, and multi-target drugs.

Lysine benzoylation (Kbz) is a recently identified post-translational modification on a histone that plays a crucial role in regulating cellular processes. Current detection methods primarily rely on mass spectrometry, which limits the ability to dynamically track lysine benzoylation within living cells. Although azide/alkyne small-sized probes have enabled in vitro labeling of various protein acylated modifications, their use in dynamic tracking in cellular levels is limited. Herein, we report a novel 1-methylcyclopropene chemical reporter that undergoes an IEDDA reaction with S-tetrazine-BODIPY 8, which was evaluated for its optical properties, kinetic constants, and bio-orthogonality, revealing it to be the most efficient benzoic acid probe 2. In addition, when SIRT2 acts on the peptides labeled with probe 2, the kinetic parameters of these peptides are comparable to those of endogenously benzoylated peptides. Finally, the metabolic labeling of lysine benzoylation was successfully validated in RAW and HepG2 cells using probe 2. Furthermore, by using a SIRT2 inhibitor, it was confirmed that this metabolic labeling can be applied to dynamically detect changes in lysine benzoylation levels in cells. These findings provide a solid foundation for the development of novel metabolic labeling strategies for dynamically tracking post-translational modifications, particularly in live cells.

This article explores the asymmetric Michael addition reaction of 2-hydroxy-1,4-naphthoquinone and indole-3-ones catalyzed by cinchona alkaloids. This strategy utilizes 2-hydroxy-1,4-naphthoquinone and easily prepared indole-3-one as substrates, resulting in the synthesis of 23 unprecedented indolin-3-ones bearing a 1,4-naphthoquinone unit at the C2 position of indole under simple and mild reaction conditions, with up to 88% yield, 98% ee, and >20:1 dr.

Prostate-specific membrane antigen (PSMA) overexpressed in prostate cancer cells can serve as a target for imaging and radioligand therapy (RLT). Previously, [68Ga]Ga-P16-093, containing a Ga(III) chelator, N,N'-bis[2-hydroxy-5-(carboxyethyl)benzyl]ethylenediamine-N,N'-diacetic acid (HBED-CC), displayed excellent PSMA-targeting properties and showed a high tumor uptake and retention useful for diagnosis in prostate cancer patients. Recently, [177Lu]Lu-PSMA-617 has been approved by the U.S. food and drug administration (FDA) for the treatment of prostate cancer patients. Derivatives of PSMA-093 using AAZTA (6-amino-6-methylperhydro-1,4-diazepinetetraacetic acid), as the chelator, were designed as alternative agents forming complexes with both diagnostic and therapeutic radiometals, such as gallium-68 (log K = 22.18) or lutetium-177 (log K = 21.85). The aim of this study is to evaluate AAZTA-Gly-O-(methylcarboxy)-Tyr-Phe-Lys-NH-CO-NH-Glu (designated as AZ-093, 1) leading to a gallium-68/lutetium-177 theranostic pair as potential PSMA targeting agents. Synthesis of the desired precursor, AZ-093, 1, was effectively accomplished. Labeling with either [68Ga]GaCl3 or [177Lu]LuCl3 in a sodium acetate buffer solution (pH 4-5) at 50 °C in 5 to 15 min produced either [68Ga]Ga-1 or [177Lu]Lu-1 with high yields and excellent radiochemical purities. Results of in vitro binding studies, cell uptake, and retention (using PSMA-positive prostate carcinoma cells line, 22Rv1-FOLH1-oe) were comparable to that of [68Ga]Ga-P16-093 and [177Lu]Lu-PSMA-617, respectively. Specific cellular uptake was determined with or without the competitive blocking agent (2 μM of "cold" PSMA-11). Cellular binding and internalization showed a time-dependent increase over 2 h at 37 °C in the PSMA-positive cells. The cell uptakes were completely blocked by the "cold" PSMA-11 suggesting that they are competing for the same PSMA binding sites. In the mouse model with implanted PSMA-positive tumor cells, both [68Ga]Ga-1 and [177Lu]Lu-1 displayed excellent uptake and retention in the tumor. Results indicate that [68Ga]Ga/[177Lu]Lu-1 (68Ga]Ga/[177Lu]Lu-AZ-093) is potentially useful as PSMA-targeting agent for both diagnosis and radiotherapy of prostate cancer.

Sirtuins belong to a specific class of enzymes called NAD+-dependent protein deacetylases. Among them, SIRT2 is predominantly localized in the cytoplasm and plays a vital role in tumor development and progression. As a result, it becomes an important target for the development of anticancer drugs. While SIRT2 inhibitors have shown broad-spectrum cytotoxicity against various cancer cells, their ability to inhibit the growth of certain cancers like prostate cancer has been limited, possibly due to insufficient targeting properties. To overcome this limitation, our goal was to target prostate-specific membrane antigen (PSMA), a valuable biomarker for prostate cancer, using lysine-urea-glutamic acid (KUE) as a PSMA ligand. This approach allowed us to systematically design new SIRT2 inhibitors. Evaluation showed that compound 17 exhibited superior inhibitory activity, improved targeting properties, and enhanced antiproliferative efficacy specifically in prostate cancer cells. These findings suggest a promising strategy for utilizing SIRT2 inhibitors in prostate cancer therapy.

Since the appearance of SARS-CoV-2 in 2019, the ensuing COVID-19 (Corona Virus Disease 2019) pandemic has posed a significant threat to the global public health system, human health, life, and economic well-being. Researchers worldwide have devoted considerable efforts to curb its spread and development. The latest studies have identified five viral proteins, spike protein (Spike), viral main protease (3CLpro), papain-like protease (PLpro), RNA-dependent RNA polymerase (RdRp), and viral helicase (Helicase), which play crucial roles in the invasion of SARS-CoV-2 into the human body and its lifecycle. The development of novel anti-SARS-CoV-2 drugs targeting these five viral proteins holds immense promise. Therefore, the development of efficient, high-throughput screening methodologies specifically designed for these viral proteins is of utmost importance. Currently, a plethora of screening techniques exists, with fluorescence-based assays emerging as predominant contenders. In this review, we elucidate the foundational principles and methodologies underpinning fluorescence-based screening approaches directed at these pivotal viral targets, hoping to guide researchers in the judicious selection and refinement of screening strategies, thereby facilitating the discovery and development of lead compounds for anti-SARS-CoV-2 pharmaceuticals.

Nsp13, a non-structural protein belonging to the coronavirus family 1B (SF1B) helicase, exhibits 5′–3′ polarity-dependent DNA or RNA unwinding using NTPs. Crucially, it serves as a key component of the viral replication–transcription complex (RTC), playing an indispensable role in the coronavirus life cycle and thereby making it a promising target for broad-spectrum antiviral therapies. The imidazole scaffold, known for its antiviral potential, has been proposed as a potential scaffold. In this study, a fluorescence-based assay was designed by labeling dsDNA substrates with a commercial fluorophore and monitoring signal changes upon Nsp13 helicase activity. Optimization and high-throughput screening validated the feasibility of this approach. In accordance with the structural characteristics of ADP, we employed a structural-based design strategy to synthesize three classes of imidazole-based compounds through substitution reaction. Through in vitro activity research, pharmacokinetic parameter analysis, and molecular docking simulation, we identified compounds A16 (IC50 = 1.25 μM) and B3 (IC50 = 0.98 μM) as potential lead antiviral compounds for further targeted drug research.

Hepatitis B virus (HBV) infection remains a significant global health challenge, often leading to severe liver complications such as cirrhosis and cancer. Current treatments rely heavily on nucleos(t)ide analogues like adefovir and tenofovir due to their potent antiviral effects. However, their clinical utility is limited by insufficient liver targeting, leading to off-target side effects, particularly nephrotoxicity. To improve liver-specific drug delivery and reduce adverse effects, we designed novel liver-targeted prodrugs by conjugating adefovir and tenofovir with N-acetylgalactosamine (GalNAc) and tris-GalNAc ligands, which have high affinity for the asialoglycoprotein receptor (ASGPR) predominantly expressed in hepatocytes. Four prodrugs (A1, A2, T1, and T2) were synthesized and evaluated for cytotoxicity, maximum tolerated dose, anti-HBV activity, metabolic stability, pharmacokinetics, and liver-targeting properties. The prodrugs exhibited low cytotoxicity, robust anti-HBV activity, and enhanced selectivity compared to their parent drugs. Notably, the tris-GalNAc conjugates A2 and T2 demonstrated superior liver targeting, showing a threefold higher concentration in the liver compared to the kidneys, thus minimizing renal exposure. These findings suggest that GalNAc and tris-GalNAc conjugation is a promising strategy for enhancing the therapeutic efficacy and safety of adefovir and tenofovir, with potential for further optimization as liver-targeted anti-HBV prodrugs.

ABSTRACTBackgroundThalassemia is an inherited hemolytic disease, the complications and sequelae of which have posed a huge impact on both patients and society. But limited studies have investigated the molecular characterization of α‐ and β‐thalassemia in children from Guizhou, China.MethodsBetween January 2019 and December 2022, a total of 3301 children, aged 6 months to 18 years, suspected of having thalassemia underwent molecular analysis.ResultsOut of the total sample, 824 (25%) children were found to carry thalassemia mutations. The carrier rates of α‐thalassemia, β‐thalassemia, and α + β‐thalassemia were determined as 8.1%, 15.6%, and 1.3%, respectively. Approximately 96.5% of the α‐thalassemia gene mutations were ‐‐SEA (51%), ααCS (20.9%), ‐α3.7 (19.6%), and ‐α4.2 (5.0%). The most prevalent mutations of β‐thalassemia were βCD17(A>T) (41.5%), βCD41‐42(‐TTCT) (37.7%), and βIVS‐II‐654(C>T) (11.3%). Additionally, we identified rare cases, including one case with ααHb Nunobiki/αα, two cases with triplicated α‐thalassemia (one case with ααα/ααα and βCD41‐42/βN and the other with ααα‐3.7/αα and βE CD26/βN), and also one case with α Q‐Thailandα/‐α4.2 and βCD41‐42/βN.ConclusionsOur study findings provide important insights into the heterogeneity of thalassemia carrier rates and molecular profiles among children in the Guizhou region. The findings support the development of prevention strategies to reduce the incidence of severe thalassemia in the future.

Fibroblast activation protein (FAP), which is overexpressed in cancer-associated fibroblasts (CAFs), represents a promising target for cancer diagnosis and therapy. Hypoxia is a common feature of solid tumors. A bivalent agent, DOTA-NI-FAPI-04 (1), was developed by incorporating hypoxia-sensitive nitroimidazole (NI) into the FAP-targeting agent FAPI-04. Compound 1 exhibited a strong FAP binding affinity with an IC50 of 7.44 nM. Radiolabeled [68Ga]Ga-1 and [177Lu]Lu-1 demonstrated enhanced in vitro cell uptake. In vivo positron emission tomography/computed tomography (PET/CT) imaging showed that [68Ga]Ga-1 displayed significantly higher specific uptake and retention in U87MG tumor-bearing mice compared to [68Ga]Ga-FAPI-04 (SUVavg: 7.87 vs 1.99% ID/mL at 120 min). Biodistribution studies confirmed superior tumor uptake of [68Ga]Ga-1 (48.15 vs 5.72% ID/g at 120 min). Similarly, [177Lu]Lu-1 exhibited higher tumor uptake than [177Lu]Lu-FAPI-04 (50.75 vs 20.48% ID/g at 120 min). These preliminary results suggest that a nitroimidazole-containing bivalent-targeting agent, [68Ga]Ga/[177Lu]Lu-1, is a promising candidate for tumor theranostics.

Background Anemia is a signi fi cant contributor to the global disease burden, of which thalassemia is the most common hereditary anaemic disease. Previous estimates were based on data that were geographically limited and lacked comprehensive global analysis. This study provides the prevalence, incidence, mortality and disability-adjusted life years (DALYs) of thalassemia in 204 countries and regions of thalassemia between 1990 and 2021, focusing on the age structure and time trends of the disease burden. To provide effective information for health policy, allocation of medical resources and optimization of patient management programs. Methods Using the standardised Global Burden of Disease (GBD) methodologies, we aimed to derive a more precise representation of the health burden posed by thalassemia by considering four distinct types of epidemiological data, namely the incidence at birth, prevalence, mortality and DALYs. The presented data were meticulously estimated and displayed both as numerical counts and as age-standardised rates per 100,000 persons of the population, accompanied by uncertainty interval (UI) to highlight potential statistical variability. The temporal trends spanning the years 1990 - 2021 were subjected to a rigorous examination utilizing Join point regression analysis. This methodological approach facilitated the computation of the annual percentage change (APC) and the average annual percentage change (AAPC), along with their corresponding 95% confidence intervals (CIs). Findings Globally, the age-standardized prevalence rates (ASPR), age-standardized incidence rates (ASIR), age standardized mortality rates (ASMR), and age-standardized DALYs rates for thalassemia in 2021 were 18.28 per 100,000 persons (95% UI 15.29 - 22.02), 1.93 per 100,000 persons (95% UI 1.51 - 2.49), 0.15 per 100,000 persons(95% UI 0.11 - 0.20), and 11.65 per 100,000 persons (95% UI 8.24 - 14.94), respectively. Compared to 1990, these rates have decreased by 0.18 (95% UI - 0.22 to - 0.14), 0.25 (95% UI - 0.30 to - 0.19), 0.48 (95% UI - 0.60 to - 0.28), and 0.49 (95% UI - 0.62 to - 0.29) respectively. In 2021, the ASIR of thalassemia was highest in East Asia at 7.35 per 100,000 persons (95% UI 5.37 - 10.04), and ASMR was highest in Southeast Asia at 0.37 per 100,000 persons (95% UI 0.29 - 0.45).Gender comparisons showed negligible differences in disease burden, with the highest prevalence noted in children under five, decreasing with age. The global ASPR and ASMR declined from 1990 to 2021 overall, though an increasing trend in prevalence was found among the elderly. Join point analysis revealed that the global ASPR increased between 2018 and 2021 (APC = 9.2%, 95% CI: 4.8% - 13.8%, P < 0.001), ASIR decreased (APC = - 7.68%, 95% CI: - 10.88% to - 4.36%, P < 0.001), and there was a significant rise in ASMR from 2019 to 2021 (APC = 4.8%, 95% CI: 0.1% - 9.6%, P < 0.05). Trends in ASPR and ASMR varied across regions, with notable changes in South Asia. Interpretation The global burden of thalassemia, reflected in its prevalence, incidence, mortality, and DALYs, exhibits significant disparities. Geographic and demographic shifts in disease distribution have been observed from 1990 to 2021, with an overall decrease in burden, yet an increase in cases among the elderly population. Analysis of epidemiological trends over time highlights the influence of health policies and significant public health interventions on thalassemia outcomes. There data are crucial for healthcare professionals, policymakers, and researchers to re fi ne and enhance management strategies, aiming to further mitigate thalassemia ' s global impact. Funding National Natural Science Foundation of China; Guizhou Province Science and Technology Project; Guizhou Province Science and Technology Foundation of Health Commission. Copyright (c) 2024 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY -NC -ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Histone Deacetylase 6 (HDAC6) is an essential regulator of histone acetylation processes, exerting influence on a multitude of cellular functions such as cell motility, endocytosis, autophagy, apoptosis, and protein trafficking through its deacetylation activity. The significant implications of HDAC6 in diseases such as cancer, neurodegenerative disorders, and immune disorders have motivated extensive investigation into the development of specific inhibitors targeting this enzyme for therapeutic purposes. Single targeting drugs carry the risk of inducing drug resistance, thus prompting exploration of dual targeting therapy which offers the potential to impact multiple signaling pathways simultaneously, thereby lowering the likelihood of resistance development. While pharmacological studies have exhibited promise in combined therapy involving HDAC6, challenges related to potential drug interactions exist. In response to these challenges, researchers are investigating HDAC6 hybrid molecules which enable the concomitant targeting of HDAC6 and other key proteins, thus enhancing treatment efficacy while mitigating side effects and reducing the risk of resistance compared to traditional combination therapies. The published design strategies for dual targeting inhibitors of HDAC6 are summarized and discussed in this review. This will provide some valuable insights into more novel HDAC6 dual targeting inhibitors to meet the urgent need for innovative therapies in oncology and other related fields.