Understanding the interactions between repurposed drugs sertindole and temoporfin with receptor for advanced glycation endproducts: Therapeutic implications in cancer and metabolic diseases.

CONTEXT: In the pursuit of novel therapeutic possibilities, repurposing existing drugs has gained prominence as an efficient strategy. The findings from our study highlight the potential of repurposed drugs as promising candidates against receptor for advanced glycation endproducts (RAGE) that offer therapeutic implications in cancer, neurodegenerative conditions and metabolic syndromes. Through careful analyses of binding affinities and interaction patterns, we identified a few promising candidates, ultimately focusing on sertindole and temoporfin. These candidates exhibited exceptional binding affinities, efficacy, and specificity within the RAGE binding pocket. Notably, they displayed a pronounced propensity to interact with the active site of RAGE. Our investigation further revealed that sertindole and temoporfin possess desirable pharmacological properties that highlighted them as attractive candidates for targeted drug development. Overall, our integrated computational approach provides a comprehensive understanding of the interactions between repurposed drugs, sertindole and temoporfin and RAGE that pave the way for future experimental validation and drug development endeavors. METHODS: We present an integrated approach utilizing molecular docking and extensive molecular dynamics (MD) simulations to evaluate the potential of FDA-approved drugs, sourced from DrugBank, against RAGE. To gain deeper insights into the binding mechanisms of the elucidated candidate repurposed drugs, sertindole and temoporfin with RAGE, we conducted extensive all-atom MD simulations, spanning 500 nanoseconds (ns). These simulations elucidated the conformational dynamics and stability of the RAGE-sertindole and RAGE-temoporfin complexes.

Nanozyme as a rising star for metabolic disease management.

Nanozyme, characterized by outstanding and inherent enzyme-mimicking properties, have emerged as highly promising alternatives to natural enzymes owning to their exceptional attributes such as regulation of oxidative stress, convenient storage, adjustable catalytic activities, remarkable stability, and effortless scalability for large-scale production. Given the potent regulatory function of nanozymes on oxidative stress and coupled with the fact that reactive oxygen species (ROS) play a vital role in the occurrence and exacerbation of metabolic diseases, nanozyme offer a unique perspective for therapy through multifunctional activities, achieving essential results in the treatment of metabolic diseases by directly scavenging excess ROS or regulating pathologically related molecules. The rational design strategies, nanozyme-enabled therapeutic mechanisms at the cellular level, and the therapies of nanozyme for several typical metabolic diseases and underlying mechanisms are discussed, mainly including obesity, diabetes, cardiovascular disease, diabetic wound healing, and others. Finally, the pharmacokinetics, safety analysis, challenges, and outlooks for the application of nanozyme are also presented. This review will provide some instructive perspectives on nanozyme and promote the development of enzyme-mimicking strategies in metabolic disease therapy.

GLP-1 receptor agonist improves metabolic disease in a pre-clinical model of lipodystrophy.

Aims: Individuals with lipodystrophies typically suffer from metabolic disease linked to adipose tissue dysfunction including lipoatrophic diabetes. In the most severe forms of lipodystrophy, congenital generalised lipodystrophy, adipose tissue may be almost entirely absent. Better therapies for affected individuals are urgently needed. Here we performed the first detailed investigation of the effects of a glucagon like peptide-1 receptor (GLP-1R) agonist in lipoatrophic diabetes, using mice with generalised lipodystrophy. Methods: Lipodystrophic insulin resistant and glucose intolerant seipin knockout mice were treated with the GLP-1R agonist liraglutide either acutely preceding analyses of insulin and glucose tolerance or chronically prior to metabolic phenotyping and ex vivo studies. Results: Acute liraglutide treatment significantly improved insulin, glucose and pyruvate tolerance. Once daily injection of seipin knockout mice with liraglutide for 14 days led to significant improvements in hepatomegaly associated with steatosis and reduced markers of liver fibrosis. Moreover, liraglutide enhanced insulin secretion in response to glucose challenge with concomitantly improved glucose control. Conclusions: GLP-1R agonist liraglutide significantly improved lipoatrophic diabetes and hepatic steatosis in mice with generalised lipodystrophy. This provides important insights regarding the benefits of GLP-1R agonists for treating lipodystrophy, informing more widespread use to improve the health of individuals with this condition.

Bioactive Compounds Formulated in Phytosomes Administered as Complementary Therapy for Metabolic Disorders.

Metabolic disorders (MDs), including dyslipidemia, non-alcoholic fatty liver disease, diabetes mellitus, obesity and cardiovascular diseases are a significant threat to human health, despite the many therapies developed for their treatment. Different classes of bioactive compounds, such as polyphenols, flavonoids, alkaloids, and triterpenes have shown therapeutic potential in ameliorating various disorders. Most of these compounds present low bioavailability when administered orally, being rapidly metabolized in the digestive tract and liver which makes their metabolites less effective. Moreover, some of the bioactive compounds cannot fully exert their beneficial properties due to the low solubility and complex chemical structure which impede the passive diffusion through the intestinal cell membranes. To overcome these limitations, an innovative delivery system of phytosomes was developed. This review aims to highlight the scientific evidence proving the enhanced therapeutic benefits of the bioactive compounds formulated in phytosomes compared to the free compounds. The existing knowledge concerning the phytosomes' preparation, their characterization and bioavailability as well as the commercially available phytosomes with therapeutic potential to alleviate MDs are concisely depicted. This review brings arguments to encourage the use of phytosome formulation to diminish risk factors inducing MDs, or to treat the already installed diseases as complementary therapy to allopathic medication.

Angiotensinogen as a Therapeutic Target for Cardiovascular and Metabolic Diseases.

AGT (angiotensinogen) is the unique precursor for the generation of all the peptides of the renin-angiotensin system, but it has received relatively scant attention compared to many other renin-angiotensin system components. Focus on AGT has increased recently, particularly with the evolution of drugs to target the synthesis of the protein. AGT is a noninhibitory serpin that has several conserved domains in addition to the angiotensin II sequences at the N terminus. Increased study is needed on the structure-function relationship to resolve many unknowns regarding AGT metabolism. Constitutive whole-body genetic deletion of Agt in mice leads to multiple developmental defects creating a challenge to use these mice for mechanistic studies. This has been overcome by creating Agt-floxed mice to enable the development of cell-specific deficiencies that have provided considerable insight into a range of cardiovascular and associated diseases. This has been augmented by the recent development of pharmacological approaches targeting hepatocytes in humans to promote protracted inhibition of AGT synthesis. Genetic deletion or pharmacological inhibition of Agt has been demonstrated to be beneficial in a spectrum of diseases experimentally, including hypertension, atherosclerosis, aortic and superior mesenteric artery aneurysms, myocardial dysfunction, and hepatic steatosis. This review summarizes the findings of recent studies utilizing AGT manipulation as a therapeutic approach.

Peroxisome Proliferator-Activated Receptor agonists and antagonists: an updated patent review (2020-2023).

INTRODUCTION: The search for novel compounds targeting Peroxisome Proliferator-Activated Receptors (PPARs) is currently ongoing, starting from the previous successfully identification of selective, dual or pan agonists. In last years, researchers' efforts are mainly paid to the discovery of PPARγ and δ modulators, both agonists and antagonists, selective or with a dual-multitarget profile. Some of these compounds are currently under clinical trials for the treatment of primary biliary cirrhosis, nonalcoholic fatty liver disease, hepatic, and renal diseases. AREAS COVERED: A critical analysis of patents deposited in the range 2020-2023 was carried out. The novel compounds discovered were classified as selective PPAR modulators, dual and multitarget PPAR agonists. The use of PPAR ligands in combination with other drugs was also discussed, together with novel therapeutic indications proposed for them. EXPERT OPINION: From the analysis of the patent literature, the current emerging landscape sees the necessity to obtain PPAR multitarget compounds, with a balanced potency on three subtypes and the ability to modulate different targets. This multitarget action holds great promise as a novel approach to complex disorders, as metabolic, inflammatory diseases, and cancer. The utility of PPAR ligands in the immunotherapy field also opens an innovative scenario, that could deserve further applications.

The combination of Brassica rapa L. polysaccharides and cisplatin enhances the anti liver cancer effect and improves intestinal microbiota and metabolic disorders.

Polysaccharides are commonly used as low-toxicity anticancer active substances to enhance the chemotherapeutic effect of cisplatin and reduce toxicity. Brassica rapa L. polysaccharides have been shown to have hepatoprotective effects; however, their anticancer effects in combination with cisplatin and their mechanisms have not been reported. An acidic polysaccharide from Brassica rapa L. (BRCPe) using hydroalcohol precipitation-assisted sonication was Characterized. The effects of BRCPe combined with cisplatin treatment on tumor growth in hepatocellular carcinoma mouse model were investigated. The impact of the combined treatment on the composition of intestinal flora, levels of short-chain fatty acids and endogenous metabolites in tumor mice were analyzed based on macrogenomic and metabolomic data Our results showed that the BRCPe combined with low-dose Cisplatin group showed better inhibitory activity against hepatocellular carcinoma cell growth in terms of tumor volume, tumor weight, and tumor suppression rate compared with the BRCPe and Cisplation alone group, and reduced the side effects of cisplatin-induced body weight loss, immune deficiency, and liver injury. Furthermore, BRCPe combined with cisplatin was found to induce apoptosis in hepatocellular carcinoma cell through the activation of the caspase cascade reaction. In addition, the intervention of BRCPe were observed to modulate the composition, structure and functional structure of intestinal flora affected by cisplatin. Notably, Lachnospiraceae bacteria, Lactobacillus murinus, Muribaculaceae, and Clostridiales bacteria were identified as significant contributors to microbial species involved in metabolic pathways. Moreover, BRCPe effectively regulate the metabolic disorders in cisplatin-induced hepatocellular carcinoma mice. In conclusion, BRCPe could potentially function as an adjuvant or dietary supplement to augment the effectiveness of cisplatin chemotherapy through the preservation of a more efficient intestinal microenvironmental homeostasis.

Palmitoleic Acid Ameliorates Metabolic Disorders and Inflammation by Modulating Gut Microbiota and Serum Metabolites.

SCOPE: Palmitoleic acid (POA) is an omega-7 monounsaturated fatty acid that has been suggested to improve metabolic disorders. However, it remains unclear whether gut microbiota plays a role in the amelioration of metabolic disorders by POA. This study aims to investigate the regulation of POA on metabolism, as well as systemic inflammation in HFD-fed mice from the perspective of serum metabolome and gut microbiome. METHODS AND RESULTS: Thirty-six C57BL/6 male mice are randomly assigned to either a normal chow diet containing 1.9% w/w lard or an HFD containing 20.68% w/w lard or 20.68% w/w sea buckthorn pulp oil for 16 weeks. The study finds that POA significantly attenuated hyperlipidemia, insulin resistance, and inflammation in HFD-fed mice. POA supplementation significantly alters the composition of serum metabolites, particularly lipid metabolites in the glycerophospholipid metabolism pathway. POA obviously increases the abundance of Bifidobacterium and decreases the abundance of Allobaculum. Importantly, the study finds that glycerophosphocholine mediates the effect of Bifidobacterium on LDL-C, sphingomyelin mediates the effect of Bifidobacterium on IL-6, and maslinic acid mediates the effect of Allobaculum on IL-6. CONCLUSION: The results suggest that exogenous POA can improve metabolic disorders and inflammation in HFD-fed mice, potentially by modulating the serum metabolome and gut microbiome.

The cytoplasmic sensor, the AIM2 inflammasome: A precise therapeutic target in vascular and metabolic diseases.

Cardio-cerebrovascular diseases encompass pathological changes in the heart, brain and vascular system, which pose a great threat to health and well-being worldwide. Moreover, metabolic diseases contribute to and exacerbate the impact of vascular diseases. Inflammation is a complex process that protects against noxious stimuli but is also dysregulated in numerous so-called inflammatory diseases, one of which is atherosclerosis. Inflammation involves multiple organ systems and a complex cascade of molecular and cellular events. Numerous studies have shown that inflammation plays a vital role in cardio-cerebrovascular diseases and metabolic diseases. The absent in melanoma 2 (AIM2) inflammasome detects and is subsequently activated by double-stranded DNA in damaged cells and pathogens. With the assistance of the mature effector molecule caspase-1, the AIM2 inflammasome performs crucial biological functions that underpin its involvement in cardio-cerebrovascular diseases and related metabolic diseases: The production of interleukin-1 beta (IL-1ß), interleukin-18 (IL-18) and N-terminal pore-forming Gasdermin D fragment (GSDMD-N) mediates a series of inflammatory responses and programmed cell death (pyroptosis and PANoptosis). Currently, several agents have been reported to inhibit the activity of the AIM2 inflammasome and have the potential to be evaluated for use in clinical settings. In this review, we systemically elucidate the assembly, biological functions, regulation and mechanisms of the AIM2 inflammasome in cardio-cerebrovascular diseases and related metabolic diseases and outline the inhibitory agents of the AIM2 inflammasome as potential therapeutic drugs.

Protein tyrosine phosphatase 1B in metabolic diseases and drug development.

Protein tyrosine phosphatase 1B (PTP1B), a non-transmembrane phosphatase, has a major role in a variety of signalling pathways, including direct negative regulation of classic insulin and leptin signalling pathways, and is implicated in the pathogenesis of several cardiometabolic diseases and cancers. As such, PTP1B has been a therapeutic target for over two decades, with PTP1B inhibitors identified either from natural sources or developed throughout the years. Some of these inhibitors have reached phase I and/or II clinical trials in humans for the treatment of type 2 diabetes mellitus, obesity and/or metastatic breast cancer. In this Review, we summarize the cellular processes and regulation of PTP1B, discuss evidence from in vivo preclinical and human studies of the association between PTP1B and different disorders, and discuss outcomes of clinical trials. We outline challenges associated with the targeting of this phosphatase (which was, until the past few years, viewed as difficult to target), the current state of the field of PTP1B inhibitors (and dual phosphatase inhibitors) and future directions for manipulating the activity of this key metabolic enzyme.

Exploring the Therapeutic Potential of Royal Jelly in Metabolic Disorders and Gastrointestinal Diseases.

Metabolic disorders, encompassing diabetes mellitus, cardiovascular diseases, gastrointestinal disorders, etc., pose a substantial global health threat, with rising morbidity and mortality rates. Addressing these disorders is crucial, as conventional drugs often come with high costs and adverse effects. This review explores the potential of royal jelly (RJ), a natural bee product rich in bioactive components, as an alternative strategy for managing metabolic diseases. RJ exhibits diverse therapeutic properties, including antimicrobial, estrogen-like, anti-inflammatory, hypotensive, anticancer, and antioxidant effects. This review's focus is on investigating how RJ and its components impact conditions like diabetes mellitus, cardiovascular disease, and gastrointestinal illnesses. Evidence suggests that RJ serves as a complementary treatment for various health issues, notably demonstrating cholesterol- and glucose-lowering effects in diabetic rats. Specific RJ-derived metabolites, such as 10-hydroxy-2-decenoic acid (10-HDA), also known as the "Queen bee acid," show promise in reducing insulin resistance and hyperglycemia. Recent research highlights RJ's role in modulating immune responses, enhancing anti-inflammatory cytokines, and suppressing key inflammatory mediators. Despite these promising findings, further research is needed to comprehensively understand the mechanisms underlying RJ's therapeutic effects.

Targeting Metabolic Diseases: The Role of Nutraceuticals in Modulating Oxidative Stress and Inflammation.

The escalating prevalence of metabolic and cardiometabolic disorders, often characterized by oxidative stress and chronic inflammation, poses significant health challenges globally. As the traditional therapeutic approaches may sometimes fall short in managing these health conditions, attention is growing toward nutraceuticals worldwide; with compounds being obtained from natural sources with potential therapeutic beneficial effects being shown to potentially support and, in some cases, replace pharmacological treatments, especially for individuals who do not qualify for conventional pharmacological treatments. This review delves into the burgeoning field of nutraceutical-based pharmacological modulation as a promising strategy for attenuating oxidative stress and inflammation in metabolic and cardiometabolic disorders. Drawing from an extensive body of research, the review showcases various nutraceutical agents, such as polyphenols, omega-3 fatty acids, and antioxidants, which exhibit antioxidative and anti-inflammatory properties. All these can be classified as novel nutraceutical-based drugs that are capable of regulating pathways to mitigate oxidative-stress- and inflammation-associated metabolic diseases. By exploring the mechanisms through which nutraceuticals interact with oxidative stress pathways and immune responses, this review highlights their potential to restore redox balance and temper chronic inflammation. Additionally, the challenges and prospects of nutraceutical-based interventions are discussed, encompassing bioavailability enhancement, personalized treatment approaches, and clinical translation. Through a comprehensive analysis of the latest scientific reports, this article underscores the potential of nutraceutical-based pharmacological treatment modulation as a novel avenue to fight oxidative stress and inflammation in the complex landscape of metabolic disorders, particularly accentuating their impact on cardiovascular health.

Influence of metabolic state and body composition on the action of pharmacological treatment of migraine.

Migraine is a disabling neurovascular disorder among people of all ages, with the highest prevalence in the fertile years, and in women. Migraine impacts the quality of life of affected individuals tremendously and, in addition, it is associated with highly prevalent metabolic diseases, such as obesity, diabetes mellitus and thyroid dysfunction. Also, the clinical response to drugs might be affected in patients with metabolic disease due to body composition and metabolic change. Therefore, the efficacy of antimigraine drugs could be altered in patients with both migraine and metabolic disease. However, knowledge of the pharmacology and the related clinical effects of antimigraine drugs in patients with metabolic disease are limited. Therefore, and given the clinical relevance, this article provides a comprehensive overview of the current research and hypotheses related to the influence of metabolic state and body composition on the action of antimigraine drugs. In addition, the influence of antimigraine drugs on metabolic functioning and, vice versa, the influence of metabolic diseases and its hormonal modulating medication on migraine activity is outlined. Future exploration on personalizing migraine treatment to individual characteristics is necessary to enhance therapeutic strategies, especially given its increasing significance in recent decades.

The Arylamine N-Acetyltransferases as Therapeutic Targets in Metabolic Diseases Associated with Mitochondrial Dysfunction.

In humans, there are two arylamine N-acetyltransferase genes that encode functional enzymes (NAT1 and NAT2) as well as one pseudogene, all of which are located together on chromosome 8. Although they were first identified by their role in the acetylation of drugs and other xenobiotics, recent studies have shown strong associations for both enzymes in a variety of diseases, including cancer, cardiovascular disease, and diabetes. There is growing evidence that this association may be causal. Consistently, NAT1 and NAT2 are shown to be required for healthy mitochondria. This review discusses the current literature on the role of both NAT1 and NAT2 in mitochondrial bioenergetics. It will attempt to relate our understanding of the evolution of the two genes with biologic function and then present evidence that several major metabolic diseases are influenced by NAT1 and NAT2. Finally, it will discuss current and future approaches to inhibit or enhance NAT1 and NAT2 activity/expression using small-molecule drugs. SIGNIFICANCE STATEMENT: The arylamine N-acetyltransferases (NATs) NAT1 and NAT2 share common features in their associations with mitochondrial bioenergetics. This review discusses mitochondrial function as it relates to health and disease, and the importance of NAT in mitochondrial function and dysfunction. It also compares NAT1 and NAT2 to highlight their functional similarities and differences. Both NAT1 and NAT2 are potential drug targets for diseases where mitochondrial dysfunction is a hallmark of onset and progression.

Targeting the PDK/PDH axis to reverse metabolic abnormalities by structure-based virtual screening with in vitro and in vivo experiments.

In humans and animals, the pyruvate dehydrogenase kinase (PDK) family proteins (PDKs 1-4) are excessively activated in metabolic disorders such as obesity, diabetes, and cancer, inhibiting the activity of pyruvate dehydrogenase (PDH) which plays a crucial role in energy and fatty acid metabolism and impairing its function. Intervention and regulation of PDH activity have become important research approaches for the treatment of various metabolic disorders. In this study, a small molecule (g25) targeting PDKs and activating PDH, was identified through multi-level computational screening methods. In vivo and in vitro experiments have shown that g25 activated the activity of PDH and reduced plasma lactate and triglyceride level. Besides, g25 significantly decreased hepatic fat deposition in a diet-induced obesity mouse model. Furthermore, g25 enhanced the tumor-inhibiting activity of cisplatin when used in combination. Molecular dynamics simulations and in vitro kinase assay also revealed the specificity of g25 towards PDK2. Overall, these findings emphasize the importance of targeting the PDK/PDH axis to regulate PDH enzyme activity in the treatment of metabolic disorders, providing directions for future related research. This study provides a possible lead compound for the PDK/PDH axis related diseases and offers insights into the regulatory mechanisms of this pathway in diseases.

Neuroprotection of rhubarb extract against cerebral ischaemia-reperfusion injury via the gut-brain axis pathway.

BACKGROUND: The gut-brain axis (GBA) plays a central role in cerebral ischaemia-reperfusion injury (CIRI). Rhubarb, known for its purgative properties, has demonstrated protective effects against CIRI. However, it remains unclear whether this protective effect is achieved through the regulation of the GBA. AIM: This study aims to investigate the mechanism by which rhubarb extract improves CIRI by modulating the GBA pathway. METHODS: We identified the active components of rhubarb extract using LC-MS/MS. The model of middle cerebral artery occlusion (MCAO) was established to evaluate the effect of rhubarb extract. We conducted 16S rDNA sequencing and untargeted metabolomics to analyze intestinal contents. Additionally, we employed HE staining, TUNEL staining, western blot, and ELISA to assess intestinal barrier integrity. We measured the levels of inflammatory cytokines in serum via ELISA. We also examined blood-brain barrier (BBB) integrity using Evans blue (EB) penetration, transmission electron microscopy (TEM), western blot, and ELISA. Neurological function scores and TTC staining were utilized to evaluate neurological outcomes. RESULTS: We identified twenty-six active components in rhubarb. Rhubarb extract enhanced α-diversity, reduced the abundance of Enterobacteriaceae, and partially rectified metabolic disorders in CIRI rats. It also ameliorated pathological changes, increased the expressions of ZO-1, Occludin, and Claudin 1 in the colon, and reduced levels of LPS and d-lac in serum. Furthermore, it lowered the levels of IL-1ß, IL-6, IL-10, IL-17, and TNF-α in serum. Rhubarb extract mitigated BBB dysfunction, as evidenced by reduced EB penetration and improved hippocampal microstructure. It upregulated the expressions of ZO-1, Occludin, Claudin 1, while downregulating the expressions of TLR4, MyD88, and NF-κB. Similarly, rhubarb extract decreased the levels of IL-1ß, IL-6, and TNF-α in the hippocampus. Ultimately, it reduced neurological function scores and cerebral infarct volume. CONCLUSION: Rhubarb effectively treats CIRI, potentially by inhibiting harmful bacteria, correcting metabolic disorders, repairing intestinal barrier function, alleviating BBB dysfunction, and ultimately improving neurological outcomes.

Potential of postbiotics for the treatment of metabolic disorders.

Postbiotics, the next generation of probiotics, are extracts that are free of living and nonviable bacteria and show strong modulatory effects on the gut flora. Examples include vitamin B12, vitamin K, folate, lipopolysaccharides, enzymes, and short-chain fatty acids (SCFAs), representing a subset of essential nutrients commonly found in the human diet. Postbiotics have been observed to demonstrate antiobesity and antidiabetic effects through a variety of mechanisms. These pathways primarily involve an elevation in energy expenditure, a decrease in the formation and differentiation of adipocytes and food intake, modification of lipid and carbohydrate absorption and metabolism, and regulation of gut dysbiosis. Based on these above effects and mechanisms, the use of postbiotics can be considered as potential strategy for the treatment of metabolic disorders.

Engineering novel scaffolds for specific HDAC11 inhibitors against metabolic diseases exploiting deep learning, virtual screening, and molecular dynamics simulations.

The prevalence of metabolic diseases is increasing at a frightening rate year by year. The burgeoning development of deep learning enables drug design to be more efficient, selective, and structurally novel. The critical relevance of Histone deacetylase 11 (HDAC11) to the pathogenesis of several metabolic diseases makes it a promising drug target for curbing metabolic disorders. The present study aims to design new specific HDAC11 inhibitors for the treatment of metabolic diseases. Deep learning was performed to learn the properties of existing HDAC11 inhibitors and yield a novel compound library containing 23,122 molecules. Subsequently, the compound library was screened by ADMET properties, Lipinski & Veber rules, traditional machine classification models, and molecular docking, and 10 compounds were screened as candidate HDAC11 inhibitors. The stability of the 10 new molecules was further evaluated by deploying RMSD, RMSF, MM/GBSA, free energy landscape mapping, and PCA analysis in molecular dynamics simulations. As a result, ten compounds, Cpd_17556, Cpd_2184, Cpd_8907, Cpd_7771, Cpd_14959, Cpd_7108, Cpd_12383, Cpd_13153, Cpd_14500and Cpd_21811, were characterized as good HDAC11 inhibitors and are expected to be promising drug candidates for metabolic disorders, and further in vitro, in vivo and clinical trials to demonstrate in the future.