Novel ketoprofen–antioxidants mutual codrugs as safer nonsteroidal anti‐inflammatory drugs: Synthesis,kinetic and pharmacological evaluation

Ketoprofen belongs to one of the most common nonsteroidal anti‐inflammatory drugs (NSAIDs) but its clinical usefulness has been restricted due to the high incidence of gastrointestinal complications. The release of reactive oxygen species (ROS) in NSAIDs therapy plays a major role in causing gastric complications. Antioxidants not only prevent gastric ulceration and lipid peroxidation but also preserve glutathione‐type peroxidase (GPO) activity. Therefore, the present study investigates the utility of combining anti‐inflammatory and antioxidant properties of two different compounds in a single molecule to form a series of 16 ketoprofen–antioxidant mutual codrugs. The free carboxylic group, which is believed to be one of the reasons for gastric toxicity of ketoprofen, was masked temporarily by simple and double esterification with alcoholic/phenolic–OH of natural antioxidants. In simple esterification, ketoprofen is directly linked to natural antioxidants ( IIa–h ) in the hope to obtain drugs free of gastric side effects. In an attempt to improve the in vivo lability, as well as gastric side effects, the double ester codrugs, that is, ketoprofen–antioxidant through the glycolic acid spacer (–CH₂COO; IIIa–h ), have also been designed and synthesized. The synthesized codrugs were characterized by IR, ¹H NMR, ¹³C NMR, mass spectroscopy and elemental analysis. The in vitro hydrolysis studies showed the lowest hydrolysis (highest stability) in acidic pH 1.2, whereas moderate hydrolysis was seen at pH 7.4 and significant hydrolysis in 80% human blood plasma, as indicated by their t_1/2. The pharmacological evaluation results indicate that these ketoprofen–antioxidant mutual codrugs showed the retention of anti‐inflammatory and analgesic activity with a significant reduction in the ulcer index.     

Review article: anti‐fibrotic agents for the treatment of Crohn’s disease – lessons learnt from other diseases

Background The current therapies for Crohn’s disease (CD) are mainly focused on blockade of inflammation. Fibrosis remains one of the major complications of CD often leading to surgery, affecting patients’ quality‐of‐life. Aim To summarize the published data regarding the potential anti‐fibrotic role of drugs commonly used in CD and the most effective anti‐fibrotic drugs used in other diseases evaluating their potential use to treat intestinal fibrosis in CD. Methods A literature search was performed in the PubMed, Medline, Cochrane and EMBASE databases, considering in vitro, animal and human studies on fibrosis in inflammatory bowel disease and other similar chronic pathologies. Results Treatment of fibrosis in CD is limited to surgery or endoscopic dilatation, although some of the drugs currently used may have anti‐fibrotic activity. In other diseases, anti‐fibrotic agents are already used or are in preclinical or clinical trials. ACE inhibitors, Angiotensin Receptor Blockers, and HMG‐CoA inhibitors merit further investigation in CD because of their role in preventing fibrosis in cardiovascular and renal diseases. Conclusions Anti‐fibrotic drugs are under evaluation or already used in clinical practice in other chronic inflammatory diseases. In CD, there is a great need for investigation into agents that may prevent, reduce or reverse intestinal fibrosis. Aliment Pharmacol Ther 31 , 189–201     

Synthesis and pharmacological evaluation of novel derivatives of anti‐inflammatory drugs with increased antioxidant and anti‐inflammatory activities

The role of reactive oxygen species in inflammatory processes has been well documented, while several antioxidant compounds have been shown to exhibit anti‐inflammatory activity. We designed novel compounds as potential agents that combine enhanced antioxidant and anti‐inflammatory activities. Derivatives of indomethacin, diclofenac, tolfenamic acid, and ibuprofen, four widely used nonsteroidal anti‐inflammatory drugs, with cysteamine, a polar antioxidant molecule, were synthesized. The compounds were evaluated for their effect on free radical processes (protection against rat hepatic microsomal lipid‐peroxidation and interaction with the stable free radical 1,1‐diphenyl‐2‐picrylhydrazyl), as well as on carrageenan‐induced inflammation (mouse paw edema inhibition). Furthermore, ulcerogenicity tests in rats were performed in order to evaluate the gastrointestinal irritation of the novel indomentacin derivative. It was found that all compounds were very potent antioxidants in vitro; they could inhibit lipid peroxidation very significantly, having IC₅₀ values ranging from 55 to 510 μM, while they could also interact ∼90% with DPPH at equimolar concentrations. We attribute these activities to their sulfhydryl group, as well as to their increased lipophilicity compared to cysteamine. Furthermore, the derivatives demonstrated significant anti‐inflammatory activity, comparable to that of the parent molecules, while they showed significantly reduced ulcerogenic potency. Our results indicate that the combined pharmacological properties of these new derivatives may prove useful for the design and development of novel cytoprotective/anti‐inflammatory molecules with potentially important therapeutic applications. Drug Dev. Res. 47:9–16, 1999. © 1999 Wiley‐Liss, Inc.     

Inhibition of key enzymes in the inflammatory pathway by hybrid molecules of terpenes and synthetic drugs: In vitro and in silico studies

The aim of this work was to compare the anti‐inflammatory activity of compounds prepared from terpenes and the synthetic drugs ibuprofen and naproxen. The anti‐inflammatory activity of the hybrid compounds was compared with the activity of the parent compounds. This was accomplished using in vitro inhibition of lipoxygenases (LOX) and COX‐2, and in silico docking studies in 15‐LOX and COX‐2. The synthesized hybrids showed an inhibition of COX‐2 and LOX between 9.8%–57.4% and 0.0%–97.7%, respectively. None of the hybrids showed an improvement in the inhibitory effect toward these pro‐inflammatory enzymes, compared to the parent terpenes and non‐steroidal anti‐inflammatory drugs. The docking studies allowed us to predict the potential binding modes of hybrids 6 – 15 within COX‐2 and 15‐LOX active sites. The relative affinity of the compounds inside the binding sites could be explained by forming non‐covalent interactions with most important and known amino acids reported for those enzymes. A good correlation (r² = 0.745) between docking energies and inhibition percentages against COX‐2 was found. The high inhibition obtained for compound 10 against COX‐2 was explained by hydrogen bond interactions at the enzyme binding site. New synthetic possibilities could be obtained from our in silico models, improving the potency of these hybrid compounds.     

Mitogen‐Activated Protein Kinase Phosphatase 1 as an Inflammatory Factor and Drug Target

Mitogen‐activated protein kinases (MAPKs) are signaling proteins that are activated through phosphorylation, and they regulate many physiological and pathophysiological processes in cells. Mitogen‐activated protein kinase phosphatase 1 (MKP‐1) is an inducible nuclear phosphatase that dephosphorylates MAPKs, and thus, it is a negative feedback regulator of MAPK activity. MKP‐1 has been found as a key endogenous suppressor of innate immune responses, as well as a regulator of the onset and course of adaptive immune responses. Altered MKP‐1 signaling is implicated in chronic inflammatory diseases in man. Interestingly, MKP‐1 expression and protein function have been found to be regulated by certain anti‐inflammatory drugs, namely by glucocorticoids, antirheumatic gold compounds and PDE4 inhibitors, and MKP‐1 has been shown to mediate many of their anti‐inflammatory effects. In this Mini Review, we summarize the effect of MKP‐1 in the regulation of innate and adaptive immune responses and its role as a potential anti‐inflammatory drug target and review recent findings concerning the role of MKP‐1 in certain anti‐inflammatory drug effects.     

Monoterpenes modulating autophagy: A review study

From the beginning of the 21st century, much attention has been made towards the medicinal herbs due to their low side effects and valuable biological activities. Among them, terpenes comprise a large group of naturally occurring chemical compounds that are considered as main components of flavours, antifeedants and pheromones. Monoterpenes have demonstrated a favourable profile as compounds that have antioxidant, anti‐inflammatory, anti‐diabetic, hepatoprotective and anti‐tumour activities. On the other hand, autophagy is a ‘self‐digestion’ mechanism which plays a remarkable role in a number of pathological conditions such as cancer, ageing, metabolic disorders and infection. Also, autophagy is considered as a stress adaptor that may lead to apoptotic cell death under severe and sustained stress. Autophagy modulation is a promising strategy in cancer treatment, and a variety of drugs have been designed in line with this strategy. In the present MiniReview, we discuss the effects of monoterpenes on autophagy and its relationship with therapeutic impacts of monoterpenes.     

Development of Anti‐Inflammatory Drugs – the Research and Development Process

The research and development process for novel drugs to treat inflammatory diseases is described, and several current issues and debates relevant to this are raised: the decline in productivity, attrition, challenges and trends in developing anti‐inflammatory drugs, the poor clinical predictivity of experimental models of inflammatory diseases, heterogeneity within inflammatory diseases, ‘improving on the Beatles’ in treating inflammation, and the relationships between big pharma and biotechs. The pharmaceutical research and development community is responding to these challenges in multiple ways which it is hoped will lead to the discovery and development of a new generation of anti‐inflammatory medicines.     

Discovery of naphthyl‐N‐acylhydrazone p38α MAPK inhibitors with in vivo anti‐inflammatory and anti‐TNF‐α activity

Protein kinases constitute attractive therapeutic targets for development of new prototypes to treat different chronic diseases. Several available drugs, like tinibs, are tyrosine kinase inhibitors; meanwhile, inhibitors of serine/threonine kinases, such as mitogen‐activated protein kinase (MAPK), are still trying to overcome some problems in one of the steps of clinical development to become drugs. So, here we reported the synthesis, the in vitro kinase inhibitory profile, docking studies, and the evaluation of anti‐inflammatory profile of new naphthyl‐N‐acylhydrazone derivatives using animal models. Although all tested compounds ( 3a–d ) have been characterized as p38α MAPK inhibitors and have showed in vivo anti‐inflammatory action, LASSBio‐1824 ( 3b ) presented the best performance as p38α MAPK inhibitor, with IC₅₀ = 4.45 μm , and also demonstrated to be the most promising anti‐inflammatory prototype, with good in vivo anti‐TNF‐α profile after oral administration.     

Screening of curcumin‐derived isoxazole,pyrazoles, and pyrimidines for their anti‐inflammatory,antinociceptive, and cyclooxygenase‐2 inhibition

Curcumin has shown pharmacological properties against different phenotypes of various disease models. Different synthetic routes have been employed to develop its numerous derivatives for diverse and improved therapeutic roles. In this study, we have synthesized curcumin derivatives containing isoxazole, pyrazoles, and pyrimidines and then the synthesized molecules were evaluated for their anti‐inflammatory and antinociceptive activities in experimental animal models. Acute toxicity of synthesized molecules was evaluated in albino mice by oral administration. Any behavioral and neurological changes were observed at dose of 10 mg/kg body weight. Additionally, cyclooxygenase‐2 (COX‐2) enzyme inhibition studies were performed through in vitro assays. In vivo anti‐inflammatory studies showed that curcumin with pyrimidines was the most potent anti‐inflammatory agent which inhibited induced edema from 74.7% to 75.9%. Compounds 7 , 9 , and 12 exhibited relatively higher prevention of writhing episodes than any other compound with antinociceptive activity of 73.2%, 74.9%, and 71.8%, respectively. This was better than diclofenac sodium (reference drug, 67.1% inhibition). Similarly, COX‐2 in vitro inhibition assays results revealed that compound 12 (75.3% inhibition) was the most potent compound. Molecular docking studies of 10 , 11 , and 12 compounds in human COX‐2 binding site revealed the similar binding modes as that of other COX‐2‐selective inhibitors.     

Exploring novel pharmacotherapeutic applications and repurposing potential of sodium glucose CoTransporter 2 inhibitors

Sodium glucose cotransporter 2 (SGLT2) inhibitors are a relatively new class of anti‐hyperglycaemic drugs with a distinctive mechanism of action focusing on renal absorption of glucose. Apart from its anti‐hyperglycaemic effects, a multitude of research studies on this class have revealed that these drugs have far more versatile and comprehensive pharmacological effects than previously believed. Approximately 30% of FDA approved drugs are repurposed and used for indications other than those for which they were initially intended. Repurposing already approved drugs leads to significant reduction in pre‐clinical and clinical R&D costs as well as minimizing the burden with respect to obtaining regulatory approval. SGLT2 inhibitors have been found to exhibit cardioprotective, renoprotective, anti‐hyperlipidaemic, anti‐atherosclerotic, anti‐obesity, anti‐neoplastic, hepatoprotective, and renoprotective effects in in vitro, pre‐clinical, and clinical studies. The pleiotropic effects of this class have been attributed to a variety of its pharmacodynamic actions such as natriuresis, haemoconcentration, deactivation of RAAS, ketone body formation, alterations in energy homeostasis, glycosuria, lipolysis, anti‐inflammatory, and anti‐oxidative actions. These favourable observations encourage further research on this multifaceted class in order to effectively explore and harness its full potential and consequently lead to clinical outcomes.     

The Impact of NSAID Treatment on Cardiovascular Risk – Insight from Danish Observational Data

This MiniReview describes the present evidence for the relationship between cardiovascular risk and use of non‐steroidal anti‐inflammatory drugs (NSAIDs) with special focus using Danish register‐based data. NSAIDs are among the most widely used drugs worldwide and mainly used for management of pain and inflammatory conditions. Through the past decade, much attention has been given to the cardiovascular safety of these drugs, and several studies have shown increased risk of adverse cardiovascular effects associated with NSAID use. Current guidelines discourage any use of NSAIDs in patients with cardiovascular disease, yet over a period of 8–10 years, 35–44% of patients with myocardial infarction or heart failure were exposed to NSAIDs in Denmark. Furthermore, NSAID use was associated with an increased risk of death or myocardial infarction by up to 5 times that of non‐users. There was also a clear indication for a dose‐related response in risk associated with NSAID therapy, supporting a causal association. Notably, the cardiovascular risk associated with NSAID treatment was prevalent at start of treatment, suggesting no safe treatment window for NSAIDs in patients with cardiovascular disease. Thus, evidence from observational studies is accumulating, suggesting that NSAIDs are a major public health concern due to the widespread use of these drugs. Although it seems unlikely that we can completely avoid use of NSAIDs, even among high‐risk patients, these results highlight the importance of balancing the benefit versus the risk of treatment before initiating NSAID treatment.     

Dual PDE3/4 and PDE4 Inhibitors: Novel Treatments For COPD and Other Inflammatory Airway Diseases

Selective phosphodiesterase (PDE) 4 and dual PDE3/4 inhibitors have attracted considerable interest as potential therapeutic agents for the treatment of respiratory diseases, largely by virtue of their anti‐inflammatory (PDE4) and bifunctional bronchodilator/anti‐inflammatory (PDE3/4) effects. Many of these agents have, however, failed in early development for various reasons, including dose‐limiting side effects when administered orally and lack of sufficient activity when inhaled. Indeed, only one selective PDE4 inhibitor, the orally active roflumilast‐n‐oxide, has to date received marketing authorization. The majority of the compounds that have failed were, however, orally administered and non‐selective for either PDE3 (A,B) or PDE4 (A,B,C,D) subtypes. Developing an inhaled dual PDE3/4 inhibitor that is rapidly cleared from the systemic circulation, potentially with subtype specificity, may represent one strategy to improve the therapeutic index and also exhibit enhanced efficacy versus inhibition of either PDE3 or PDE4 alone, given the potential positive interactions with regard to anti‐inflammatory and bronchodilator effects that have been observed pre‐clinically with dual inhibition of PDE3 and PDE4 compared with inhibition of either isozyme alone. This MiniReview will summarize recent clinical data obtained with PDE inhibitors and the potential for these drugs to treat COPD and other inflammatory airways diseases such as asthma and cystic fibrosis.     

Molecular Modeling,Synthesis, and Anti‐HIV Activity of Novel Isoindolinedione Analogues as Potent Non‐nucleoside Reverse Transcriptase Inhibitors

Different isoindolinedione derivatives bearing imine, amide, thioamide, and sulfonamide linkages have been designed in silico using discovery studio software (BIOVIA, San Diego, CA, USA), synthesized, and evaluated for their anti‐HIV activity. SAR studies revealed that the linkages in these molecules did affect their anti‐HIV activity and the molecules having sulfonamide linkages were the most potent HIV‐RT inhibitors as the S=O bonds of the sulfonamide moiety interacted with Lys103 (NH or carbonyl or both) and Pro236; the NH part of the sulfonamide linkage formed bond with carbonyl of Lys101. blood–brain barrier (BBB) plots were also studied, and it was found that all the designed molecules have potential to cross BBB, a very vital criteria for anti‐HIV drugs. In vitro screening was performed using HIV‐1 strain IIIB in MT‐4 cells using the MTT assay, and it was seen that some of these molecules were effective inhibitors of HIV‐1 replication at nanomolar concentration with selectivity indices ranging from 33.75 to 73.33 under in vitro conditions. Some of these molecules have shown good anti‐HIV activity at 3–4 nm concentrations. These derivatives have potential to be developed as lead molecules effective against HIV‐1. Novel isoindolinedione derivatives as probable NNRTIs have been synthesized and characterized. Some of these molecules have shown good anti‐HIV activity at 3–4 nm concentrations.     

Design,Synthesis, and Biological Evaluation of Novel Quinazoline Derivatives as Anti‐inflammatory Agents against Lipopolysaccharide‐induced Acute Lung Injury in Rats

Quinazoline has been reported to exhibit multiple bioactivities. The aim of this study was to discover new quinazoline derivatives with preventive effect on lipopolysaccharide‐induced acute lung injury via anti‐inflammatory actions. Thirty‐three 4‐amino quinazolin derivatives were synthesized and screened for anti‐inflammatory activities in lipopolysaccharide‐induced macrophages. The most potent four compounds, 6h, 6m, 6p , and 6q , were shown dose‐dependent inhibition against lipopolysaccharide‐induced TNF‐α and IL‐6 release. Then, the preliminary structure–activity relationship and quantitative structure–activity relationship analyses were conducted. To further determine the effects of quinazolines on acute lung injury treatment, lipopolysaccharide‐induced acute lung injury model was employed. Male Sprague Dawley rats were pretreated with 6m or 6q before instillation of lipopolysaccharide. The results showed that 6m and 6q, especially 6q , obviously alleviated lung histopathological changes, inflammatory cells infiltration, and cytokines mRNA expression initiated by lipopolysaccharide. Taken together, this work suggests that 6m and 6q suppressed the lipopolysaccharide‐induced acute lung injury through inhibition of the inflammatory response in vivo and in vitro, indicating that quinazolines might serve as potential agents for the treatment of acute lung injury and deserve the continuing drug development and research.     

Antinociceptive and anti‐inflammatory properties of 7‐hydroxycoumarin in experimental animal models: potential therapeutic for the control of inflammatory chronic pain

Objectives In the present study we investigated the antinociceptive, anti‐inflammatory and antipyretic effects of 7‐hydroxycoumarin (7‐HC) in animal models. Methods The effects of oral 7‐HC were tested against acetic acid‐induced writhing, formalin test, tail flick test, complete Freund's adjuvant (CFA)‐induced hypernociception, carrageenan‐induced paw oedema, lipopolysaccharide‐induced fever and the rota rod test. Key findings 7‐HC (3–60 mg/kg) produced a dose‐related antinociception against acetic acid‐induced writhing in mice and in the formalin test. In contrast, treatment with 7‐HC did not prevent thermal nociception in the tail flick test. A single treatment with 7‐HC, 60 mg/kg, produced a long‐lasting antinociceptive effect against CFA‐induced hypernociception, a chronic inflammatory pain stimulus. Notably, at 60 mg/kg per day over 4 days the administration of 7‐HC produced a continuous antinociceptive effect against CFA‐induced hypernociception. 7‐HC (30–120 mg/kg) produced anti‐inflammatory and antipyretic effects against carrageenan‐induced inflammation and lipopolysaccharide‐induced fever, respectively. Moreover, 7‐HC was found to be safe with respect to ulcer induction. In the rota rod test, 7‐HC‐treated mice did not show any motor performance alterations. Conclusions The prolonged antinociceptive and anti‐inflammatory effects of 7‐HC, in association with its low ulcerogenic activity, indicate that this molecule might be a good candidate for development of new drugs for the control of chronic inflammatory pain and fever.     

3‐Acetyl‐11‐keto‐β‐boswellic acid loaded‐polymeric nanomicelles for topical anti‐inflammatory and anti‐arthritic activity

Objectives The aim of this study was to develop 3‐acetyl‐11‐keto‐β‐boswellic acid (AKBA)‐loaded polymeric nanomicelles for topical anti‐inflammatory and anti‐arthritic activity. Methods Polymeric nanomicelles of AKBA were developed by a radical polymerization method using N‐isopropylacrylamide, vinylpyrrolidone and acrylic acid. The polymeric nanomicelles obtained were characterized by Fourier transform infrared (FTIR), transmission electron microscopy (TEM) and dynamic light scattering (DLS). In‐vitro and in‐vivo evaluations of AKBA polymeric nanomicelles gel were carried out for enhanced skin permeability and anti‐inflammatory and anti‐arthritic activity. Key findings TEM and DLS results demonstrated that polymeric nanomicelles were spherical with a mean diameter approximately 45 nm. FTIR data indicated a weak interaction between polymer and AKBA in the encapsulated system. The release of drug in aqueous buffer (pH 7.4) from the polymeric nanomicelles was 23 and 55% after 2 and 8 h, respectively, indicating sustained release. In‐vitro skin permeation studies through excised abdominal skin indicated a threefold increase in skin permeability compared with AKBA gel containing the same amount of AKBA as the AKBA polymeric nanomicelles gel. The AKBA polymeric nanomicelle gel showed significantly enhanced anti‐inflammatory and anti‐arthritic activity compared with the AKBA gel. Conclusions This study suggested that AKBA polymeric nanomicelle gel significantly enhanced skin permeability, and anti‐inflammatory and anti‐arthritic activity.     

Lipoxin A4 ameliorates renal ischaemia–reperfusion‐induced acute lung injury in rats

Lipoxin A4 (LA4), a bioactive product of arachidonic acid, has been shown to exert strong anti‐inflammatory activity. By contrast, the anti‐inflammatory action of LA4 in a renal ischaemia–reperfusion (RIR)‐mediated acute lung inflammation (ALI) model and the potential pathogenesis of the condition is still unclear. The aim of the current research was to investigate the effect of LA4 on RIR‐induced ALI. The rat ALI model was induced by RIR. LA4 was injected via the tail vein immediately after RIR. The results indicate that LA4 markedly inhibits inflammatory cells infiltration, attenuates myeloperoxidase activity, and reduces the concentration of inflammatory mediators and Toll‐like receptor 4 (TLR4) in RIR‐induced ALI. Furthermore, LA4 suppressed nuclear factor kappa B (NF‐κB) p65 and mitogen‐activated protein kinase (MAPK) activation. The protective effect of LA4 in RIR‐stimulated ALI was reversed by BOC‐2 (an antagonist of the LA4 receptor). These results indicate that LA4 exerts powerful anti‐inflammatory functions in RIR‐induced ALI by attenuating TLR4 expression via MAPK and NF‐κB signalling. Accordingly, LA4 might be an underlying treatment drug for RIR‐induced ALI.     

Anti‐angiogenesis effect of β‐D‐mannuronic acid (M2000) as a novel NSAID with immunosuppressive properties under experimental model

Angiogenesis is a process through which new capillaries are formed from pre‐existing ones, which contributes significantly to the pathogenesis of numerous diseases, such as cancer and chronic inflammatory disorders. The β‐D‐mannuronic acid (M2000) is a novel non‐steroidal anti‐inflammatory drug (NSAID) with immunosuppressive effects and is a matrix metalloproteinase (MMP) inhibitor. This research aimed to study the anti‐angiogenesis effects of M2000 under in vitro and in vivo models. The cytotoxic and anti‐proliferative effects of M2000 were examined using the trypan blue method and the MTT assay, respectively. The 3D collagen‐cytodex model and the chick chorioallantoic membrane (CAM) assay were then used to evaluate the anti‐angiogenesis property of M2000. Cytotoxicity assay revealed that M2000 (at concentrations of less than 100 μg/mL) had no cytotoxic effect on human umbilical vein endothelial cells (HUVECs). It was also illustrated that M2000 had little or no anti‐proliferative effect on HUVECs. In addition, the anti‐angiogenesis effects of M2000 were shown to be marginal in the in vitro model and both significant and dose‐dependent in the in vivo status. This study showed that M2000 could be considered as an anti‐angiogenic molecule which more likely exerts its activity mainly via indirect effects on endothelial cells and its anti‐inflammatory effects may partly be attributable to its anti‐angiogenic activity. Therefore, it could be recommended as a candidate for prevention and treatment of cancer, chronic inflammatory diseases, and other angiogenesis‐related disorders.     

Genus Bupleurum: a review of its phytochemistry, pharmacology and modes of action

Objectives Radix Bupleuri represents one of the most successful and widely used herbal drugs in Asia for treatment of many diseases over the past 2000 years. Thorough studies have been carried out on many species of this genus and have generated immense data about the chemical composition and corresponding biological activity of extracts and isolated secondary metabolites. In this work, we review the chemistry and pharmacology of the genus Bupleurum and explore the relationships between the pharmacological effects and the chemical composition of these drugs. Key findings Early studies on the genus Bupleurum had focused only on the traditional uses of the plants in the treatment of inflammatory disorders and infectious diseases. After chemical profiling, several groups of secondary metabolites were characterized with relevant biological activity: triterpene saponins (saikosaponins), lignans, essential oils and polysaccharides. As a result, present interest is now focused on the bioactivity of the isolated triterpene saponins acting as immunomodulatory, anti‐inflammatory and antiviral agents, as well as on the observed ant‐iulcer activity of the polysaccharides and anti‐proliferative activity of different lignans. Many saikosaponins exhibited very potent anti‐inflammatory, hepatoprotective and immunomodulatory activities both in vivo and in vitro. Conclusions Further investigations and screenings are required to explore other Bupleurum species, to evaluate the clinical safety and possible interactions with other drugs or herbs. Standardization of Bupleuri extracts is crucial for them being integrated into conventional medicine due to large chemical and biological variations between different species and varieties.