The Therapeutic Potential of Andrographolide and Its Derivatives in Inflammatory Diseases

ABSTRACT

Andrographolide, a diterpenoid component found in traditional Chinese medicine Andrographis paniculata , is known as a natural antibiotic and can be used to treat inflammatory lesions of various systemic diseases. In recent years, andrographolide derivatives have been continuously synthesized and have shown good anti‐inflammatory pharmacological activity. These derivatives are mainly obtained by chemical synthesis methods, for example, by altering the hydroxyl and double bond groups in the molecule of andrographolide and introducing different substituents, thus obtaining derivatives with different biological activities and pharmacological properties. This paper summarizes the anti‐inflammatory mechanism of andrographolide derivatives and the progress of pharmacological research in inflammatory diseases, such as viral infectious diseases, respiratory or lung injury, gastrointestinal diseases, liver injury, and neurological disorders. It also incorporates the results of our own team's research to deeply explore their therapeutic potential in different inflammatory diseases, which provides direction and rationale for in‐depth follow‐up research.

1. Introduction

Inflammatory diseases refer to a category of disorders with an abnormal and persistent inflammatory response in tissues and organs of the body. Most clinical diseases have inflammatory lesions [1]. The clinical manifestations of inflammation are redness, swelling, heat, pain, and systemic reactions, and the pathologic manifestations are exudation, hyperplasia, and necrosis. According to the cause, inflammatory diseases can be generally divided into infectious and noninfectious. Infectious inflammatory diseases are caused by the infection of microorganisms such as bacteria, viruses, fungi, and parasites, which cause immune responses to protect the health of the body by recruiting macrophages and neutrophils to release inflammatory mediators and kill pathogens [2]. Noninfectious inflammatory diseases, on the other hand, are mainly acute or chronic inflammatory lesions caused by microbial factors such as trauma, metabolic disorders, chemical poisoning, and autoimmune disorders [3].

Andrographolide, a diterpene lactone constituent found in the dried above‐ground parts of Andrographis paniculata (Burm. f.) Nees, family Jurassicaceae, was isolated in 1951 as the main bioactive constituent of A. paniculata, and has shown potential as a natural‐chemical treatment for various human ailments, including viral infections and immune system enhancement [4]. It has anti‐inflammatory, antioxidant, antibacterial, and antimicrobial effects, as well as benefits for atherosclerosis (ALS), platelet aggregation, antidiarrheal, hypoglycemic, hypolipidemic, hepatoprotective, and hypotensive effects [5]. Andrographolide is utilized in the treatment of various inflammatory diseases, including those affecting the respiratory, digestive, immune, neurological, cardiovascular, skeletal, and oncological systems. It has demonstrated effectiveness in reducing inflammation associated with systemic diseases [6]. It is particularly effective in treating bacterial and viral upper respiratory tract infections, dysentery, and early‐stage Coronaviruses [7]. It is typically administered orally in clinical settings, such as through andrographolide tablets or drops.

Low oral bioavailability poses a significant challenge to the potential use of andrographolide. By implementing alterations to the chemical structure, scientists have successfully created a range of andrographolide derivatives that exhibit enhanced bioavailability, good in vitro and in vivo anti‐inflammatory activity, and safety profiles [8]. The anti‐inflammatory properties of andrographolide and its analogs have been the subject of extensive research since 1984. Clinically, derivative agents such as Lianbizhi injection, Chuanhuning, Yanhuning injection, and Xiyanping injection can be used in the treatment of bronchitis, tonsillitis, pneumonia, etc. [9, 10, 11]. The A ring forms caprolactam, a benzyl group is introduced at the C‐15 position, an unsaturated bond is present within the pentamembered lactone ring, small phenolic compounds can serve as bioequivalents of the lactone ring, and selective esterification of the C‐19 hydroxyl group along with other structural modifications may enhance the anti‐inflammatory activity of andrographolide [12]. Research progress on the pharmacological effects of andropanolide and its derivatives on inflammatory diseases and cancer before 2021 has been previously reviewed [13]. This paper focuses on the experimental research advancements of andrographolide in the past 3 years (2022–2024). It reviews the anti‐inflammatory mechanism of action of andrographolide derivatives in different inflammatory diseases, highlighting their therapeutic potential in multiple inflammatory conditions. Additionally, this paper aims to contribute to drug discovery using andrographolide as a template, clarify the main anti‐inflammatory mechanisms of action of andrographolide derivatives, indicate the direction for future research, and showcase the prospects of its clinical application as an anti‐inflammatory agent.

2. Anti‐Inflammatory Effects and Applications of Andrographolide

Andrographolide is a multitarget anti‐inflammatory drug that interferes with signaling pathways including nuclear factor‐κB (NF‐κB), phosphatidylinositol 3‐kinase/confluent serine/threonine kinase (PI3K/Akt), mitogen‐activated‐protein kinase (MAPK), Janus kinase (JAK)/signal transduction and activation of transcription factor (STAT) pathways, as well as other signaling cascades [14]. It effectively decreases inflammation by impeding the activation of NF‐κB through modifying p50 at cysteine 62 via covalent means [15]. A summary of its anti‐inflammatory activities is outlined in Figure 1. Studies have shown that andrographolide plays an important role in different inflammatory diseases as outlined below.

FIGURE 1.

Diagram of the action of andrographolide for the treatment of inflammatory diseases.

2.1. Respiratory Diseases

Respiratory diseases have high morbidity and mortality rates globally and represent a critical unmet medical need [16]. These include asthma and chronic obstructive pulmonary disease (COPD), respiratory viral infections, cystic fibrosis, lung cancer, and other respiratory diseases [17]. In recent years, the morbidity and mortality rates of respiratory diseases have been on a continuous rise due to multiple factors such as smoking, population aging, air pollution, and new pathogens, posing a serious threat to people's health [18].

Prominent reduction in inflammation was observed with the administration of andrographolide in conditions such as asthma, pneumonia, pulmonary fibrosis, and COPD. Its mechanisms of action involve the inhibition of the NF‐κB signaling pathway and reduction in the production of cytokines, chemokines, adhesion molecules, nitric oxide, and lipid mediators. Additionally, it activates the antioxidant enzyme heme oxygenase‐1 (HO‐1), inhibits AIM2 inflammasome‐mediated pyroconjugation, and modulates the JAK/PI3K/Akt signaling pathway to combat inflammation in the lungs or airways. Furthermore, it attenuates NLRP3 inflammasome activation [15, 19, 20]. Andrographolide orchestrates the modulation of Th1/Th2 gene expression to mitigate airway inflammation, remodeling, and hyperreactivity elicited by house dust mites [21].

2.2. Nervous System Diseases

The nervous system is a collection of different cell and tissue types that have multiple levels of control over these tissues compared to other organ systems [22]. Neurological disorders include neurodegenerative diseases (e.g., Parkinson's disease and Alzheimer's disease, AD), autoimmune disorders (e.g., multiple sclerosis), ischemic events (e.g., stroke), mechanical trauma (e.g., traumatic brain injury), and neurological systemic disorders triggered by other factors that culminate in the loss of neurons and the end of acute or chronic functional impairment. Neurologic systemic disorders impose serious economic and financial burdens on patients, their families, and society as a whole [23].

Andrographolide not only inhibits brain endothelial cell inflammation and improves permeability and apoptosis of brain microvascular endothelial cells [24], but also triggers autophagy‐mediated inhibition of inflammation and attenuates depressive‐like behaviors [25, 26], as well as neuroinflammation in AD [27]. Our team found that andrographolide regulates the LRP1‐mediated PPARγ/NF‐κB pathway and enhances the ApoE4‐mediated blood–brain barrier injury by mitigating inflammation [28, 29]. Andrographolide was found to abate NLRP3 inflammasome activation in microglia, rescue dopaminergic neuron loss, and improve the behavioral parameters in the PD model [30, 31]. It mitigates spinal cord injury by decreasing inflammation in injured tissues and cortical neurons and promotes axon regeneration and functional recovery of demyelination [32].

2.3. Liver Diseases

The liver is a multifunctional organ involved in detoxification and nutrient metabolism processes [33]. Liver disease can be caused by alcoholism, drug overdose, viral attack, and nutritional imbalance, and studies have shown that about 2 million people die of liver disease every year worldwide [34]. Liver diseases involve a wide range of liver lesions, including hepatic steatosis, fatty liver, hepatitis, fibrosis, cirrhosis, and liver cancer. Despite all the studies conducted so far, there are very few therapeutic options for liver injuries and diseases [35]. Therefore, there is an urgent need to find and develop new, highly effective, and less toxic drugs for the treatment of liver diseases.

Andrographolide plays a crucial role in modulating various phenotypes associated with liver diseases [34], such as nonalcoholic fatty liver disease (NAFLD) [36], nonalcoholic steatohepatitis, liver fibrosis [37], and hepatic ischemia/reperfusion‐induced injury [38]. Andrographolide activated Nrf2 via binding to Keap1 and suppressing TGF‐β/Smad and FATP2‐mediated fatty acid uptake. Andrographolide alleviates monocrotaline‐induced HSOS via activating the Nrf2‐dependent antioxidative response and promoting mitochondrial biogenesis [39].

2.4. Inflammatory Bowel Diseases

Inflammatory bowel disease (IBD), which can be divided into Crohn's disease (CD) and ulcerative colitis (UC), is a chronic inflammatory disease that cannot be cured. UC is characterized by inflammation confined to the mucosa, and remission is associated with mucosal healing, but persistent disease recurrence of UC continues to be observed in the course of actual clinical practice. Over time, the altered disease phenotype of UC increases the risk of adverse transmural effects on the intestinal wall, raises the risk of tumor development, worsens colorectal function, and increases the risk of colectomy, hospitalization, and other extraintestinal complications [40]. The underlying cause of IBD is unknown due to the complex interplay between genetic variability, the host immune system, and environmental factors [41]. Most current treatments rely on pharmacologic interventions that suppress inflammation (i.e., corticosteroids, immunosuppressants) or reduce bacterial translocation from the lumen to the submucosa due to epithelial barrier dysfunction (antibiotics), but these pharmacologic therapies have remission rates of less than 50% and usually do not prevent recurrent disease episodes [42]. Meanwhile, more than one‐third of IBD patients fail induction therapy, and up to 60% develop tolerance to therapeutic agents over time [43]. The increasing prevalence of IBD worldwide [44] has created an urgent need for the development of new therapies with effective and sustainable medications that can be used in the long term.

Promotion of DNA damage repair in colonic epithelial cells by andrographolide resulted in the downregulation of cGAS–STING pathway activation, contributing to the alleviation of irinotecan‐induced intestinal mucositis [45]. The condition known as UC is a variant of IBD characterized by persistent inflammation in the intestines and an increased susceptibility to colon cancer. The protective impact of andrographolide on UC involves activating the Nrf2/HO‐1 antioxidant response [46]. Furthermore, when combined with a carbon monoxide donor, oral nanotherapeutics synergistically demonstrate anti‐inflammatory and pro‐resolving effects for effectively managing UC [47].

2.5. Endocrine System Diseases

The endocrine system consists of a series of organs (hypothalamus, pituitary, pineal gland, thyroid, parathyroid, pancreas, adrenal glands, and ovaries or testes) whose primary functions include hormone production and secretion. The hypothalamic–pituitary axis (HPA) maintains control of this complex system by processing in vivo and in vitro signals that release mediating hormones to act on target organs. Signals of change from these major endocrine organs may subsequently lead to alterations in autocrine or paracrine function [48]. Endocrine diseases are common disorders, and any major disorder that affects the number of hormones synthesized and released by the endocrine glands can lead to disturbances in the functioning of multiple organs [49]. Cases of hypopituitarism due to pituitary inflammation, thyroid dysfunction (hypothyroidism, hyperthyroidism, and thyroiditis), primary adrenal insufficiency (PAI), and type 1 diabetes mellitus (T1dm)/autoimmune diabetes mellitus have been frequently reported in the reports of various clinical trials and analyses concerning the endocrine system [50, 51]. Endocrine drugs are drugs that treat endocrine dysfunction. Although endocrine drugs have a lower risk compared to drugs such as chemotherapeutic agents or anticoagulants, they can also repeatedly cause neurologic adverse events (AES) such as headache, nausea, and vomiting [33].

Andrographolide effectively mitigated the production of mitochondrial reactive oxygen species (mtROS) induced by lipopolysaccharide (LPS)/palmitic acid (PA) through enhancing autophagic flux and inhibiting the activation of the NLRP3 inflammasome, thereby providing protection against chronic inflammatory diseases associated with obesity and lipotoxicity [52]. Additionally, andrographolide was shown to inhibit the synthesis of sex hormones in LPS‐induced female rats [53].

Andrographolide enhances glucose uptake and GLUT4 transport through the PKC pathway [54]; potentially activating TGR5 in diabetic rats to promote increased insulin and GLP‐1 production [55]. The synergistic effects of gallic acid and andrographolide elegantly activate AdipoR1, thereby facilitating the secretion of insulin [56]. Additionally, it is proposed that the inflammatory response and cell death (pyroptosis) in pancreatic β‐cells caused by cigarette smoke‐induced hyperglycemia involve the TXNIP‐NLRP3‐GSDMD axis, which can be alleviated through the administration of andrographolide [57].

2.6. Cardiovascular Diseases

Cardiovascular diseases (CVDs) encompass multiple pathological disorders of different etiologies of the heart and vascular system. CVDs are the number one cause of human mortality, and according to the latest WHO estimates, 32% of global mortality is due to heart disease‐related conditions (WHO, 2022) [58]. In studies of CVDs, there are five modifiable risk factors (body mass index, systolic blood pressure, non‐high‐density lipoprotein (HDL) cholesterol levels, current smoking, and diabetes) [59]. Numerous large‐scale studies have been conducted in the primary and secondary prevention of CVDs using a variety of medications, such as statins or antihypertensive drugs [60]. Despite the use of medications, patients with CVD remain at increased risk of adverse cardiovascular events. In recent years, substantial advancements have been made in the prevention, early diagnosis, and treatment of CVDs. However, there are still many challenges that need to be addressed. Therefore, there is still a need to open up new drugs to control and modify the progression of CVDs and further reduce mortality.

Andrographolide has the potential to prevent and treat atherosclerotic cardiovascular disease (ASCVD). It not only addresses obesity, diabetes, hyperlipidemia, and ASCVD but also regulates various targets and pathways to inhibit the progression of atherosclerosis (AS), including lipid buildup, inflammation, oxidative stress, and cellular abnormalities [61]. By modulating NF‐κB/CEBPB/PPARG signaling, andrographolide may alleviate AS [62]. Furthermore, andrographolide mitigates AS by inhibiting foam cell formation and NLRP3 inflammasome‐dependent vascular inflammation, as evidenced by reduced expression of scavenger receptor type A and IL‐1 release [63].

Moreover, andrographolide exhibits protective effects against atrial fibrillation by mitigating oxidative stress damage and enhancing impaired mitochondrial bioenergetics [64]. It also safeguards against LPS‐induced vascular endothelial dysfunction by abrogating oxidative stress and chronic inflammation [65]. Andrographolide shows promise in improving calcific aortic valve disease by influencing the proliferation of valve interstitial cells through the MAPK–ERK pathway [66]. Andrographolide also regulates H3 histone lactylation by interfering with p300 to alleviate aortic valve calcification [67]. Additionally, andrographolide hinders the growth and movement of vascular smooth muscle cells via the PI3K/AKT signaling pathway and amino acid metabolism to prevent excessive tissue thickening [68]. Furthermore, it contributes to reducing cardiac hypertrophy by suppressing endoplasmic reticulum stress [69]. Lastly, andrographolide exhibits potential as a cardioprotective agent by inhibiting the activation of the NLRP3 inflammasome, thereby mitigating doxorubicin‐induced cardiotoxicity [70].

2.7. Joint Diseases

Osteoarthritis (OA) is a degenerative joint disease that manifests itself in the form of increased symptoms affecting the joints [71]. The prevalence of OA is rising, in part due to an increased prevalence of OA risk factors, including obesity, physical inactivity, and joint injuries. OA‐associated joint pain affects the quality of people's lives, for example, by leading to functional limitations, poor sleep, fatigue, mood swings, and loss of independence, among other problems [71]. Treatment of OA remains a challenge. Conventional pharmacological treatments, such as nonsteroidal anti‐inflammatory drugs (NSAIDs) and analgesics, provide only temporary relief of symptoms; long‐term use may cause serious side effects such as liver and kidney toxicity and gastrointestinal problems, and they do not target the pathomechanisms of arthritis and only provide temporary pain relief. Other interventions such as thermotherapy, physiotherapy, and intra‐articular injections also provide very limited long‐term efficacy and therapeutic effects [72], therefore, there is an urgent need to find and develop a drug with safety and efficacy for the treatment of arthritis.

Andrographolide inhibits the progression of osteoarthritis by modulating the circ_Rapgef1/miR‐383‐3p/NLRP3 signaling axis [73]. Furthermore, andrographolide serves as a novel FABP4 inhibitor for the treatment of osteoarthritis [74]. Additionally, andrographolide effectively counteracted SDF‐1‐induced upregulation of TNF‐α, STAT3, TP53, IL‐6, JUN, IL‐1β, HIF‐1α and TGF‐β1 protein expression while also reversing the downregulation of AKT protein expression [72]. Andrographolide protects bone marrow mesenchymal stem cells against glucose and serum deprivation under hypoxia via the Nrf2 signaling pathway [75].

3. Structural Modification of Andrographolide Derivatives

Through the modification of hydroxyl groups, double bonds, and multiple groups, scientists have successfully synthesized a variety of andrographolide derivatives. These derivatives exhibit anti‐inflammatory activity and bioavailability. Structural modification provides a new way to enhance the efficacy of andrographolide derivatives.

3.1. Modification of Hydroxyl Group (Figure 2)

FIGURE 2.

Andrographolide derivative obtained by modification of hydroxyl group.

3.1.1. Andro‐NBD

Andro‐NBD is a derivative of andrographolide, which was synthesized by Hsu et al. [76] through modifications at the 14 and 19 hydroxyl groups of andrographolide under conditions involving 2,2‐dimethoxypropane, Ac₂O, AcOH/H₂O (7:3), and 2,4,6‐trichlorobenzoyl chloride.

3.1.2. 14β‐Andrographolide

Bianca Schulte et al. [77] used andrographolide as the starting material and added reagents such as 2,2‐Dimethoxypropane, AcOH, MeOH/H₂O (4:1), and EtOAc to synthesize the compound at room temperature. The structure involves a conformational modification of the 14‐hydroxyl group of andrographolide.

3.1.3. Compound 3 and 17b

In 2018, Li et al. [1] modified the 14‐hydroxyl group of andrographolide to obtain compound 3 under conditions of anhydrous DCM, 2,2‐dimethoxypropane, anhydrous THF, MeOH/H₂O (4:1), and TsOH·H₂O. In 2019, building on the experimental method from the previous year, Li et al. added AcCl and TEA as reagents and obtained compound 17b at 0°C [78].

3.1.4. Compound 5a

Qian et al. [79] first used andrographolide as the starting material to synthesize 14‐Deoxy‐11,12‐didehydroandrographolide; they then added TrCl, DMP, DCM, NH2OH·HCl, and other reagents to modify the 3 and 19 hydroxyl groups of andrographolide, resulting in the synthesis of compound 5a.

3.1.5. Andrographolide Total Sulfonate (Xiyanping)

Xiyanping is derived from andrographolide, which is treated with sulfur trioxide under conditions where the pH is neutralized with an alkaline solution; then the solution is evaporated to obtain the product [2].

3.1.6. Compound 2

Dai et al. [80] used andrographolide as the starting material and added anhydrous THF, MeOH/H₂O (4:1), TsOH·H₂O, mCPBA, and other reagents to obtain Compound 2 at room temperature.

3.1.7. ZAF‐47

Tian et al. [81] started with andrographolide as the raw material, first synthesized the aforementioned compound 3, and then added AcCl and NaHCO₃ as reagents to synthesize ZAF‐47, a compound whose structure involves modifications at the 3rd, 14th, and 19th hydroxyl groups of andrographolide.

3.1.8. Compound 3b

Compound 3b is synthesized from andrographolide as the starting material, with the addition of 2,2‐dimethoxypropane, anhydrous HOAc, DIAD, and MeOH/H₂O (4:1) as reagents, resulting in a structure that modifies the 14‐OH group of andrographolide [82].

3.1.9. Al‐1

Wang Dingyuan et al. [3] used andrographolide as the starting material and introduced the thioctic acid structure into andrographolide under the action of reagents such as PPTS, α‐lipoic acid, and AcOH to synthesize the andrographolide derivative AL‐1.

3.1.10. 3, 14, 19‐Triacetylandrographolide (CX‐10, ADA)

Liu Tianfu et al. [34] used andrographolide as the starting material and, under the action of reagents such as acid anhydride, introduced the lipoic acid structure into andrographolide to synthesize the andrographolide derivative AL‐1; and then synthesized 3,14,19‐triacetylanhydroandrographolide (CX‐10, ADA) through dehydration and acetylation steps.

3.1.11. 19‐O‐Succinate Dehydrated Andrographolide (Andro‐III)

Andro‐III is synthesized starting from andrographolide, with the main hydroxyl groups protected by triphenylchloromethane (TrCl). The protected compound is then reacted with 4‐chloro‐4‐oxobutyric acid in a dichloromethane(DCM) solution, followed by deprotection to obtain the final product [4].

3.1.12. Compound 5a–f

Surendra Jatavd et al. [83] attached deoxyazetidinone and the corresponding monosaccharides to the andrographolide structure to obtain compounds 5a–f.

3.1.13. Compound 12g

Zhang et al. [84] first synthesized 14‐deoxy‐11,12‐didehydroandrographolide from andrographolide under the conditions of Al₂O₃, pyridine, and heat. Then, by adding reagents such as TEMPO, NCS, amines, and NaBH₃CN, they synthesized compound 12g.

3.1.14. Compound Id

Hao et al. [85] used andrographolide as the starting material and added reagents such as HCHO and CH₃COCl to synthesize compound Id.

3.2. Modification of Double Bonds (Figure 3)

FIGURE 3.

Andrographolide derivative obtained by modification of double bond.

3.2.1. AG5

Andrographolide is treated with ethanol, sodium sulfite, and sulfuric acid, under conditions of pH 6–7 and room temperature; after refluxing, reduced pressure filtration, purification, and drying, AG5 powder is obtained [80].

3.2.2. ASB

Guo Haihui et al. [5] used andrographolide as the starting material and, under the conditions of Na₂SO₃, H₂SO₄, and 95% EtOH, introduced the sodium sulfite group into andrographolide through a Michael addition reaction, resulting in the production of ASB.

3.3. Modification of Multiple Groups (Figure 4)

FIGURE 4.

Andrographolide derivative obtained by modification of multiple groups.

3.3.1. 14‐Deoxy‐11,12‐didehydroAndrographolide

Yu Qingqing et al. [5] utilized andrographolide as the raw material and added pyridine and succinic anhydride. Under heated conditions, 14‐deoxy‐11,12‐didehydroandrographolide was prepared by reflux.

3.3.2. Compound 24

Under the catalysis of anhydrous zinc chloride, andrographolide reacts with TBSCl‐imidazole to introduce TBS. The conversion of 3‐alcohol to 3‐ketone is achieved through oxidation using dichloromethane (DCM). Subsequently, the addition of mCPBA and sodium bicarbonate at 0°C or room temperature initiates the epoxidation of the 8,17‐olefin, yielding the product as described in [6].

3.3.3. Compound 8h and Compound 8m

Compound 8h and compound 8m are directly obtained by altering the core structure of andrographolide through the action of reagents such as DMP, Ac₂O, HCl/ethyl acetate, and others [86].

3.3.4. IAN‐19P

The addition of concentrated hydrochloric acid causes the cyclization of the C‐11, 12, and 17 positions of androsgrapholide [7]. Subsequently, propionic anhydride is added in an anhydrous solution to react and produce a crude product. Further purification is then carried out to obtain the corresponding esterified derivative of andrographolide, IAN‐19P [87].

3.3.5. Compound 10

Compound 10 [88] is obtained by reacting andrographolide with concentrated HCl, Ac₂O, and ZnCl₂ at room temperature.

4. Screening and Optimization of Andrographolide Derivatives

4.1. Biological Activity Screening Criteria

Among the many andrographolide derivatives, screening for derivatives with superior bioactivity is key. First, the inhibitory effect of the derivatives on the release of inflammatory mediators was assessed by in vitro cellular assays. For example, using a LPS‐induced macrophage inflammation model, the effect of derivatives on the secretion of pro‐inflammatory cytokines (e.g., TNF‐α, IL‐6) was examined, and those derivatives that could significantly reduce the levels of cytokines were selected [89]. Secondly, antiviral experiments were carried out, in which the derivatives were co‐incubated with viruses to observe their inhibitory effects on viral replication, and derivatives with strong antiviral activity and clear mechanisms of action were selected [90]. In addition, they can be further screened by other bioactivity tests (e.g., antimicrobial, antitumor) to obtain derivatives that are positively differentiated [91].

4.2. Pharmacokinetic Evaluation Index

Pharmacokinetic properties play an important role in the selection of andrographolide derivatives. Through in vivo pharmacokinetic experiments, the rate and extent of absorption of derivatives can be examined, and derivatives with high bioavailability can be selected to ensure the effective concentration of the drug in the body. At the same time, their tissue distribution is evaluated to understand the degree of drug enrichment at the site of inflammation to improve the therapeutic effect. Metabolites and their rate of metabolism are also key considerations. Derivatives with stable metabolism and low toxicity of metabolites are selected to reduce the toxic side effects of the drug. Finally, the excretion route and rate of the drug are examined, and derivatives with a clear excretion route and moderate excretion rate are selected to maintain the effective concentration and duration of action of the drug in the body. These pharmacokinetic evaluation indexes are important for understanding the behavior of derivatives in vivo, optimizing their efficacy and safety, and guiding the clinical use of drugs [8].

5. Andrographolide Derivatives for Treatment of Viral Infectious Diseases

5.1. Coronavirus

Studies have shown that andrographolide and its fluorescent derivative, nitrobenzoxediazole‐conjugated andrographolide (Andro‐NBD) (the chemical structure is depicted in Figure 5), can inhibit the activity of Mpro, the main protease of COVID‐19 and SARS‐CoV‐2 and have acceptable safety and multiple pharmacological activities in clinical application, which is helpful to alleviate the symptoms of COVID‐19 [76]. The system biology approach explores the impact of 14‐deoxy‐11,12‐didehydroandrographolide on COVID‐19 through modulation of multiple pathways. Among these pathways, the chemokine signaling pathway is particularly intriguing due to its direct influence on immune response and its significantly low rate of false discovery [92]. Initial molecular docking analysis suggests that derivatives of andrographolide could be promising candidates for treating SARS‐CoV‐2 infection; however, further investigations involving molecular dynamics and pharmacological screening are necessary [93]. Andrographolide, by the minor structural modifications, could lead to derivatives (14ß andrographolide) (chemical structure is depicted in Figure 5) with stronger targeting keap1‐Nrf2 shaft activity and improve its physical and chemical properties [77]. 14‐deoxy‐12(R,S)‐sulfo‐andrographolide(AG5) (chemical structure is depicted in Figure 5), a synthetic derivative of andrographolide with high absorbability and low toxicity, inhibits caspase‐1 in THP‐1 cells and modulates immune response in DC cells, exhibiting in vivo anti‐inflammatory efficacy. It has demonstrated potential antiviral activity against SARS‐CoV‐2 in humanized mice [94]. A chemoinformatics‐based approach was employed to discover potent derivatives of andrographolide that exhibit affinity toward the methyl transferases (MTase) of SARS‐CoV‐2, specifically nsp14 and nsp16, which play a crucial role in virus replication and evasion from host immune response. Two novel derivatives of andrographolide (PubChem CID: 2734589 and 138968421) (chemical structure is depicted in Figure 5) were identified as naturally occurring bioactive compounds capable of forming stable complexes with both proteins through hydrophobic interactions, hydrogen bonding, and electrostatic interactions. However, further in vitro and in vivo evaluations are necessary to validate their effectiveness and safety for potential clinical applications [95].

FIGURE 5.

Andrographolide derivatives for treatment of viral infectious diseases including coronavirus, Zika virus, and enterovirus A71.

5.2. Zika Virus

The genome of the Zika virus (ZIKV) consists of a single‐stranded RNA with a linear structure and positive polarity. It encodes a polyprotein that contains multiple transmembrane domains. This polyprotein is cleaved into 3 structural proteins and 7 non‐structural (NS) proteins by both host and viral proteases. 19‐acetylated 14α(5′,7′‐dichloro‐8′‐quinolyloxy) derivative (17b) and 14β‐(8′‐quinolyloxy)‐3,19‐diol derivative (3) (chemical structure is depicted in Figure 5) showed the strongest anti‐ZIKV activity. Both derivatives are suitable for guiding the design of a new generation of andrographolide derivatives with quinolines or moieties related to their structure and properties, with strong inhibitory effects against ZIKV and other arboviruses [78]. Bulky group modification is necessary for effective anti‐ZIKV infection and replication. The anti‐ZIKV activity of compound 5a (chemical structure is depicted in Figure 5) is attributed to its hindered trityl ether, rather than instability. Dehydroandrographolide's backbone proves more effective against ZIKV infection compared to that of andrographolide. Furthermore, 3‐oxime derivatives exhibit greater potency against ZIKV infection than their 3‐alcohol counterparts. Compound 5a has the ability to interact with the MTase domain of ZIKV N55, making it the first reported MTase inhibitor among andrographolide derivatives [79].

5.3. Enterovirus A71

Human enterovirus A71 (EV‐A71) is a prominent etiological agent of hand‐foot‐and‐mouth disease (HFMD). Xiyanping injection, also known as andrographolide sulfonate, is recommended in China for treating severe HFMD due to its antipyretic and detoxifying effects. In a therapeutic regimen‐dependent manner, Xiyanping injection effectively protects mice from lethal EV‐A71 challenge by modulating the immune activities of neutrophils and T lymphocytes [96]. Compound 2(chemical structure is depicted in Figure 5), known as 14S‐(2′‐chloro‐4′‐nitrophenoxy)‐8R/S,17‐epoxy andrographolide, hinders the later stages of the EV‐A71 viral replication cycle and significantly diminishes the expression of viral proteins VP0 and VP2 by inhibiting the replication of EV‐A71 RNA. Additionally, compound 2 specifically targets the replication process of viral RNA [80]. Andrographolide derivatives like quinoline oxyandrographolide ZAF‐47(chemical structure is depicted in Figure 5) have been identified as inhibitors of EV‐A71 virus replication and protein expression, suggesting their potential for treating HFMD [81].

6. Andrographolide Derivatives for Treatment of Airway or Lung Damage

The lung, as a core component of the respiratory system, is responsible for gas exchange and maintaining immune function and has manifested a potent capacity for self‐repair and regeneration. 14‐Deoxy‐11,12‐didehydroandrographolide (chemical structure is depicted in Figure 6) exhibited a dose‐dependent reduction of ovalbumin (OVA)‐induced asthma in an experimental model, accompanied by a decrease in the levels of IL‐4, IL‐5, and IL‐13, as well as an elevation in serum OVA‐specific IgE levels. Furthermore, it attenuated airway eosinophilia, mucus production, mast cell degranulation, expression of pro‐inflammatory biomarkers in lung tissues, and airway hyper‐responsiveness [97]. 14‐deoxy‐11,12‐didehydroandrographolide may maintain the anti‐inflammatory activity of andrographolide in asthma by blocking NF‐κBp65 nuclear translocation and DNA‐binding activity, as well as being a safer analog for potential asthma treatment.

FIGURE 6.

Andrographolide derivatives for treatment of airway or lung damage and its related action mechanism.

Nie et al. have synthesized different andrographolide derivatives to investigate their effects on the production of pro‐inflammatory factors induced by Toll‐like receptor (TLR) in acute lung injury, a serious respiratory disease with a high mortality rate. Among these derivatives, compound 3b protected mice from LPS‐induced acute lung inflammation by inhibiting NF‐κBp65 phosphorylation and decreasing serum pro‐inflammatory factors and chemokines, suggesting that it is a potent immunosuppressant with the potential to protect against acute lung infection [82]. Andrographolide sulfonate also exhibited potential in reducing the severity of ALI induced by LPS, potentially through modulation of the expression levels of neutrophil‐derived proteases such as neutrophil elastase, cathepsin G, and myeloperoxidase (MPO) [98].

Andrographolide derivative AL‐1(chemical structure is depicted in Figure 6) effectively attenuated lung injury by decreasing the levels of inflammatory factors, MPO activity, and lung W/D ratio; it was able to ameliorate the histopathological changes in lungs and significantly reduced the inflammatory cell infiltration and the activation of the inflammatory vesicle pathway of NLRP3 [99]. Research has also found that Isoandrographolide inhibits NLRP3 inflammasome activation and attenuates silicosis in mice [100].

As shown in Figure 6, based on current research, the mechanism of action of andrographolide derivatives in treating lung injury is primarily still focused on the classical NF‐κB and NLRP3 inflammasome, while the mechanism of regulating cellular immune responses is gradually being uncovered by researchers. The lungs are richly innervated by nerves, and neuroimmune interactions play a modulatory role in the initiation and development of inflammatory lung diseases, particularly acute lung injury. The neuroimmune modulation can be achieved through the following pathways: cholinergic anti‐inflammatory pathway, sympathetic–immune pathway, purinergic signaling, neuropeptides, and renin–angiotensin system [101]. Andrographolide and its derivatives targeting neuroimmune crosstalk in acute lung injury warrant further discussion.

7. Andrographolide Derivatives for Treatment of Gastrointestinal Diseases

UC is characterized by chronic non‐recessive inflammation of the intestinal mucosa involving both innate and adaptive immune responses. 3,14,19‐triacetyl andrographolide (CX‐10, ADA) (chemical structure is depicted in Figure 7) possesses strong anti‐inflammatory properties. CX‐10 treatment resulted in weight loss, shortened colon length, a lower colon weight, a lower splenic index, and less histologic damage to the colon in dextran sulfate sodium (DSS)‐induced colitis models. The mechanism is to attenuate UC by inhibiting the activation of the NF‐κB and MAPK pathways and decreasing the levels of TNF‐α and IL‐6, which are potential therapeutic agents for UC [102]. Another andrographolide derivative, AL‐1, has been newly discovered for treating DSS‐induced UC. Its mechanism involves activating the NF‐κB and MAPK signaling pathways through inhibition. Oral administration of AL‐1 alleviated DSS‐induced colitis in mice by reducing weight loss, shortening colon length, lowering disease activity index score, attenuating colonic histological damage, inhibiting MPO activity in colonic tissues, suppressing immune‐inflammatory responses, and reversing the expression of inflammatory cytokines [103]. Meanwhile, AL‐1 also had a protective effect on the intestinal barrier function in a trinitrobenzene sulfonic acid‐induced colitis model in mice, which was achieved through the inhibition of myosin light chain kinase (MLCK)‐dependent pathway to maintain normal mucus secretion and keep the tight junctions, which suggests that AL‐1 is a better therapeutic agent for UC [104].

FIGURE 7.

Andrographolide derivatives for treatment of ulcerative colitis and its related action mechanism.

In addition to this, Xiyanpin ameliorates chronic colitis by decreasing the levels of inflammatory factors IL‐6, TNF‐α and IFN‐γ in colonic tissues, attenuating the inflammatory response and epithelial damage and fibrosis, and may be used in the future for the clinical treatment of chronic colitis [105]. The efficacy of andrographolide derivative 3b(chemical structure is depicted in Figure 7) on the DSS‐induced acute colitis model was evaluated, and 3b significantly reduced the disease activity index and inhibited the expression of pro‐inflammatory factors at both serum and transcriptional levels. It was suggested that 3b has anti‐inflammatory and anti‐apoptotic effects by increasing the number of proliferating cell nuclear antigen (PCNA)‐positive cells and cup cells in the intestinal crypts and effectively inhibits TLR4‐NF‐κB and increased β‐catenin signaling pathways [106].

The disruption of the colonic barrier allows LPS to enter the liver via the portal vein, causing liver injury. This liver injury worsens UC, creating a vicious cycle that necessitates treatment for both conditions. Andrographolide has a protective effect against colitis and liver injury, but its bioavailability is low. However, andrographolide sodium bisulfite (ASB) (chemical structure is depicted in Figure 7) provides better protection against DSS‐induced UC and liver injury compared to regular andrographolide. ASB achieves this by reducing the disease activity index and inhibiting intestinal‐derived LPS leakage through macrophage inhibition on the gut–hepatic axis [107].

Andrographolide and its derivatives have demonstrated their potential in the prevention and treatment of gastrointestinal disorders, including gastric cancer, colorectal cancer, and IBD. These compounds exhibit significant efficacy as protective agents for the gastrointestinal system [108]. As depicted in Figure 7, based on the current research, it is gratifying that several andrographolide derivatives have shown potential in treating UC. Their mechanisms of action encompass inhibiting the activation of the NF‐κB and MAPK pathways, upregulating the β‐catenin pathway, suppressing cellular immune‐inflammatory responses, and maintaining the junctional function of the intestinal barrier. Currently, autophagy, ferroptosis, and neutrophil extracellular traps (NETs) are new therapeutic options for UC [88, 109, 110]; andrographolide and its derivatives can be further explored in these mechanisms.

8. Hepatoprotective Effect of Andrographolide Derivatives

An andrographolide derivative (compound 24) (chemical structure is depicted in Figure 8) may act as a STAT3 inhibitor, effectively ameliorating carbon tetrachloride‐induced acute liver injury through mechanisms related to promoting hepatocyte proliferation and activating STAT3. Compound 24 effectively inhibited phosphorylation and dimerization of STAT3 but not its DNA‐binding activity [111].

FIGURE 8.

Hepatoprotective effect and mechanism of andrographolide derivatives.

NAFLD is one of the growing epidemics worldwide, reported to be present in 76% of T2D subjects and 80%–90% of obese adults. Andrographolide has previously been shown to treat obesity and insulin resistance by regulating sterol regulatory element‐binding protein (SREBP) target genes and metabolism‐related genes in liver or brown adipose tissue. Toppo et al. reported the hepatoprotective effect of andrographolide and its two derivatives. The OH groups of C‐14 were removed, and the OH groups of C‐3 and C‐19 were protected. It was found that isoandrographolide may be a promising treatment for NAFLD with lower toxicity and higher efficacy. Compared with andrographolide and 3, 19‐acetyl andrographolide, isoandrographolide treatment showed better liver protection by reducing lipid, aminotransferase, and ALP levels [112]. Additionally, 19‐propionyl isoandrographolide (IAN‐19P) (chemical structure is depicted in Figure 8) for the treatment of NAFLD as evidenced by lowering plasma lipids, transaminases, LDH, and GGT (γ Glutamyl transferase) levels and upregulating the expressions of PPARα, PPARγ, Carnitine Palmitoyltransferase 1 (CPT‐1) and Farnesoid X Receptor (FXR), which significantly downregulated the expressions of SREBP‐1c and TNFα [113]. And IAN‐19P was better than andrographolide and isoandrographolide in reducing plasma ALT and AST levels.

9. Neuroprotective Effect of Andrographolide Derivatives

9.1. Brain Ischemic Stroke

Cerebral ischemic stroke, also known as ischemic stroke, is a disease caused by ischemia and hypoxia of brain tissue due to blockage of blood vessels in the brain. It is the most common type of stroke, accounting for more than 80% of all strokes. Ischemic stroke is associated with its high morbidity, disability, and mortality rates. Once the disease develops, irreversible damage to brain tissues occurs rapidly under ischemia and hypoxia, resulting in neurological dysfunction, such as paralysis of limbs, speech disorders, and cognitive decline, which seriously affects the quality of life of patients. In addition, cerebral ischemic stroke may cause a series of complications, such as lung infection and deep vein thrombosis, which further aggravate the condition. Therefore, cerebral ischemic stroke is a very dangerous cerebrovascular disease that requires great attention to its prevention and timely treatment [114].

Inflammation plays a crucial role in the pathophysiology of acute ischemic stroke. In addition to the reported treatment of colitis, CX‐10 (chemical structure is depicted in Figure 9) was also found to have significant neuroprotective effects throughout the body after perfusion. The administration of CX‐10 resulted in a significant reduction in the infarct area associated with local cerebral ischemia, improvement in neurological function, mitigation of motor deficits, decrease in inflammatory factor levels, enhancement of antioxidant capacity, and effective suppression of TLR4, NF‐κB, TNF‐α, and iNOS protein expression. Additionally, it induced Nrf2 and HO‐1 expression. Therefore, the inhibition of TLR4/NF‐κB activity and upregulation of the Nrf2/ARE signaling pathway may represent crucial mechanisms underlying the neuroprotective effects exerted by CX‐10 [83].

FIGURE 9.

Neuroprotective effect and mechanism of andrographolide derivatives. The orange box represents activation and the blue box represents suppression.

9.2. AD

AD is a neurodegenerative disorder that primarily causes dementia and is characterized by the accumulation of beta‐amyloid plaques and tau protein tangles in the brain. The disease is the most common cause of dementia in the elderly. As the disease progresses, patients experience symptoms such as memory loss, cognitive dysfunction, behavioral and personality changes, and ultimately an inability to take care of themselves, which seriously affects the quality of life of patients and their family members. AD not only imposes a heavy financial and emotional burden on patients and their families, but also poses a huge challenge to the social healthcare system, making it one of the most challenging diseases of this century [115].

Inflammation is an important pathogenetic link in neurological disorders, in which microglia‐mediated chronic inflammation is currently more studied in a variety of chronic neurodegenerative disorders. Some studies suggest that andrographolide derivatives have therapeutic potential for AD. Yuan‐Zhen Xu et al. [116] prepared a variety of analogues of andrographolide, in which compounds 3 and 12 were able to protect neurons by inhibiting LPS‐induced NO production, iNOS, TNF‐α and IL‐6 expression from microglia‐mediated neurotoxicity. Compound 12 acts on acetylcholine receptors. In addition, compound 10 (chemical structure is depicted in Figure 9) promotes nerve growth factor‐induced neurite growth in PC12 cells and may exert anti‐AD effects through the thyroid hormone signaling pathway. Studies have shown that andrographolide sulfonate (Xinyanping) (chemical structure is depicted in Figure 9) attenuates oxidative stress and mitochondrial swelling in APP/PS1 transgenic mice, suggesting that it may be a potent drug for the treatment of AD through mitochondrial protection [117]. Jatav et al. [84] assessed the efficacy of the deoxynandrolactone triazolyl compounds, 5a–f (chemical structure is depicted in Figure 9), on AD, which demonstrated that 5a–f improves cognitive function in mice with SCOP‐induced memory impairment by inhibiting oxidative stress and neuroinflammatory cascade mechanisms in the mouse brain. Andro‐III (chemical structure is depicted in Figure 9) synthesized by our team [118] was shown to improve learning memory ability in 3xTg‐AD mice and attenuate neuroinflammation in the brain by modulating GSK‐3β/NF‐κB/CREB. In addition, Hai‐Yu Zhang et al. [119] used the 3xTg mimetic AD mouse model and β‐amyloid‐induced mouse hippocampal neuronal cells to establish an AD cell model, confirming that CX‐10 (ADA) (chemical structure is depicted in Figure 9) triggers autophagy initiation and normalizes lysosomal function through the Akt/mTOR pathway. Researchers further found that ADA targeted SIRT3‐FOXO3a signaling to activate mitochondrial autophagy, inhibited the activated NLRP3 inflammasome to attenuate neuroinflammation and cognitive impairment in the brains of APOE4 mice [85].

9.3. Parkinson's Disease

Parkinson's disease is a common neurodegenerative disease, which is mainly characterized by motor dysfunction, such as tremors, rigidity, and slow movement. As the disease progresses, the quality of life of the patients will gradually decline, and they may even lose the ability to take care of themselves, which brings a heavy burden to the patients and their families. In addition, Parkinson's disease is accompanied by many non‐motor symptoms, such as cognitive impairment, mood disorders, sleep problems, etc., which further aggravate the physical and mental pain of patients [120].

At present, there are few studies on derivatives in the treatment of PD. Only one study has demonstrated that AL‐1 exerts a neuroprotective effect both in vitro and in an animal model of PD by significantly improving the reduced expression of tyrosine hydroxylase (TH) protein in the substantia nigra and inhibiting the increased activation of phosphorylated NF‐κBp65 [121].

As illustrated in Figure 9, the above andrographolide derivatives obtained by 3, 14, and 19 hydroxyl substitutions are a class of candidate drugs with significant neuroprotective effects and can be applied in cerebral stroke, PD, and AD, which are worthy of further exploration by researchers. The underlying mechanisms involve regulating the thyroid hormone signaling pathway, the GSK‐3β/NF‐κB/CREB pathway, suppressing the NLRP3 inflammasome, upregulating the Nrf2/HO‐1 and SIRT3/FOXO3a antioxidant pathways, modulating the Akt/mTOR pathway to influence autophagy, and attenuating mitochondrial function. Nevertheless, there is currently a scarcity of studies on regulating the immune functions of microglia and astrocytes.

10. Other Diseases Treated by Andrographolide Derivatives

10.1. Osteoporosis

Osteoporosis is a metabolic bone disease characterized by decreased bone density and destruction of bone microarchitecture, leading to increased bone fragility, which significantly increases the risk of fractures. It is particularly common in the elderly population, severely affecting the quality of life of patients and increasing the risk of disability and death. The seriousness of osteoporosis lies in the fact that it is usually asymptomatic and is not detected until a fracture occurs, which is difficult to recover from and has many complications, posing a significant risk to both the patient's physical and psychological health [122].

14‐Deoxy‐11,12‐didehydroandrographolide is considerably less cytotoxic and has moderate anti‐osteoclastogenic activity compared to andrographolide. Of the derivatives synthesized through the introduction of an anti‐osteoporotic chemotype at its C‐19, six showed stronger inhibition of osteoclastogenesis than andrographolide. Notably, compound 12g (chemical structure is depicted in Figure 10) had the strongest activity to down‐regulate the expression levels of osteoclast‐specific genes including TRACP, CTSK, NFATC1, and MMP‐9. In addition, compound 12g inhibited osteoclast differentiation by downregulating the RANKL‐induced NF‐κB signaling pathway and significantly ameliorated bone loss in the deovulated female mouse model. Thus, compound 12g exhibited favorable in vivo efficacy and low toxicity, suggesting its potential for the treatment of osteoporosis [86].

FIGURE 10.

Other diseases like osteoporosis, light aging, insecticidal and diabetes treated by andrographolide derivatives and its related action mechanism. The orange box represents activation and the blue box represents suppression.

10.2. Anti‐Light Aging

Skin photoaging refers to the accelerated aging process of skin structure and function due to overexposure to ultraviolet radiation. It is serious in that it not only affects the appearance of the skin, such as leading to wrinkles, laxity, and hyperpigmentation, but it may also increase the risk of skin cancer, posing a long‐term hazard to skin health. Photoaging destroys the cellular structure of the skin, triggering chronic inflammation and immunosuppression, leading to loss of elasticity and luster, roughness, sagging, discoloration, etc. It also reduces the skin's self‐repairing ability, which makes the skin more susceptible to external environmental aggressions [123].

Inflammation‐induced damage plays a crucial role in the development of skin photoaging. The application of ASB demonstrated inhibitory effects on UV‐induced changes in skin thickness, elasticity, wrinkles, and moisture levels. It also significantly increased collagen content by approximately 53.17% while reducing epidermal thickness by about 41.38%. Moreover, ASB effectively prevented the degradation of collagen fibers and elastic fibers caused by UV exposure. Additionally, ASB exhibited antioxidant properties by decreasing MDA levels and enhancing SOD and CAT activities. Furthermore, it downregulated the production of inflammatory cytokines IL‐1β, IL‐6, IL‐10, and TNF‐α while potentially serving as a promising agent for combating photoaging [124]. Researchers further investigated the molecular mechanisms through which ASB attenuates UV photodamage in cellular experiments. ASB significantly reduced apoptosis, decreased excess ROS levels induced by UV, activated Nrf2 production, and increased mRNA expression of the catalytic subunit of glutamate‐cysteine ligase and NAD(P)H quinone oxidoreductase 1. Additionally, ASB downregulated NF‐κBp65 protein expression while activating the Keap1/Nrf2 pathway and suppressing the NF‐κB pathway in HaCaT keratinocytes [125]. Another study demonstrated that ASB dramatically suppressed protein expressions of NF‐κB, Nrf2, p62, LC3 II/I, and p‐p62 (Ser 349) induced by UV in mouse skin [87].

10.3. Diabetes Mellitus

Diabetes mellitus is a group of metabolic diseases characterized by persistent hyperglycemia and is mainly classified into type 1 and type 2. Type 1 diabetes mellitus is usually caused by immune‐mediated destruction of pancreatic β‐cells leading to absolute insulin deficiency, while type 2 diabetes mellitus is characterized by insulin resistance and relative insulin deficiency and is often associated with obesity and unhealthy lifestyle choices. The seriousness of diabetes lies in the fact that its long‐term hyperglycemic state can lead to a variety of complications, such as cardiovascular disease, nephropathy, retinopathy, and neuropathy, which can seriously affect patients' quality of life and life expectancy [126].

Li et al. found that AL‐1 holds promise as a novel drug for treating and preventing diabetes mellitus. AL‐1 enhanced insulin secretion, reduced blood glucose levels, and protected cell mass and function in a mouse model of tetracycline‐induced diabetes. It also decreased ROS and NO production while increasing SOD and CAT activities in high glucose‐induced insulinoma epithelial (RIN‐m) cells. Additionally, AL‐1 upregulated the expression of Nrf2, thioredoxin‐1 (Trx‐1), and HO‐1 proteins. By activating the Nrf2 signaling pathway and inhibiting the NF‐κB signaling pathway, AL‐1 prevented oxidative damage caused by high glucose in RIN‐m cells, thereby protecting pancreatic islets from such damage [127].

In addition, the therapeutic potential of (8R, 12S)‐isoandrographolide in tubulointerstitial fibrosis is demonstrated as it effectively safeguards against kidney injury by inhibiting the abnormal activation of the AKT/GSK‐3β/β‐catenin pathway in mice with diabetic nephropathy [128].

11. Other Anti‐Inflammatory Activity of Andrographolide Derivatives

By employing Beckman rearrangement, two sets of derivatives based on andrographolide were synthesized, wherein the A ring was partially modified with an amide group. The conformational analysis revealed that incorporating a caprolactam moiety into the derivative's A ring and esterifying the C‐19‐hydroxyl group enhanced its inhibitory effect on glycolysis enzyme Hexokinase 2 (HK2) activity, a new and effective anti‐inflammatory target (specifically compound 8h) (the chemical structure is depicted in Figure 11). Furthermore, compound 8h exhibited reduced levels of IL‐1β and IL‐6, as well as downregulation of iNOS and COX‐2. The anti‐inflammatory properties of this derivative were attributed to its ability to inhibit both the NF‐κB pathway and HK2 [129]. HK2 is a key enzyme that converts cells from oxidative phosphorylation to glycolytic metabolism on the outer mitochondrial membrane, specifically expressed in the synovial lining of rheumatoid arthritis and regulating the function of fibroblast‐like synoviocyte invasion. During the same period, synthesized derivatives of andrographolide containing nitrogen‐containing heterocycles, phenols, and aromatic acids were found to possess bioisosteric segments similar to the lactone ring. Among these derivatives, compound 8m (chemical structure is depicted in Figure 11) exhibited a stronger inhibitory effect on the production of NO induced by LPS in RAW264.7 macrophages compared to hydrocortisone. Furthermore, its mechanism of action against inflammation was attributed to its ability to inhibit the COX‐2, iNOS, and NF‐κB signal pathway [130].

FIGURE 11.

Anti‐inflammatory activity of andrographolide derivatives compound 8h and 8m.

The introduction of tetrahydrofuran ring and cyclic olefinic bond plays an important role in enhancing the anti‐inflammatory activity. Some researchers prepared 3,19‐dipalmitoyl‐14‐deoxy‐11,12‐dihydroandrographolide by modifying the structure of andrographolide by esterification with anhydrides or chlorides on 3,14,19‐OH and evaluated in vivo anti‐inflammatory effects, which were found to be much higher than that of its parent compound. The anti‐inflammatory activity of isoandrographolide and 14‐deoxyandrographolide was found to be stronger than that of andrographolide in an egg white‐induced foot‐plantar edema model in rats [131].

12. Current Status and Challenges in the Application of Andrographolide Derivatives

Andrographolide and its derivatives are mainly used clinically for the treatment of various inflammatory diseases, such as respiratory tract infections, bronchitis, pneumonia, etc., with demonstrated anti‐inflammatory, antibacterial, and antiviral effects. In recent years, with the deepening of research, the potential applications of andrographolide and its derivatives in the fields of diabetes, osteoporosis, anti‐photo‐aging, insecticidal/acaricidal, and so on have also been gradually explored, showing good prospects for clinical applications. However, the clinical application of andrographolide and its derivatives still faces many challenges. First, their pharmacokinetic properties are not satisfactory, such as low oral bioavailability and large fluctuations in blood concentration, which limit their clinical efficacy. Secondly, the scale and quality of clinical studies are relatively insufficient, and there is a lack of large‐scale, multi‐center, randomized controlled trials to fully verify their efficacy and safety, which leads to the limitation of the promotion of clinical application. In addition, the toxicity and adverse reactions of andrographolide and its derivatives need to be further clarified to ensure their safety in clinical application.

13. Conclusions and Perspectives

Researchers have continued research into andrographolide derivatives, and they continue to seek new andrographolide derivatives based on previous research results. These studies have laid a solid foundation for the research and development of new drugs based on hololactone as a lead compound. Extensive research in modern pharmacology has demonstrated that andrographolide and similar compounds offer anti‐inflammatory advantages in different models of inflammatory diseases (Table 1). Among the various signaling pathways investigated, the primary anti‐inflammatory effect of andrographolide is the inhibition of NF‐κB activity. Before applying the current discoveries in clinical settings, it is crucial to establish validation and agreement on the main mechanism of action of andrographolide and its similar compounds in various inflammatory conditions. Efforts are needed to identify potent andrographolide lead compounds with improved pharmacokinetic and toxicological characteristics.

TABLE 1.

Application and mechanism of action of andrographolide derivatives in inflammatory diseases.

Andrographolide derivatives	Inflammatory diseases	Experimental model	Mechanisms	References
Andrographolide sodium bisulfite (ASB)	UC and liver injury	DSS‐induced mice	YAP‐mediated and TLR4/MyD88/NF‐κB‐mediated pro‐inflammatory factor release, the gut‐hepatic axis	[107]
	Photodamage	HaCaT keratinocytes	Activating Keap1/Nrf2 pathway, downregulating NF‐κB pathway	[124, 128]
Xiyanping (Andrographolide Total Sulfonate)	Chronic colitis	TNBS‐induced C57BL/6 mice	Decreasing IL‐6, IL‐ 17A, TNF‐α and IFN‐γ	[105]
	Alzheimer's disease	APP/PS1 transgenic mice	Reduction of oxidative stress and mitochondrial swelling	[117]
Potassium dehydroandrographolide succinate (PDA)	Vascular remodeling	The complete ligation of the carotid artery in C57BL/6 mice	Inhibition of MyD88/CDH13 signaling pathway	[132]
AL‐1	Lung damage	LPS‐induced Male Balb/c mice	Reduces inflammatory cytokine levels, MPO activity; inhibiting NLRP3 inflammasome	[99]
	UC	DSS or TNBS‐induced C57BL/6 mice	Inhibition of NF‐κB, PPARγ，MAPK and MLCK‐dependent pathway	[103, 105, 133]
	Diabetes	High glucose‐induced RIN‐m cells	Upregulation of Nrf2 pathway, downregulation of NF‐κB pathway	[127]
CX‐10, ADA,3, 14, 19‐Triacetyl andrographolide	UC	DSS‐induced mice	Inhibiting the activation of NF‐κB and MAPK pathways	[108]
	Localized cerebral ischemia	LPS‐induced BALB/c mice; MCAO and reperfusion in rats	Activation of Nrf2/ARE and inhibition of TLR/NF‐κB pathway	[83]
	Alzheimer's disease	3 × Tg‐AD mice; APOE mice	Activation of mitophagy and SIRT3‐FOXO3a pathway, inhibition of NLRP3 inflammasome	[85, 122]
Andrographolide derivative 3b	Acute colitis	HCT‐116 cells; DSS‐induced C57BL/6J mice	Upregulation of the number of PCNA‐positive cells and cup cells and the mRNA of β‐Catenin target genes	[106]
Compound 10	Alzheimer's disease	LPS/H2O2(−)/6‐OHDA/NGF‐induced PC12 cells	NO production and iNOS expression, pro‐inflammatory cytokines; the thyroid hormone signaling pathway	[116]
Compound 5a–f	Alzheimer's disease	Scopolamine‐induced memory impairment mice model	Inhibiting oxidative stress and neuroinflammatory cascade; anti‐cholinesterase properties	[84]
Compound 12g	Osteoporosis	Ovariectomized female mice model	Downregulation of the RANKL‐induced NF‐κB pathway	[86]
Andro‐III	Alzheimer's disease	3 × Tg‐AD mice; Aβ‐induced BV‐2 cells	Downregulation of GSK‐3β/NF‐κB/CREB pathway	[118]

At present, the molecular activity mechanism of andrographolide derivatives has not been extensively studied; few of the active derivatives have been applied in the clinic. Therefore, in future derivative synthesis and activity screening work, with the help of computer‐aided drug design (CADD) technology, the molecular structure of andrographolide was studied to predict its interaction mode with key targets, such as p65 protein in the NF‐κB signaling pathway, and to precisely locate the active site. Through molecular docking and molecular dynamics simulation, potential advantageous structures with high affinity were screened to lay a theoretical foundation for structure optimization. Meanwhile, a high‐throughput screening (HTS) model was established to rapidly assess the inhibitory effect of a large number of andrographolide derivatives on the release of inflammatory mediators using cell‐based experiments such as the LPS‐induced macrophage inflammation model, and efficiently screen out derivatives with significant activity, providing abundant candidate compound resources for subsequent pharmacodynamic studies and structure optimization. In addition, we will conduct pharmacokinetic studies of andrographolide and its derivatives in different animal models (e.g., rats, mice, rabbits) to determine their absorption, distribution, metabolism, and excretion in vivo; to obtain pharmacokinetic parameters of the drugs, such as bioavailability, half‐life, volume of distribution, etc.; to evaluate their behavioral characteristics in vivo and to study their relationship with other commonly used drugs (e.g., antibiotics, antiviral drugs). We also investigated the interactions between andrographolide and its derivatives with other commonly used drugs (e.g., antibiotics and antiviral drugs), and explored the pharmacokinetic changes and potential drug–drug interactions when they are used in combination with other drugs so as to provide references for the rational use of drugs in clinical practice. The growing body of preclinical data on andrographolide and its derivatives holds promise for uncovering the primary anti‐inflammatory mechanisms in inflammatory diseases and guiding future research. Ultimately, andrographolide and its analogs could emerge as a new class of anti‐inflammatory medications, with the potential for more andrographolide molecules to undergo clinical trials in the near future.

Author Contributions

Lili Gu: conceptualization, writing – original draft, writing – review and editing. Xinyue Zhang: conceptualization, writing – review and editing. Yao Wei, Xiaoqin Shan: software, writing – original draft. Jiayi Shi, Can Wang, and Jiayi Liu: writing – original draft.

Conflicts of Interest

The authors declare no conflicts of interest.

Shan X., Li S., Liu J., et al., “The Therapeutic Potential of Andrographolide and Its Derivatives in Inflammatory Diseases,” Pharmacology Research & Perspectives 13, no. 5 (2025): e70161, 10.1002/prp2.70161.

Data Availability Statement

The authors have nothing to report.