Andrographolide and its Analogs: Botanical Sources, Phytochemistry, Pharmacology, and Biotechnology

The genus Andrographis is usually bitter and is the source of several diterpenoids, of which water-soluble labdane diterpenoid is andrographolide. Among the various diterpene lactones reported from most of the species of Andrographis, andrographolide is considered one of the major bioactive secondary metabolites. The genus Andrographis possesses diverse phytochemical constituents with significantly interesting biological potentials. Diterpenes, flavonoids, xanthoflavones, iridoids, and other groups of miscellaneous compounds have been characterized from the various species of Andrographis. Andrographolide has been isolated as a notable major phytochemical compound among the andrographolides, which is a common diterpene flavonoid with phytochemical constituents and therapeutic activities.

The genus Andrographis Wall. ex Nees is recognized for its potential medicinal properties, playing a vital role in traditional and indigenous medicinal systems, particularly in India. It is used for treating various common ailments such as cold, fever, diarrhea, jaundice, cancer, and tumor. In addition, Andrographis is valued as a health tonic for fever and cardiovascular health as an antioxidant. Its applications extend to improving sexual dysfunctions and acting as a contraceptive. The therapeutic properties of Andrographis are primarily attributed to the major phytochemical andrographolide, although the composition of phytoconstituents can vary significantly among different species. These phytochemical variations are significantly influenced by geographical location, soil types, seasonal changes, and the specific time of harvest. The diversity in chemical composition highlights the importance of understanding the specific context and conditions under which Andrographis species are grown and harvested to optimize their medicinal efficacy. This chapter deals with the botany of andrographolide-yielding Andrographis species and their taxonomy, identification key, citation, description, and distribution for their availability and conservation.

Various species of the Genus Andrographis are used in multiple tribal and community medicinal systems in India and adjoining countries for more than 20 different local ailments. A. paniculata is predominantly used for treating jaundice, liver diseases, fever, cardiovascular diseases, cancer, stomach problems, and common cold and as a blood purifier. This chapter gives an overview of the ethnobotanical uses of various species of Andrographis by several tribal communities and local inhabitants in almost all the states of India and other countries.

Andrographolide is a pharmacologically significant labdane diterpenoid primarily isolated from Andrographis paniculata, and later, from many of its allied species. A. paniculata is used in many Indian traditional and alternative medicinal systems for treating several human ailments. The phytochemical studies on species has yielded a number of diterpenoids and flavonoids, which have been screened for their pharmacological potential by various scientific groups. The results proved that andrographolides and their analogs have the potential to treat cancer and cardiovascular, hepatic, and various other diseases. In this chapter, the phytochemistry of Andrographis and the structure and properties of major andrographolides and their analogs have been reviewed.

Andrographis paniculata (Burm. f.) Nees is a well-known medicinal plant of the genus Andrographis belonging to the family Acanthaceae. This species is widely distributed throughout tropical and sub-tropical Southeast Asia, including India. This herb finds its place not only in the traditional systems of medicine but is also registered under Indian Pharmacopoeia. A. paniculata is bestowed with high therapeutic value and is used for the treatment of various ailments. This herb is adulterated with other species like Andrographis echioides and Swertia chirayita due to the lack of constant supply and less availability of A. paniculata. The herbaceous species possess apparent macroscopic similarities, and it is a tedious job to identify the actual raw drug. This chapter will provide in-depth knowledge of the pharmacognostical characterization of A. paniculata. Detailed macroscopic evaluation will help in the identification of the species in the field, and the comprehensive microscopic evaluation with the help of a transverse section will help delineate the species from its adulterant. The powder microscopic study will help in the identification of this medicinal plant, even in its powder form. The pharmacognostic standards put forward for the correct identification and authentication will prove to be a benchmark standard for this highly potent medicinal herb.  

Andrographis paniculata (AP) is a traditional herb known as “king of bitters” and belongs to Acanthaceae. This plant is used traditionally to treat fever, sore throat, snake bites, and upper respiratory tract infections. The pharmacological effects exhibited by AP are actually due to the presence of several classes of phytocompounds. Among the numerous bioactive compounds generated by Androgrpahis paniculata, Andrographolide (AG) is the primary active phytochemical. This compound shows various biological functions, such as anti-inflammatory, anticancer, antimicrobial, neuroprotective, cardioprotective, and organ- and bone-protective activities. On the other hand, AG's structural analogs also showed various potent biological effects against different kinds of dreadful diseases. Hence, it is noteworthy to summarize the various pharmacological effects of AG and its analogs to help the researchers focus on this area. Therefore, in this chapter, we elaborated on various biological functions of AG and its derivatives; this review would be a standalone reference for AG's bioactives and analogs.

Parkinson’s disease (PD), a leading movement disorder, is instigated due to the progressive apoptosis of dopaminergic neurons in the substantia nigra pars compacta and due to exhausted levels of dopamine in the striatum of the brain. Currently, all treatments available for PD are palliative rather than curative. Researchers are still investigating the complex interplay of genetic and environmental factors that contribute to the development of PD. Natural product's renaissance is due to their ability to target multiple molecular pathways involved in the disease, as well as due to fewer side effects. A diterpenoid lactone compound, andrographolide, is found in the plant Andrographis paniculata and is commonly used in traditional medicine to treat various ailments. It has been discovered to have numerous biological activities, including antioxidant, anti-inflammation, anticancer, and neuroprotective effects. In preclinical studies, andrographolide has been shown to have neuroprotective effects in animal models of PD due to its high antioxidant potential, which can help reduce the impact of inflammation in the brain, and its ability to promote the survival and growth of dopaminergic cells. Several structural analogs of andrographolide have been studied for neuroprotective effects, including 14-deoxy-11-oxoandrographolide, 14-deoxy-11, 12-didehydroandrographolide (DDA), and 14-deoxy andrographolide (DA). Both DDA and DA are analogs of andrographolide that have been shown to have neuroprotective effects in animal models of PD disease. DDA is more potent than andrographolide in terms of neuroprotection. The anti-inflammatory and antioxidant properties of 14- deoxy-11, 14-deoxy-11, 12-didehydroandrographolide-19-oic acid (DDAA), and 7-- -Methyl-andrographolide were found to be more potent than andrographolide. On the other hand, andrographolide derivatives, such as 14-deoxyandrographolide, andrographolide epoxide, and andrographolide sulfonates possess potent antiinflammatory and anticancer properties. Given that andrographolide and its structural analogs and derivatives have substantial therapeutic potential and have been proven to be neuroprotective, we intend to highlight this promising compound's role in PD disease.

Alzheimer's disease (AD) is a brain disorder that usually has a chronic or progressive nature and results in a reduction in cognitive function that is more than what would be expected from the typical effects of the biological aging process, which is a significant cause of dementia. Even though tau and amyloid-β (Aβ) have been identified as the main components in the formation of tangles and plaques, respectively, there is still little known about the causes of Alzheimer’s disease, and no effective treatments are available. It affects an estimated 40 million people worldwide, most of whom are over 60, and is expected to double every 20 years, at least until 2050. Most current efforts at therapeutic intervention are based on the hypothesized pathogenic mechanisms for AD. These include amyloids, inflammatory mediators, excitotoxicity, steroid hormone deficiencies, loss of cholinergic function, dietary factors, oxidative stress, band g-secretase effectors, etc. Still, these therapies were neither completely effective nor safe for prolonged usage to check this problem. Various natural products have been tested. One such natural product is andrographolide (AG), which has several potential therapeutic benefits, including anti-inflammatory, immunomodulatory, and antiangiogenic properties. It is traditionally used for the treatment of various ailments. AG and its derivatives were found to be effective in the reduction of synaptic proteins associated with Alzheimer's disease by overturning the microglia-mediated growth of pro-inflammatory cytokines, and the research has shown that these compounds decrease amyloid beta aggregation and suppress the neuroinflammatory response and synaptic dysfunction. In the current review, the therapeutic potential of andrographolide and its analogs is outlined, and its mechanism of action against this disease is examined to explore the possibility of AG for the prevention and treatment of AD.

One of the most common cancers in males is prostate cancer, which frequently appears later in life after 65 years. Prostate cancer is the second most frequent disease in men globally, according to the World Health Organization (WHO), with 1.3 million new cases identified in 2018. Although the composite molecular mechanisms that cause prostate cancer are still not fully understood, certain important factors have been identified. These include mutations in the androgen receptor gene and the tumor suppressor gene known as prostate cancer gene 1 (PCA1) or “BRCA1”, which are linked to prostate cancer. Furthermore, overproduction of prostate-specific antigen (PSA) and changes in the concentrations or functions of particular proteins, such as cyclin-dependent kinase 4 (CDK4), function as indicators of prostate cancer and aid in its progression. Age, family history, ethnicity, food, obesity, and exposure to specific chemicals and hormones are risk factors. Depending on the stage of the disease and the patient's general condition, the main treatment options for prostate cancer include surgery, radiation therapy, hormone therapy, chemotherapy, immunotherapy, and active surveillance. Examining several strategies, natural products—especially those derived from plants—have shown signs of having anti-cancer qualities and are being researched as possible treatments for prostate cancer. Among these, andrographolide—a diterpenoid lactone compound—has attracted attention. It is extracted from the leaves of the Andrographis paniculata plant, traditionally used in Chinese and Ayurvedic medicine. Andrographolide and its analogs are being studied for their potential to treat a variety of malignancies, including prostate cancer, due to their well-known pharmacological actions, which include anti-inflammatory, anticancer, antiviral, and antioxidant qualities. Studies show that they have antiproliferative, pro-apoptotic, and antimetastatic properties in animal models and prostate cancer cell lines, suggesting they may be a valuable treatment for prostate cancer.

Lung cancer refers to the changes in the lung tissue and cells that lead to cancer growth due to gene mutations and cellular changes that result in uncontrollable cell growth and division. However, the exact pathophysiology of lung cancer is not yet fully understood. It is a significant cause of mortality worldwide and can be divided into two main types: small-cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC). The specific subtypes of NSCLC are adenocarcinoma, large-cell carcinoma, and squamous cell carcinoma. Risk factors for lung cancer include exposure to radon, smoking, air pollution, and a family history of lung cancer. Symptoms may include shortness of breath, chest pain, coughing, and weight loss. Early detection and proper treatment, including chemotherapy, radiation therapy, surgery, and targeted therapy, can improve the prognosis and survival rates. However, the deaths and the cases of lung cancer are constantly rising. This increases the need for potential drug treatment for lung cancer. Among the various available sources for identifying novel therapies for multiple diseases, such as cancer, medicinal plants and plant-derived compounds play a significant role. In addition, several studies revealed that Andrographis paniculata and its derived compounds have shown various pharmacological effects, including anticancer effects. Recently, andrographolide and its structural analogs have also gained attention in lung cancer due to their unique potential. Studies have shown that andrographolide and its analogs can restrict the development of lung cancer cells via the induction of apoptosis, a programmed cell death. They have also been shown to target specific signaling pathways that play a role in the development and progression of lung cancer, including the NF-kB and MAPK pathways. Additionally, andrographolide and its analogs have been shown to exhibit low toxicity, making them attractive as potential therapeutic agents for the treatment of lung cancer. Additional investigations are required to thoroughly understand these compounds' mechanisms of action and potential clinical applications in lung cancer treatment. In summary, andrographolide and its structural analogs have shown promising results in both in vitro and in vivo studies as potential therapeutic agents for lung cancer treatment. Their anti-cancer properties, including inhibition of cancer cell growth and induction of apoptosis, make them of significant interest for further research.

Colorectal cancer (CRC) is a highly prevalent and leading cause of death globally. Though well-developed treatment strategies are available, colorectal cancer is still a challenging health problem in developed and developing countries. Despite advanced treatment methods, all may not exterminate the tumor since most cases of CRCs are diagnosed at the last stage, and treatment-associated drug toxicity and resistance are major concerns. Therefore, it is imperative to discover anticancer drugs with less toxicity and no drug resistance. During the process of new drug discovery, medicinal plants and their derivatives play a significant role. This chapter/review explores andrographolides and their derivatives as potential anticancer drug candidates to combat colorectal cancer. This chapter describes the molecular mechanisms of colorectal cancer, potential drug targets in cancer, the anticancer potential of andrographolide derivatives in various malignancies, and its specific function in preventing CRC. This review provides concise information and possible clues for researchers to develop andrographolides, their derivatives and anticancer drugs to treat colorectal cancer.

Myocardial infarction is a sudden and fatal disease that causes a significant number of deaths in the world. The current treatment strategy for MI is only for symptomatic relief and cannot cure or reverse the disease condition. Hence, there is a need to identify novel, definitive, and minimal toxic drugs to treat MI. Phytochemicals always draw attention as an alternative and upgraded choice to combat various ailments. Photochemical compounds are non-nutritive biologically active secondary metabolites abundantly found in plants. Andrographolide and its derivatives obtained from a medicinal herb, Andrographis paniculata, are broadly utilized in traditional medicinal systems to treat various diseases, including cardiovascular diseases. In the present chapter, we explore andrographolide and its derivatives for its cardioprotective potential both in vitro and in vivo. Andrographolides show their cardioprotective potential by demonstrating multiple mechanisms, including ERK1/2 inhibition associated with anti-platelet action, PI3K/Akt pathway-associated inflammation inhibition, and activation of Nrf-2/HO-1pathway-associated antioxidant mechanism. Cardioprotection of andrographolide and its derivatives are shown by various animal models' anti-arrhythmic, antihypertensive, anti-inflammatory, and antioxidant mechanisms. In this way, andrographolide and its derivatives can offer a better choice for developing a novel therapeutic molecule for myocardial infarction.

Andrographis (Acanthaceae) is a genus of 26 species native to India, mainly used for the treatment of snake bites, diabetes, fever, cholera, dysentery, gonorrhea, and malaria. Medicinal properties of Andrographis are attributed to the presence of phytochemicals such as andrographolide, neoandrographolide, 14-deoxy-11,- 2-didehydroandrographolide, 14-deoxy andrographolide, isoandrographolide, 14-deoxy andrographolide 19 β-Dglucoside, homoandrographolide, andrographan, andrographosterin, and stigmasterol. Nanotechnology is a technique capable of achieving a high degree of precision in functions. By creating eco-friendly materials that can be applied to nanomedicine, plants have mediated the synthesis and fabrication of materials in nanotechnology. Mostly, silver nanoparticles biosynthesized using Andrographis species showed significant pharmacological activities viz ., antimicrobial, antioxidant, anti-inflammatory, antidiabetic, mosquito larvicidal, hepatocurative, and anticancer activity. 

The present chapter provides different cultivation methods used to propagate Andrographis paniculata and other factors that regulate the growth and yield of the bioactive principles of andrographolides. The propagation of the Kalmegh is of two types: vegetative, utilizing stem cuttings, and sexual, through seeds. Much work has been done on the in vitro propagation of Kalmegh. The growth and quality of the plant are affected by the following factors: plant geometry, planting density and harvesting time, soil health, fertigation, shading level, endophytes, plant growth regulators, weeding control techniques, different accessions of seeds, plant density, co-cultivation, and aging. The available result revealed plots with 30 × 20 cm, cocopeat-RHA medium, and 50 ppm magnesium composition, and integrated use of chemical fertilizers, biofertilizers, and vermicompost treatments were optimum conditions for better yield. Among different seed cultivars, Pranchiburi cultivars showed a good percentage of germination and growth, and the highest andrographolide content was recorded at 135 DAP in the flowering stage. GA3 treatment, 25% shading level, and co-cultivation with Cajanus cajan exhibited better yield and quality of A. paniculata. In dry storage, 1 to 3 months and 25°C temperature were recommended. Further works in vegetative propagation may bring out alternative and rapid multiplication methods for large-scale propagation of A. paniculata. 

The Andrographis of the Acanthaceae family is one of the potential sources for many pharmacological drugs with a wide array of essential phytochemicals. The present review summarizes the micropropagation of several Andrographis species viz., A. affinis Nees, A. alata (Vahl) Nees, A. echioides (L.) Nees, A. lineata Nees, A. lobelioides Wight, A. macrobotrys Nees, A. neesiana Wight, A. paniculata (Burm. f.) Wall. ex Nees, and A. producta Gamble. Nodal and shoot tip explants were suitable for in vitro shoot regeneration, whereas, for callus induction and indirect regeneration studies, cotyledonary leaf and hypocotyl segments were better choices as explants. The major surface sterilants used were alcohol (70%) and mercuric chloride (0.1-0.2%). Murashige and Skoog (MS) medium was the prime choice for in vitro regeneration studies of Andrographis.

Andrographis L. (Acanthaceae) is a vital genus that produces the most potential secondary metabolites, such as labdane diterpenoids called andrographolides. Pharmaceutical requirements for andrographolides are sustained through habitat collection and limited cultivation of Andrographis paniculata. However, in India, the genus is represented by about 26 species distributed in the southern Peninsula, most of which are endemic to the region. Commercial exploitation for andrographolide extraction is met with A. paniculata alone. The low rate of seed production in this plant and enormous variation in andrographolide content were found in the natural population. Tissue culture techniques help us to produce commercially viable andrographolides on a large scale. The present review analyzes the alternative sources of andrographolides from diverse species of Andrographis. Also, the review describes in vitro culture of callus and suspension cultures, the development of adventitious and hairy root cultures, the addition of biotic and abiotic elicitors for enhancing andrographolide production, and also the production of valuable compounds by utilizing bioreactors, Agrobacterium-mediated transformation, and genetic engineering for increasing biosynthesis of andrographolides.