Natural products are significant sources of lead compounds and functional organic molecules used in pharmaceuticals. Screening pharmacological lead compounds from natural products has long been an efficient approach to creating novel medications [1]. According to statistics, from 1981 to 2010, 34 % of the drugs approved for marketing by the Food and Drug Administration (FDA) came from natural products or their derivatives [2]. The characteristics of natural products are the diversity of scaffolds and the complexity of structures. In comparison to the synthetic compound libraries, natural compounds usually have larger molecular weight, more sp3 carbon atoms and oxygen atoms, but fewer nitrogen and halogen atoms, more hydrogen bond receptors and donors, lower calculated octanol–water partition coefficients and greater molecular rigidity [1], [3], [4], [5].

According to a recent study [6], from 01/1981 to 09/2019, 33.6 % of all small-molecule drugs approved by the FDA were derived from natural products or their derivatives. Among the 48 new drugs approved for 2019, 7 were natural products (allopregnanolone or brexanolone, cefiderocol, fedratinib, fluorodopa, istradefylline, lefamulin, solriamfetol) [7]. The 53 approvals in 2020 were divided between 13 biologics and 40 new chemical entities, including nine natural-product-based small molecules (artesunate, cedazuridine, clascoterone, decitabine, fluoroestradiol F18, lurbinectedin, lactitol, remdesivir and triheptanoin) [8]. Among the 50 drugs approved in 2021, only five were natural-product-based small compounds (drospirenone and estetrol, samidorphan, maribavir, ibrexafungerp) [9]. In 2022, the US FDA approved a total of 37 new drugs, including 22 new molecular entities and 15 new biological products, including 7 drugs inspired by natural products [10].

Although many natural products exhibit a wide range of pharmacophores, drug discovery may be limited due to their separation, identification, dereplication, intellectual property, and other issues [3]. Terpenoids are widely distributed among the numerous naturally occurring active substances and are distinguished by their complicated structures, enormous diversities and wide range of biological activities [11], [12], [13], [14], serving as useful resources for finding natural medicines. Common clinical drugs such as artemisinin [15], paclitaxel [16] and oridonin [17] (Fig. 1) are terpenoids isolated from plants.

Diterpenoids are the most abundant natural product of terpenoids with diverse structures found in addition to sesquiterpenoids [18].

Steviol glycosides are naturally produced diterpenoids with a wide range of biological activities. Stevioside and its hydrolysates steviol and isosteviol are good starting points in the field of medicinal chemistry. They have a wide range of bioactivities, such as antibacterial, anti-tumor, and anti-hyperglycemia, and are the focus of pharmaceutical chemistry research [19], [20], [21].

Stevia rebaudiana Bertoni, also known as sweet herb, honey leaf, and sweet leaf, is a perennial herb of the genus Stevia of the family Compositae native to Argentina, Brazil and Paraguay. It was eaten by people more than 1000 years ago and attracted great attention because of its high sweetness with zero calories [22], [23], [24].

This sweetener is extracted from the leaves of stevia, and its main component is stevioside. This plant also contains dulcoside A, rebaudiosides A, B, C, D, E, and F (Fig. 2) in addition to stevioside. All rebaudiosides share the aglycone steviol, however, they differ from each other by the nature and number of sugar moieties [25], [26]. The percentages of steviosides in total dry weight of stevia leaves were as follows: stevioside 5–10 %, rebaudiosides A 2–5 % and rebaudiosides C 1 %, dulcoside A 0.5 %, rebaudiosides D, E and F 0.2 % [27], [28], [29].

According to the references, Cargill, Merisant and Blue California were the original companies to commercialize Stevia in the US market [21], [30]. To date, Ingredion Incorporated, Tate & Lyle PLC, Archer Daniels Midland Company, Cargill Incorporated, and Zhucheng Haotian Pharma Co. Ltd are the major leading companies operating in the stevia market [31]. The application of stevia as an ingredient in different food products and other fields was systematically summarized in those reviews [27], [32], [33], [34]. However, gradually reducing sugar content is a challenge that food manufacturers must face without affecting the quality of the final product and its different aspects of sensory perception [33]. Although steviol glycosides are considered safe, more research is needed to confirm their safety for long-term use [34].

There are three types of stevia sweeteners: the regular product, mainly containing stevioside; the Reva A product, mainly composed of rebaudiosides A, and the sugar metastasis product. In the regular product, the ratio of stevioside to rebaudiosides A is 7: 3 to 8: 2, while in the Reva A, the ratio is about 1: 3. Since the taste of rebaudiosides A is very sweet, the sweetness quality of Reva A is higher than that of the regular product [35], [36]. It has been reported that the sweetness (multiples) of these glycosides compared with sucrose was as follows: stevioside 300, rebaudiosides A 250–450, rebaudiosides B 300–350, rebaudiosides C 50–120, rebaudiosides D 250–450, rebaudiosides E 150–300, steviobioside 100–125, and dulcoside A 50–120 [37], [38].

Stevioside is a diterpene glycoside, which contains one aglycone (steviol) and three glucose molecules [38]. Due to their significant sweetness (250–300 times sweeter than sucrose), they are used in various foods and products, such as soft drinks, tea, coffee, ice cream, candies, bakeries, etc. [39], [40]. Further studies showed that in addition to sweetness, stevioside and its related compounds have different medicinal properties, such as anti-inflammatory [41], [42], [43], [44], anti-diabetic [45], [46], [47], [48], anti-tumor [49], [50], [51], [52], [53], [54], [55], [56], [57], [58], anti-oxidant [59], [60], [61], [62], [63], [64], effect on gut microbiota [65], [66], anti-virus [67], [68], [69] and immune regulation [41], [70], [71], [72] and so on.

Review articles on the biological activity of various isosteviol derivatives were published sometimes. Ullah et al. described a review of the potential pharmacological effects of derivatives of isosteviol [73]. Various biological activities and medicinal chemistry of isosteviol derivatives were summarized comprehensively [74]. Some applications of isosteviol in supramolecular chemistry and organocatalysis, and the chemical modification of this scaffold, as well as its biological activity, were surveyed [75]. Moons et al. classified and summarized the microbial transformations and structural modifications of isosteviol based on their reaction sites [76].