Ethnobotanical, Phytochemistry, and Pharmacological Activity of Onosma (Boraginaceae): An Updated Review

Abstract

The genus Onosma belongs to the Boraginaceae family and contains over 230 species. The present review sheds light on the ethnopharmacology, phytoconstituents, bioactivity, and toxicology of the Onosma species from previous investigations. Furthermore, the paper also highlights the unresolved issues for the future investigations. The review included previous studies of the genus Onosma available from Google Scholar and Baidu Scholar, Science Direct, SciFinder, Wiley Online Library, and Web of Science. Until now, more than 200 chemical compounds have been detected from the genus Onosma, including naphthoquinone (33), flavonoids (30), hydrocarbon (23), phenolic (22), ester (17), alkaloids (20), aromatics (12), carboxylic acid (11), fatty acids (9), terpenoids (10), while the most important ones are rosmarinic, ferulic, protocatechuic, chlorogenic, caffeic, p-coumaric acids, and apigenin. The Onosma species are reported as traditional medicine for wound healing, heart disease, and kidney disorders, while the pharmacological investigations revealed that the extracts and the phytochemicals of Onosma species have different therapeutic properties including antioxidant, enzyme inhibitory, antitumor, hepatoprotective, antiviral, anti-inflammatory, and antimicrobial actions. The summarized knowledge in this review provides valuable ideas for the current and future drug discovery and a motivation for further investigation on the genus Onosma.

1. Introduction

The genus Onosma comprises more than 230 species across the globe. The Asian continent has the highest share in terms of Onosma species existence [1], most of which are represented in Turkey by 88 species [2] followed by countries such as Iran and China by 58 [3] and 29 species [4], respectively. Iraqi Kurdistan represents 32 species of the genus Onosma based on the latest botanical studies [5]. However, recent investigations have revealed seven new species of Onosma in Asian countries, particularly Iran [6]. Continuous exploration on the ethnobotanical and plant taxonomy studies led to the discovery of several new Onosma species across our continent [7,8]. Some Onosma species have been well studied pharmacologically than others, and the most common ones are shown in Figure 1.

The ethnobotanical and in vitro studies have revealed that most of this Onosma species has many medicinal capabilities such as sedatives [9], antioxidant [10], anti-inflammatory [11], gastric disorders [11], antithrombotic [12], wound healing [13], Alzheimer [14], enzyme inhibitory [15], anti-tumor [16], anti-viral [17], antifungal [18], and COVID-19 curatives [19] (Figure 2).

The phytochemical studies on the genus Onosma have reported several chemical compounds as their main active ingredients, including naphthaquinones (5,8-dihydroxy-2-(4-methylpent-3-enyl) naphthalene-1,4-dione) [16], Phenolics (ferulic acid, vanillic acid), flavonoids (apigenin, luteolin) [10,20], alkannin, and shikonines (deoxyshikonin, isobutyrylshikonin, α-methylbutyrylshikonin, acetylshikonin) [21,22].

The past decades have showed numerous new records, phytochemical, and pharmacological studies of the new Onosma species, and the published two reviews were found lacking integrity as they contained incoherent data with skipping of some biological activities of the genus Onosma [23,24]. Therefore, in order to provide theoretical reference for further research and to comprehensively understand the medicinal applications of this genus, this article systematically reviewed traditional uses, chemical constituents, pharmacological activities, and clinical applications of the Onosma species based on the published literature.

2. Methodology

The authors independently extracted systematic literature data search from seven electronic databases: Google Scholar, PubMed, Science Direct, Sci-Finder, Wiley Online Library, Web of Science, and Baidu Scholar. The scientific name “Onosma” was searched to cover all relevant information from April 1800–2022, including folkloric uses, phytochemical contents, and pharmacological potentials (antimicrobial, anti-inflammatory, anticancer, antioxidant, enzyme inhibitory, and antidiabetic) of the Onosma species are presented in this review. More than 1000 articles were detected with keyword Onosma, about 132 articles were found with keyword Onosma phytochemical, 187 articles were found with keyword Onosma pharmacology, biological activity, medicinal uses, pharmacology, and toxicology. Out of these, 125 articles were published detailing the isolation and properties of different phytochemical contents of the Onosma genus, and a total of 95 papers were selected based on the quality, specificity, and the procedure of the investigation of Onosma extracts and its isolated compounds.

3. Regional (Folkloric) Name

The folkloric names of most Onosma species in most Middle east countries is Gaozaban, an Urdu word. It was first referred to O. bracteatum Wall, and among Arabic populations it is known as “Lisan-al-Thawr” or “Saqil ul-Hammam”. Furthermore, its English popular name is “Vipers Bugloss”, while, in Hindi language, the Onosma species known as “Ratanjot” as first referred to O. echioides L. [25,26].

4. Regional Distribution

Distribution map of some Onosma species collected from different regions of Iran, Iraq, and Turkey is shown in Figure 3. The point inputs to the models developed in this study were collected from their habitats of Iran such as Fars, Lorestan, Khuzestan, Kermanshah, Hamedan, Markazi, Ilam, Kohgiluyeh, Kerman, and Boyer-Ahmad provinces, and their habitats of Iraq include mainly some areas of Kurdistan, Sulaimani, Hawraman, Rwanduz, and Amedia districts. Meanwhile, their habitats of Turkey includes Sirt, Hakary, Anatolia, and Van [27,28,29].

5. Onosma Taxonomy

Onosma species belongs to the Boraginaceae family. The Boraginaceae family contains more than 100 genera and over 200 species, which are classified into five subfamilies: Boraginoideae, Cordioideae, Ehretioideae, Hydrophylloideae, and Lennooideae [30,31] (

Table 1. Onosma taxonomy according to Global Biodiversity Information Facility [1].

Kingdom	Plantea
Phylum	Tracheophyta
Class	Angiosperms
Order	Boraginales
Family	Boraginaceae
Subfamily	Boraginoideae
Genus	Onosma L.

).

6. Traditional Use

The folkloric use of many Onosma species as medicinal plants for different health problems by local ethnic groups in several countries such as Iraq, Turkey, Iran, China, and India roots back to hundreds of years ago. Almost all plant parts, such as leaves, roots, underground parts, flowers, and the whole plant of this genus species are reported to have a broad range of therapeutic potentials (Table 2) [32,33]. Species such as Onosma alborosea have traditionally been utilized by Iraqi Kurdistan populations as a remedy for sedative, heart diseases, and kidney disorders through ingesting its aerial part extracts prepared by aqueous extraction methods [33]. The aerial parts of Onosma orientalis has been macerated with hot water for treating sedatives by Kurdish nations living in Iraqi Kurdistan [33]. Furthermore, the O. armeniacum K. has been used as Turkish folkloric medicine for healing wounds, peptic ulcers, burns, dyspnea, hoarseness, hemorrhoids, and abdominal pains through methods of cooking and filtration of its roots with butter [34]. The extracts (oil and aqueous extracts) of O. argentatum and O. chlorotricum has been traditionally utilized in Turkey and Iran (Lorestan province) for the treatment of wounds and cutaneous injures [35,36]. Furthermore, the root extracts of O. hispidum Wall. have been used traditionally by the Iranian nation as curatives for headache, wounds, insect stings, bits, and inflammatory diseases, while its flowers have been ingested for cardiovascular problems [37]. Moreover, same species has been used as a dye and as a substitute for alkanet [38]. The O. bracteatum Wall. extracts have been reported as traditional herbal medicine as a tonic agent for improving the body’s immune system with enhancing regulation of urine output [39]. The O. bracteatum Wall. also has been used as remedy for asthma, respiratory problems, tonic, alterative, demulcent, diuretic, spasmolytic, rheumatoid arthritis, diuretic, and antileprotic in India, Nepal, Kashmir, and northwestern Himalayas countries [40,41]. The root extracts of O. sericeum have been traditionally used in cream preparations for skin injuries and burn scar treatments in Adıyaman, Turkey [13].

The O. microcarpum has traditional medicine record for the healing of wounds and burn scars by rural residents of Il’yca district, Erzurum, Turkey [36,42]. The leaf aqueous extracts of O. echioides DC. are prepared for children suffering from constipation and metabolic disorders. Meanwhile, its flowers are reported as a cordial and as a stimulant for orthopedic and cardiac problems [43]. The dried roots of O. paniculata have a traditional medicinal record in Chinese herbal medicine for curing several human diseases including tumors [44]. The O. aucheriana is another species with traditional medicinal usage for itchiness, leucoderma, bronchitis, abdominal pain, strangury, fever, wounds, burns, and urinary calculi. Meanwhile, its flowers have been highlighted as stimulants and cardio-tonics, and its leaf extracts have been ingested as laxatives, purgatives, and as wound curatives [45]. Out of more than 230 species of Onosma, only 12 species were reported in traditional medicines as herbal medicine until now. This could be due to the large geographical distribution of the Onosma species and lack of scientific interest in the past, but this number is expected to increase in upcoming years as the researchers extensively search and investigate for other Onosma species after discovering some interesting phytochemical and pharmacological potentials of this genus in recent years.

Table 2. The traditional use of Onosma medicinal plants.

Species	Traditional Name	Country of Habitat	Medicinal Parts	Medicinal Use
O. alborosea		Safeen mountain, Shaqlawa district, Iraqi Kurdistan	Aerial parts	Sedative, heart diseases, kidney disorders [33]
O. orientalis		Safeen mountain, Shaqlawa district, Iraqi Kurdistan	Aerial parts	Sedative [33]
O. armeniacum		Turkey, Anatolia	Leaves	healing wound, peptic ulcers, burns, dyspnea, hoarseness, hemorrhoids, and abdominal pains [34]
O. argentatum,		Turkey	roots	Wound healing [35]
O. chlorotricum		Iran, Lorestan	roots	Wound healing [36]
O. hispidum		Iran (Korrassan)	roots	headache, wounds, insect stings and bits, inflammatory diseases, while its flowers are used for cardiovascular problems [37] and as a dye and a substitute for alkanet [38]
O. bracteatum Wall	Gaozaban, Sedge	India, Nepal, Kashmir, and in the northwestern Himalayas	Roots, flowers	asthma, respiratory problems, tonic, alterative, demulcent, diuretic, spasmolytic, rheumatoid arthritis, diuretic, and antileprotic [40,41].
O. sericeum		Turkey, Adıyaman	roots	As curatives for cutaneous wounds and burns [13]
O. microcarpum		Turkey, Il’yca district, Erzurum province	Roots and leaves	Wound healing [36]
O. echioides		Turkey	Leaves and flowers	Laxatives for children and as a cordial, stimulant for orthopedic and cardiac problems [46]
O. paniculata		China	roots	Anticancer [44]
O. aucheriana		Turkey	Roots, leaves, flowers	itchiness, leucoderma, bronchitis, abdominal pain, strangury, fever, wounds, burns, and urinary calculi. Stimulants and cardio-tonics. Laxative, purgative, and as wound remedy [45]

Table 2. The traditional use of Onosma medicinal plants.

Species	Traditional Name	Country of Habitat	Medicinal Parts	Medicinal Use
O. alborosea		Safeen mountain, Shaqlawa district, Iraqi Kurdistan	Aerial parts	Sedative, heart diseases, kidney disorders [33]
O. orientalis		Safeen mountain, Shaqlawa district, Iraqi Kurdistan	Aerial parts	Sedative [33]
O. armeniacum		Turkey, Anatolia	Leaves	healing wound, peptic ulcers, burns, dyspnea, hoarseness, hemorrhoids, and abdominal pains [34]
O. argentatum,		Turkey	roots	Wound healing [35]
O. chlorotricum		Iran, Lorestan	roots	Wound healing [36]
O. hispidum		Iran (Korrassan)	roots	headache, wounds, insect stings and bits, inflammatory diseases, while its flowers are used for cardiovascular problems [37] and as a dye and a substitute for alkanet [38]
O. bracteatum Wall	Gaozaban, Sedge	India, Nepal, Kashmir, and in the northwestern Himalayas	Roots, flowers	asthma, respiratory problems, tonic, alterative, demulcent, diuretic, spasmolytic, rheumatoid arthritis, diuretic, and antileprotic [40,41].
O. sericeum		Turkey, Adıyaman	roots	As curatives for cutaneous wounds and burns [13]
O. microcarpum		Turkey, Il’yca district, Erzurum province	Roots and leaves	Wound healing [36]
O. echioides		Turkey	Leaves and flowers	Laxatives for children and as a cordial, stimulant for orthopedic and cardiac problems [46]
O. paniculata		China	roots	Anticancer [44]
O. aucheriana		Turkey	Roots, leaves, flowers	itchiness, leucoderma, bronchitis, abdominal pain, strangury, fever, wounds, burns, and urinary calculi. Stimulants and cardio-tonics. Laxative, purgative, and as wound remedy [45]

The traditional names, country, ingested parts, and medicinal purposes of the genus Onosma are listed in Table 2.

7. Chemical Profile of Onosma Species

The current systematic review of the phytochemical contents of Onosma species presents major identified organic classes such as naphthoquinone (33), flavonoids (30), hydrocarbon (23), phenolic (22), ester (17), alkaloids (20), terpenoids (10), carboxylic acid (11), fatty acids (9), aromatics (12), and liganin (5) compounds as shown in Figure 4. In addition, miscellaneous chemicals such as 24,25-Dihydroxycholecalciferol, 5-hydroxymethyl-furoic acid, and uplandicine also enrich the diversity of the phytochemistry in Onosma plants. Segregation of phytochemical contents in different classes is challenging and not always a clear and easy task. According to the current search, a total of 198 compounds are detected in the Onosma species as detailed in this review (

Table 3. Names and sources of compounds isolated from genus Onosma.

No.	Chemical Names	Organic Class	Plant Species	Distribution in Plant	Reference
1	Hyperoside	Flavonoid	O. isaurica, O. bracteosa, O. lycaonica, O. papillosa, O. pulchra, O. frutescens, O. aucheriana, O. sericea, O. trapezuntea, O. rigidum, O. mollis, O. inexspectata, O. armenum	Aerial parts	[10,14,47,48,49,50,51]
2	Hesperidin	Flavonoid	O. isaurica, O. bracteosa, O. lycaonica, O. papillosa, O. ambigens, O. pulchra, O. frutescens, O. aucheriana, O. sericea, O. mollis, O. inexspectata, O. armenum	Aerial parts	[10,14,30,47,48,49,51]
3	Vanillic acid	Aromatics	O. isaurica, O. bracteosa, O. ambigens, O. pulchra, O. frutescens, O. aucheriana, O. sericea, O. bracteatum, O. inexspectata, O. armenum, O. hispidum, O. mollis	Aerial parts	[10,14,30,39,47,49,51,52]
4	Pinoresinol	Phenolics	O. isaurica, O. bracteosa, O. ambigens, O. pulchra, O. frutescens, O. aucheriana, O. sericea, O. mollis, O. sericea, O. inexspectata, O. armenum	Aerial parts	[10,14,30,47,49,51]
5	Apigenin-7-glucoside	Flaconoid	O. isaurica, O. bracteosa, O. lycaonica, O. papillosa, O. ambigens, O. pulchra, O. frutescens, O. aucheriana, O. sericea, O. mollis, O. inexspectata, O. armenum	Aerial parts	[10,14,30,47,48,49,51]
6	Apigenin	Flavonoid	O. isaurica, O. bracteosa, O. lycaonica, O. papillosa, O. ambigens, O. gigantea, O. pulchra, O. frutescens, O. aucheriana, O. sericea, O. hispida, O. mollis, O. inexspectata, O. armenum	Aerial parts	[10,14,30,47,48,49,51,53,54]
7	Ferulic acid	Phenolics	O. isaurica, O. bracteosa, O. sericea, O. lycaonica, O. papillosa. O. aucheriana, O. gigantea, O. pulchra O. frutescens, O. inexspectata, O. armenum, O. hispidum, O. mollis	Aerial parts	[10,14,15,47,48,49,51,52,53,55]
8	Luteolin-7-glucoside	Flavonoid	O. isaurica, O. bracteosa, O. lycaonica, O. papillosa, O. ambigens, O. pulchra, O. frutescens, O. aucheriana, O. sericea, O. mollis, O. inexspectata, O. armenum	Aerial parts	[10,14,30,47,48,49,51]
9	Luteolin	Flavonoid	O. isaurica, O. bracteosa, O. stenoloba, O. lycaonica, O. papillosa. O. gigantea, O. pulchra, O. frutescens, O. aucheriana, O. inexspectata, O. armenum, O. sericea, O. mollis	Aerial parts	[10,14,15,47,48,49,51,53]
10	Rosmarinic acid	Aromatic	O. isaurica, O. inexspectata, O. armenum, O. bracteosa, O. lycaonica, O. papillosa, O. ambigens, O. aucheriana, O. gigantea, O. pulchra, O. frutescens, O. sericea, O. bracteatum, O. trapezuntea, O. rigidum, O. inexspectata, O. armenum, O. mutabilis, O. mollis	Aerial parts	[10,14,16,30,39,45,47,48,50,51,53]
11	3-Hydroxybenzoic acid	Carboxylic acid	O. isaurica, O. bracteosa, O. pulchra, O. aucheriana, O. sericea, O. inexspectata, O. armenum	Aerial parts	[10,14,47,49,51]
12	Protocatechuic acid	Carboxylic acid	O. isaurica, O. bracteosa, O. gigantea, O. pulchra, O. frutescens, O. aucheriana, O. sericea, O. ambigens, O. bracteatum, O. mollis, O. inexspectata, O. armenum	Aerial parts	[14,30,39,45,47,49,51,53]
13	Chlorogenic acid	Quinic acids	O. isaurica, O. bracteosa, O. ambigens, O. aucheriana, O. gigantea, O. pulchra, O. frutescens, O. sericea, O. trapezuntea, O. rigidum, O. mollis, O. inexspectata, O. armenum	Aerial parts	[14,30,45,47,49,50,51,53]
14	Gentisic acid	Carboxylic acid	O. isaurica, O. bracteosa, O. pulchra, O. frutescens, O. aucheriana, O. sericea, O. lycaonica, O. papillosa, O. mollis	Aerial parts	[14,47,48,49]
15	Caffeic acid	Carboxylic acid	O. isaurica, O. bracteosa, O. lycaonica, O. papillosa. O. aucheriana, O. gigantea, O. pulchra, O. bracteatum, O. inexspectata, O. armenum	Aerial parts	[10,14,39,45,47,48,51,53]
16	p-Coumaric acid	Aromatics	O. isaurica, O. bracteosa, O. aucheriana, O. gigantea, O. pulchra, O. frutescens, O. sericea, O. lycaonica, O. papillosa, O. ambigens, O. inexspectata, O. armenum	Aerial parts	[10,14,30,45,46,47,48,49,51,53]
17	Salvianic acid A	Phenolics	O. stenoloba, O. sericea	Aerial parts	[15]
18	Verbascoside	Phenolics	O. sericea, O. aucheriana,	Aerial parts	[15,49]
19	Rosmarinic acid-O-hexoside	Aromatics	O. sericea, O. stenoloba	Aerial parts	[15]
20	Apigenin-O-hexoside	Flavonoid	O. sericea, O. stenoloba	Aerial parts	[15]
21	Methyl caffeate	Phenolics	O. sericea, O. stenoloba	Aerial parts	[15]
22	Apigenin-O-rhamnosylhexoside	Phenolics	O. sericea, O. stenoloba	Aerial parts	[15]
23	Diosmin	Flavonoid	O. sericea	Aerial parts	[15]
24	O-Methylrosmarinic acid isomer	Phenolics	O. sericea	Aerial parts	[15]
25	Tricin	Flavonoid	O. sericea	Aerial parts	[15]
26	Cirsiliol	Flavonoid	O. sericea	Aerial parts	[15]
27	Diosmetin	Flavonoid	O. sericea	Aerial parts	[15,55]
28	Stearic acid	Fatty acid	O. sericea	Aerial parts	[15]
29	Intermedine	Ester	O. stenoloba, O. alborosea, O. arenaria	Aerial parts, roots	[15,56]
30	Lycopsamine	Alkaloid	O. stenoloba	Aerial parts	[15]
31	Caffeoylshikimic acid isomer	Phenolics	O. stenoloba	Aerial parts	[15]
32	Heliosupine	Pyrrolizidine Alkaloids	O. stenoloba	Aerial parts	[15]
33	Vicenin-2	Flavonoid	O. stenoloba	Aerial parts	[15]
34	Echimidine	Pyrrolizidine Alkaloids	O. stenoloba	Aerial parts	[15]
35	Isoferulic acid	Aromatics	O. stenoloba	Aerial parts	[15]
36	Rosmarinic acid-di-Ohexoside	Aromatics	O. stenoloba	Aerial parts	[15]
37	Quercetin-O-hexoside	Flavonoid	O. stenoloba, O. sericea	Aerial parts	[15]
38	Kaempferol-O-hexoside	Ester	O. stenoloba, O. sericea	Aerial parts	[15]
39	Isorhamnetin-O-rhamnosylhexoside	Flavonoid	O. stenoloba	Aerial parts	[15]
40	Trihydroxyisoflavone	Flavonoid	O. stenoloba	Aerial parts	[15]
41	Ursolic acid		O. stenoloba	Aerial parts	[15]
42	4-Hydroxybenzoic acid	Triterpenoids	O. lycaonica, O. papillosa, O. ambigens, O. pulchra, O. frutescens, O. aucheriana, O. sericea, O. gigantea, O. aucheriana, O. bracteatum	Aerial parts	[14,30,39,48,49]
43	Eriodictyol	Carboxylic acid	O. lycaonica, O. papillosa.	Aerial parts	[48]
44	Vanillin	Phenolics	O. lycaonica, O. papillosa. O. pulchra, O. frutescens, O.aucherian, O. sericea	Aerial parts	[14,48,49,57]
45	(+)-Catechin	Flavonoid	O. lycaonica, O. papillosa O. frutescens	Aerial parts	[48,49,57]
46	Homoprotocatechuic acid	Phenolics	O. lycaonica, O. papillosa	Aerial parts	[48,57]
47	Acetylshikonin	Naphthoquinones	O. heterophylla	Roots	[58]
48	Shikonin derivatives	Naphthoquinones	O. heterophylla	Roots	[58]
49	Acetyl shikonin	Naphthoquinones	O. heterophylla	Roots	[58]
50	Shikonin derivatives	Naphthoquinones	O. visianii	Roots	[59]
51	Shikonin derivatives	Naphthoquinones	O. visianii	Roots	[59]
52	Isobutyrylshikonin	Naphthoquinones	O. visianii	Roots	[21,59]
53	Isovalerylshikonin	Naphthoquinones	O. visianii, O. paniculata, O. exsertum, O. waltonii, O. paniculatum, O. hookeri, O. confertum, O. echioides, O. heterophylla	Roots	[21,22,59,60,61,62]
54	α-methylbutyrylshikonin	Naphthoquinones	O. visianii	Roots	[21,59]
55	5,8-O-dimethyl deoxyshikonin	Naphthoquinones	O. visianii	Roots	[59,63]
56	5,8-O-dimethyl isobutyrylshikonin	Naphthoquinones	O. visianii	Roots	[21,59,61]
57	deoxyshikonin	Naphthoquinones	O. visianii, O. paniculata, paniculatum	Roots	[21,59,60,62,63]
58	Acetylshikonin	Naphthoquinones	O. visianii, O. confertum, O. echioides, O. setosum, O. paniculata, paniculatum	Roots	[21,59,60,61,64]
59	β-Hydroxyisovalerylshikonin	Naphthoquinones	O. paniculata, O. heterophylla	Roots	[63,65]
60	β,β-dimethylacrylshikonin	Naphthoquinones	O. paniculata, O. confertum, O. exsertum, O. waltonii, O. paniculatum, hookeri, Onosma hookeri, Onosma zerizaminum	Roots	[62,63,64,65]
61	Methylbutyrylshikonin	Naphthoquinones	O. paniculata	Roots	[63]
62	Isovalerylshikonin	Naphthoquinones	O. paniculata	Roots	[63]
63	Gallic acid	Fatty acid	O. aucheriana, O. pulchra, O. frutescens, O. sericea	Aerial parts	[14,45,49]
64	Quercetin	Flavonoid	O. aucheriana, O. pulchra, O. frutescens, O. sericea	Aerial parts	[14,45,49]
65	Syringic acid	Fatty acid	O. aucheriana, O. pulchra, O. frutescens, O. sericea	Aerial parts	[14,49]
66	Shikonin derivatives	Hydrocarbon	O. mutabilis	Aerial parts	[16]
67	Shikonin derivatives	naphthoquinones	O. mutabilis	Aerial parts	[16]
68	3-O-Methyl-d-glucose	Hydrocarbon	O. mutabilis	Aerial parts	[16]
69	24,25-Dihydroxycholecalciferol	Vitamin D	O. mutabilis	Aerial parts	[16]
70	β-Sitosterol	Phytosterol	O. mutabilis, O. heterophylla	Aerial parts, roots	[16,65]
71	Phenol, 2,4-bis(1,1-dimethylethyl)-, phosphite	Phenolics	O. mutabilis	Aerial parts	[16]
72	p-Hydroxybenzoic acid	Carboxylic acid	O. gigantea, O. aucheriana, O. bracteatum	Aerial parts	[39,45,53]
73	trans-Cinnamic acid	Cinnamic acid	O. gigantea	Aerial parts	[53]
74	Kaempferol	Flavonoid	O. gigantea, O. pulchra, O. frutescens, O. aucheriana, O. sericea	Aerial parts	[14,49,53]
75	3,4-Dihydroxyphenylacetic acid	Catechol	O. pulchra	Aerial parts	[14]
76	Taxifolin	Flavonoid	O. pulchra, O. frutescens, O. aucheriana, O. sericea	Aerial parts	[14,49]
77	Sinapic acid	Aromatics	O. pulchra, O. frutescens, O. aucheriana, O. sericea	Aerial parts	[14,49]
78	Eriodictyol	Flavonoid	O. pulchra, O. frutescens, O. aucheriana, O. sericea	Aerial parts	[14,49]
79	Shikonin derivatives	Naphthoquinones	O. echioides	Aerial parts	[64]
80	Pulmonarioside C	Phenolics	O. bracteatum	Aerial parts	[39]
81	9′-Methoxyl salvianolic acid	Flavonoid	O. bracteatum	Aerial parts	[39]
82	4-O-(E)-p-coumaroyl-l-threonic acid	Phenolics	O. bracteatum	Aerial parts	[39]
83	Coumarin	Aromatics	O. bracteatum	Aerial parts	[39]
84	Umbelliferone	Aromatics	O. bracteatum	Aerial parts	[39]
85	Scopoletin	Aromatics	F	Aerial parts	[39]
86	6,7-Dimethoxycoumarin	Aromatics	O. bracteatum	Aerial parts	[39]
87	Esculetin	Aromatics	O. bracteatum	Aerial parts	[39]
88	Caffeic acid methyl ester	Ester	O. bracteatum	Aerial parts	[39]
89	1-O-Caffeoyl glycerol	Phenolics	O. bracteatum	Aerial parts	[39]
90	Latifolicinin C	Phenolics	O. bracteatum	Aerial parts	[39]
91	Oresbiusin A	Phenolics	O. bracteatum	Aerial parts	[39]
92	Ethyl 3-(3, 4-dihydroxyphenyl)lactate	Phenolics	O. bracteatum	Aerial parts	[39]
93	4, 5-Dihydroxy-3-methoxybenzoic acid	Carboxylic acid	O. bracteatum	Aerial parts	[39]
94	5-Hydroxymethyl-furoic acid	Furoic acid	O. bracteatum	Aerial parts	[39]
95	3,4-Dihydroxybenzyl alcohol	Alcohol	O. bracteatum	Aerial parts	[39]
96	Rosmarinic acid methyl ester	Ester	O. bracteatum	Aerial parts	[39]
97	Salviaflaside methyl ester	Ester	O. bracteatum	Aerial parts	[39]
98	9′-(2,3-Dihydroxypropyl)-rosmarinic acid	Phenolics	O. bracteatum	Aerial parts	[39]
99	p-Coumarinic acid ester of trigonotin	Ester	O. bracteatum	Aerial parts	[39]
100	Echiumin A	Liganin	O. bracteatum	Aerial parts	[39]
101	Ternifoliuslignan A	Liganin	O. bracteatum	Aerial parts	[39]
102	Ternifoliuslignan D	Liganin	O. bracteatum	Aerial parts	[39]
103	Eritrichin	Liganin	O. bracteatum	Aerial parts	[39]
104	Shikonin derivatives	Naphthoquinon	O. bracteatum	Aerial parts	[39]
105	Kaempferol 3-O-[α-l-rhamnopyranosyl-(1→2)-β-d-glucopyranoside]	Flavonoid	O. bracteatum	Aerial parts	[39]
106	Kaempferol 3-O-[α-l-rhamno pyranosyl-(1→6)-β-d-glucopyranoside]	Flavonoid	O. bracteatum	Aerial parts	[39]
107	Impecylone A	Flavonoid	O. bracteatum	Aerial parts	[39]
108	Tigloylshikonin	Naphthoquinon	O. hookeri	Roots	[66]
109	Acetyl shikonin	Naphthoquinon	O. hispidum	Roots	[67]
110	Alkannan	Naphthoquinon	O. hispidum, O. echioides	Roots	[67]
111	Deoxyshikonin	Naphthoquinon	O. hispidum, O. echioides, O. confertum	Roots	[62,67]
112	7-O-acetylechinatine N-oxide	Alkaloid	O. erects	Roots	[68]
113	Viridinatine N-oxide stereoisomer	Alkaloid	O. erects	Roots	[68]
114	7-Epi-echimiplatine Noxide	Alkaloid	O. erects	Roots	[68]
115	Onosmerectine N-oxide	Alkaloid	O. erects	Roots	[68]
116	Acid 2,3-dimethyl-2,3,4-trihydroxypentanoic acid	Alkaloid	O. erects	Roots	[68]
117	Acyloin 4-methyl-2-hydroxypentanon	Alkaloid	O. erects	Roots	[68]
118	2-Methyl-n-butyrylshikonin	Naphthoquinon	O. exsertum, O. waltonii, O. paniculatum, hookeri, O. confertum	Roots	[62]
119	β-Acetoxyisovalerylshikonin	Naphthoquinon	O. exsertum, O. waltonii, O. paniculatum, O. hookeri, O. confertum	Roots	[62]
120	Isobutylshikonin	Naphthoquinon	O. exsertum, O. waltonii, O. paniculatum, O. hookeri, O. confertum	Roots	[62]
121	Alkannin	Naphthoquinon	O. echioides, O. paniculata	Roots	[65]
122	Shikonin	Naphthoquinon	O. caucasicum, O. conferitum, O. hookeri, O. livanovii, O. polyphyllum, O. tauricum, O. sericium, O. setosum, O. visianii, O. zerizaminium	Roots	[65]
123	β,β-dimethylacrylalkannin	Naphthoquinon	O. heterophylla, O. hookeri, O. paniculata	Roots	[65]
124	Heliotridine	Alkaloid	O. heterophyllum	Roots	[58]
125	Necine derivative (1-methyl-8(-pyrrolizine)	Alkaloid	O. heterophyllum	Roots	[58]
126	Acetylintermedine	Alkaloid	O. alborosea, O. arenaria	Roots	[56,57]
127	O7-Acetyllycopsamine	Alkaloid	O. alborosea, O. arenaria	Roots	[56,57]
128	5,6-Dihydro-7,9-dimethoxy 7H- pyrrolizine	Alkaloid	O. arenaria	Roots	[56]
129	7-Acetylretronecine	Alkaloid	O. arenaria	Roots	[56]
130	9-(Butyryl-2-ene) supinidine		O. arenaria	Roots	[56]
131	7-Acetyl-9-(2-methylbutyryl) retronecine	Alkaloid	O. arenaria	Roots	[56]
132	7-Acetyl-9-(2,3-dimethylbutyryl) retronecine	Alkaloid	O. arenaria	Roots	[56]
133	7-Acetyl-9-(2-hydroxy-3-methylbutyryl) retronecine	Alkaloid	O. arenaria	Roots	[56]
134	3′-Acetylsupinine	Alkaloid	O. arenaria	Roots	[56]
135	7-Acetyl-9-(2,3-dihydroxybutyryl) retronecine	Alkaloid	O. arenaria	Roots	[56]
136	Uplandicine	Pyrrolizines	O. arenaria	Roots	[56]
137	Palmitic acid	Fatty acid	O. irrigans	Fruits	[69]
138	Oleic acid	Fatty acid	O. irrigans	Fruits	[69]
139	Linolenic acid	Fatty acid	O. irrigans	Fruits	[69]
140	γ-Linolenic acid	Fatty acid	O. irrigans	Fruits	[69]
141	Stearidonic acid	Fatty acid	O. irrigans	Fruits	[69]
142	monoenoic acids 20:1, 22:1, and 24:1	Fatty acid	O. irrigans	Fruits	[69]
143	Hexahydrofarnesyl acetone	Fatty acid	O. bulbotrichum, O. isaurica	Aerial parts	[70]
144	Phytol	Diterpenoid	O. bulbotrichum, O. isaurica	Aerial parts	[70]
145	Farnesyl acetone	Diterpenoid	O. bulbotrichum, O. isaurica	Aerial parts	[70]
146	Hexadecanal	Hydrocarbon	O. bulbotrichum, O. isaurica	Aerial parts	[70]
147	Hexyl hexanoate	Ester	O. isaurica	Aerial parts	[70]
148	(E)-2-Decenal	Medium-chain aldehyde Hydrocarbon	O. bulbotrichum	Aerial parts	[70]
149	1-Hexadecene	Unsaturated aliphatic Hydrocarbon	O. isaurica	Aerial parts	[70]
150	Safranal	Hydrocarbon	O. isaurica	Aerial parts	[70]
151	Heptadecane	Hydrocarbon	O. bulbotrichum	Aerial parts	[70]
152	Dodecanal	Hydrocarbon	O. bulbotrichum, O. isaurica	Aerial parts	[70]
153	E)-2-Undecenal	Hydrocarbon	O. bulbotrichum	Aerial parts	[70]
154	Tridecanal	Hydrocarbon	O. bulbotrichum	Aerial parts	[70]
155	(E)-Geranyl acetone	Diterpenoid	O. bulbotrichum, O. isaurica	Aerial parts	[70]
156	1-Isobutyl-4-isopropyl-2,2-dimethyl succinate	Dicarboxylic acid	O. bulbotrichum	Aerial parts	[70]
157	Neophytadiene isomer I	Terpenoid	O. isaurica	Aerial parts	[70]
158	Tetradecanal	Hydrocarbon	O. bulbotrichum	Aerial parts	[70]
159	(E)-β-Ionone	Sesquiterpenoid	O. bulbotrichum	Aerial parts	[70]
160	Neophytadiene	Sesquiterpenoid	O. isaurica	Aerial parts	[70]
161	Pentadecanal	Sydrocarbon	O. bulbotrichum	Aerial parts	[70]
162	(E)-Nerolidol	Sesquiterpenoid	O. bulbotrichum	Aerial parts	[70]
163	Hexadecanal	Hydrocarbon	O. bulbotrichum, O. isaurica	Aerial parts	[70]
164	3,4-Dimethyl-5-pentylidene-2(5H)-furanone	Phenolics	O. bulbotrichum, O. isaurica	Aerial parts	[70]
165	3,4-Dimethyl-5-pentyl-5H-furan-2-one	Phenolics	O. bulbotrichum, O. isaurica	Aerial parts	[70]
166	Carvacrol	Monoterpenoid	O. bulbotrichum	Aerial parts	[70]
167	Tricosane	Hydrocarbon	O. bulbotrichum, O. isaurica	Aerial parts	[70]
168	(2E, 6E)-Farnesol	Sesquiterpenoid	O. bulbotrichum	Aerial parts	[70]
169	Tetracosane	Hydrocarbon	O. isaurica	Aerial parts	[70]
170	Pentacosane	Hydrocarbon	O. bulbotrichum, O. isaurica	Aerial parts	[70]
171	Geranyl linalool	Hydrocarbon	O. isaurica	Aerial parts	[70]
172	Heptacosane	Hydrocarbon	O. bulbotrichum, O. isaurica	Aerial parts	[70]
173	Nonacosane	Hydrocarbon	O. isaurica	Aerial parts	[70]
174	1-Docosene	Unsaturated aliphatic Hydrocarbon	O. isaurica	Aerial parts	[70]
175	isorhamnetin-3-O-rutinoside	Flavonoid	O. stellulata	Aerial parts	[71]
176	sinapic acid	Aromatic	O. stellulata	Aerial parts	[71]
177	Deoxyshikonin [2-(4-methyl-pent-3-enyl)-5,8-dihydroxynaphthalene-1,4-dione]	Naphthoquinon	O. nigricaule	roots	[72]
178	β, β - Dimethylacrylshikonin (5,8-Dihydroxy-2-[1-(β, β -dimethy lacryloyloxy)-4-methyl-3-pentenyl]-1,4-naphthalenedion]	Naphthoquinon	O. nigricaule	Roots	[72]
179	Acetyl shikonin [(+)-Acetic acid 1-(5,8-dihydroxy-1,4- dioxo-1,4-dihydro-naphthalen-2-yl)-4-methyl-pent-3-enyl ester]	Naphthoquinon	O. nigricaule	Roots	[72]
180	2-[(4-methylbenzyl)amino]benzoic acid	Carboxylic acid	O. hispida	Whole plant	[54]
181	Methyl 2-[(4-methylbenzyl)amino]benzoate	Flavonoid	O. hispida	Whole plant	[54]
182	6,4′-Dimethoxy-3,5,7-trihydroxyflavone	Flavonoid	O. hispida	Whole plant	[54]
183	apigenin 7-O-β-d-glucoside	Flavonoid	O. hispida	Whole plant	[54]
184	Paraffins	Hydrocarbon	O. heterophylla	Roots	[62]
185	n-Dodecane	Hydrocarbon	O. heterophylla	Roots	[62]
186	n-Decatrian	Hydrocarbon	O. heterophylla	Roots	[62]
187	Methyl dodecanoate	Methyl ester	O. heterophylla	Roots	[62]
188	Methyl tetradecanoate	Methyl ester	O. heterophylla	Roots	[62]
189	Methyl 4-methyl tetradodecan-9,12 dien-oate	Hydrocarbon	O. heterophylla	Roots	[62]
190	Methyl 4-methyl tetradodec-9-ene-oate	Hydrocarbon	O. heterophylla	Roots	[62]
191	Methyl 4-methyl hexadec-9-ene-oate	Methyl ester	O. heterophylla	Roots	[62]
192	Methyl hexadecanoate	Methyl ester	O. heterophylla	Roots	[62]
193	Ethyl hexadecanoate	Methyl ester	O. heterophylla	Roots	[62]
194	Isopropyl hexadecanoate	Methyl ester	O. heterophylla	Roots	[62]
195	Methyl octadeca-9,12,15-triene-oate	Methyl ester	O. heterophylla	Roots	[62]
196	Methyl octadeca-9,12-diene-oate	Methyl ester	O. heterophylla	Roots	[62]
197	Methyl octadec-9-ene-oate	Methyl ester	O. heterophylla	Roots	[62]
198	Methyl octadecanoate	Methyl ester	O. heterophylla	Roots	[65]
199	diosmetin-7-O-β-glucoside	Aromatics	O. bourgaei	Aerial parts	[55]
200	allantoin	Imidazoles	O. bourgaei	Aerial parts	[55]
201	globoidnan A	Liganin	O. bourgaei	Aerial parts	[55]

), and this will open up new future study opportunities to explore pharmacological potentials of those phytochemicals. Most common Onosma compounds reported were rosmarinic acid, apigenin, ferulic acid, protocatechuic acid, chlorogenic acid, caffeic acid, p-coumaric acid, vanillic acid, luteolin, hyperoside, hesperidin, apigenin-7-Glucoside, luteolin-7, glucoside, isovalerylshikonin, acetylshikonin, pinoresinol, deoxyshikonin, 4, hydroxybenzoic acid, β,β-dimethylacryl, isovalerylshikonin, 2,5-Dihydroxybenzoic, and 3-Hydroxybenzoic acid as presented in Figure 5.

The bioactive structures of identified and characterized representative compounds, which are based on the repetition across published studies are shown in Figure 5, in addition to Figure 6.

8. Toxicity Study of the Onosma Species

8.1. Toxicity In Vivo Experiment

The chloroform and ethanolic extracts of O. aucheranum, O. isauricum O. sericeum, O. tauricum, and O. tauricum were safe in the administered doses from 100 mg/kg to 200 mg/kg based on the assessment of acute toxicity in the carrageenan-induced paw edema experiment as no abnormality in the morbidity nor mortality was recorded after 24 hours post treatment [73]. Furthermore, the 100, 200, 300, and 600 mg/kg of the MeOH of O. mutabilis administration to rats showed no changes in the appearance, behavior, and feed intake of the rats in a 7-day experiment [16]. Moreover, by the tarsal toxicity test, researchers have shown the acaricidal activity of the root extracts of O. visianii experimented against Tetranychus urticae mites in bean plants (P. vulgaris var. Carmen) after 24 h (considered as acute toxicity), which caused significant mortality of T. urticae adults with lethal doses 83.2 and 112.6 μg·cm causing 50% (LD₅₀) and 90% (LD₉₀) inhibition of oviposition, respectively. However, at 5 days (considered as chronic toxicity) from the start of the test, the lethal dose LD₅₀ was more than 30 times lower (2.6 μg·cm⁻²) as a function of time used in the LD₅₀ calculation [60]. Over the last two decades, several Onosma species have been tested for their toxicity to laboratory animal models. A study on toxicity of the bark extracts of O. echioides roots to Sprague Dawley rats (140 ± 10 g body weight) was performed and reported significant improvement in the body weight, food consumption, water intake, serum glucose, hematology, and biochemistry of rats with no adverse effect at a fixed dose [74].

8.2. Genotoxicity and Mutagenicity

Through the Allium-test, significant genotoxic effect from aqueous extracts of O. stellulata roots and aerial parts were observed in mitosis at meristematic cells of onion. Although the aerial parts showed significant genotoxicity after 4-h treatment (mitotic index was 2, 79%, vs. 9, 18% for control), but the root aqueous extracts had higher genotoxic effects. Genotoxic effects included changes in the structure of chromosomes (conglutination, spirality), and cytotoxic reaction and certain differentiation in the cell cycle, which were found to be in correlation with duration of treatment and solution concentration [75]. A genotoxic study by Allium anaphase–telophase assay reported that the safety of the ethanolic extract of O. aucheriana aerial parts at lower dose (62.5 mg/mL) had no toxic or genotoxic effects, while the higher dose (500 mg/mL) showed significantly the highest genotoxic effect including chromosomal aberrations, cells with multipolarity, cell bridges, and vagrant chromosomes (24.4%), cell fragments, and mitosis entrance [76]. In vivo genotoxic study of methanolic extracts of O. sericea and O. stenoloba at different doses (25, 50, 100, 200, and 400 μg/mL) against EMS-induced DNA damage in the flies and larvae of the wild-type strain of Drosophila melanogaster showed the absence of genotoxic effect of O. sericea and O. stenoloba at concentration 80 mg/mL. Furthermore, significant antigenotoxic effects reported after dual treatment with 80 mg/mL of both plant extracts plus EMS (ethyl methane sulfonate) caused significant decrease in DNA damage (with over 80% reduction) [15]. By using Ames assay, the antimutagenic potential of ethanolic extract of O. bracteatum has been reported against sodium azide and 2-aminofluorene mutagenicity in Salmonella typhimurium in TA100 strain (-S9 mix) as it displayed significant inhibition rate (82.30% at 250 mg/0.1 mL/plate), showing strong modulation of genotoxicity of base-pair substitution mutagen sodium azide when compared to NPD (frameshift mutagen) in TA98 tester strain. The O. bracteatum extracts showed significant antimutagenicity activity for preincubation mode than in co-incubation approach without -S9 in both TA100 and TA98 [77].

9. Pharmacological Activity of the Onosma Species

9.1. Antibacterial Activity

The essential oils isolated from roots of O. sieheana showed appreciable antibacterial activity against gram negative bacteria (Escherichia coli (MIC: 125 μg/mL) and Pseudomonas aeruginosa (MIC: 125 μg/mL) and gram positive bacteria (Staphylococcus aureus (MIC: 125 μg/mL) and Bacillus subtilis (MIC: 250 μg/mL)) [78]. The n-hexane–dichloromethane mixture extracts of O. argentatum roots showed antibacterial activity against Bacillus subtilis, Escherichia coli, and Staphylococcus aureus with MIC values 28, 13, and 32 μg/mL, respectively [18]. The chloroform fraction of O. khyberianum whole plant parts showed significant antibacterial activity against Salmonella typhi, Shigella dysenteriae, and Vibrio cholera inhibition zone 28, 26, 26 mm, respectively. Ethanol fraction of O. khyberianum demonstrated significant antiradical activity against Shigella dysenteriae (21 mm) and Vibrio cholera (20 mm), while the least active fraction of O. khyberianum n-hexane showed activity against Vibrio cholera, S. aureus, and Shigella dysenteriae (inhibition zone: 12, 9, 8 mm, respectively) but completely inactive against Salmonella and E. coli [79]. The crude ethanolic extracts of O. hispidum roots showed significant antibacterial activity against several gram positive and gram negative bacteria (Corynebacterium diphtheria, C. diphtheriticum, Micrococcus lysodiecticus, S. aureus, S. epidermidis, S. saprophyticus, Enterococcus faecalis, E. faecalis 2400, E. faecium, Streptococcus pneumonia, and S. pyogenes) with inhibition zone range between 18–20 mm [52]. The isolated naphtshoquinones (deoxyshikonin, isobutyrylshikonin, α- methylbutyrylshikonin, acetylshikonin, β-hydroxyisovalerylshikonin, 5,8-O-dimethyl isobutyrylshikonin, and 5,8-O-dimethyl deoxyshikonin) from O. visanii roots showed significant antibacterial activity against gram negative bacteria (Citrobacter koseri, Hafnia alvei, maltophilia, Yersinia intermedia, Ps. proteolytica, and Stenotrophomonas) and gram positive bacteria (Bacillus megaterium, Enterococcus faecalis, S. epidermidis, Microbacterium arborescens, and Micrococcus luteus) with MIC₅₀ and MIC₉₀ values between range 4.27–68.27 μg/mL and 4.77–76.20 μg/mL, respectively [61]. The antibacterial activity (MIC values) from methanol extract of aerial parts of O. sericea and O. stenoloba were between 2.5−10 mg/mL. Both Onosma extracts had moderate antibacterial activity only on a few strains, namely A. chroococcum and E. coli with MIC values 2.5 and 5 mg/L, respectively. O. sericea extract exhibited low activity on gram positive strain M. lysodeikticus with MIC 10 mg/mL, while O. stenoloba extract showed notable antibacterial action on E. faecalis and A. tumefaciens with MIC values 5 and 10 mg/mL, respectively [15].

9.2. Antifungal Activity

Antifungal activity of methanolic extracts of O. sericea and O. stenoloba aerial parts against fungal strains Phialophare fastigiata and Fusarium oxysporum has been reported as 2.5 and 5 μg/mLof MIC, respectively. Furthermore, the methanol extracts of O. sericea exhibited moderate activity (MIC range of 2.5−5 μg/mL) on Penicillium canescens FSB 24 and P. cyclopium FSB 23, while O. stenoloba had antifungal activity only against P. cyclopium (MIC 10 μg/mL). Moreover, the same study showed antifungal potentials (MIC 10 μg/mL) of O. sericea against Trichoderma longibrachiatum FSB 13 and Trichoderma harzianum FSB 12. Meanwhile, increased concentration (10 μg/mL) of Onosma extracts showed inactivity against Aspergillus niger FSB 31, Aspergillus glaucus FSB 32, Doratomyces stemonitis FSB 41, Phialophora fastigiata FSB 81, Alternaria alternata FSB 51, and Fusarium oxysporum FSB 91 [15]. The methanol extracts from aerial parts of O. griffithii exhibit antifungal activity against Aspergillus flavus (55%) and Fusarium solani (40%). Meanwhile, the chloroformic extracts showed better antifungal activity against A. flavus (59%) and Fusarium solani (60%) [17]. The antifungal activity of O. kheberianum against three fungal strains, Fusarium oxysporum, Alternaria alternate, and A. flavus were reported as 18, 13, and 7 mm, respectively, for ethanol fractions and 17, 11, and 9 mm, respectively, for chloroform fractions [79]. A previous study also showed a lack of antifungal activity of n-hexane–dichloromethane extracts of O. argentatum roots against Trichophyton tonsurans, Trichophyton interdigitale, Microphyton gypseum, and Candida albicans [18]. The essential oils from O. sieheana Hayek roots showed significant antifungal activity against yeast strains Candida glabrata and C. albicans, and the authors linked this activity with their phytoconstituents, namely Monoterpenes, such as cymene and thymol [80]. The essential oils from O. chlorotricum roots exhibit higher antifungal activity (21 and 19.3 mean of inhibition zones (mm) against C. albicans and C. glaberata, respectively) than that of essential oils from O. microcarpum roots [80]. The O. paniculatum cells showed strong response to fungal elicitors from Aspergillus sp., in an attempt to accelerate shikonin derivative formation and inversely arrest plant cell growth, which resulted in a slight change in shikonin contents [81].

9.3. Antioxidant Activity

Onosma species have been comprehensively studied and researchers have revealed that they are a promising resources of antioxidants using various types of extraction and solvent methods [14,82,83]. The O. ambigens aerial part extracts exhibited notable antioxidant action in the phosphomolybdenum, CUPRAC, FRAP, DPPH, and ABTS assays with values of 1.65, 0.95, 0.52, 1.86, and 1.45 mg/mL, respectively [30]. The antioxidant activity of O. gigantea were significant in phosphomolybdenum (134.31 μmol trolox (TEs)/g air dry matter (adm)), chelating effect (32.97 μmol (EDTAEs)/g adm), on DPPH (32.14 μmol TEs/g adm) and ABTS (58.68 μmol TEs/g adm)), and reducing power (CUPRAC (50.23 μmol TEs/g adm) and FRAP (40.96 μmol TEs/g adm)) assays [53].

The water extract of the aerial part of O. pulchra showed significant antioxidant actions in DPPH, ABTS, CUPRAC, and ferrous ion chelating tests (3.90, 2.55, 2.20, and 1.23 mg/mL, respectively). Meanwhile, the Phosphomolybdenum and FRAP assays showed superiority of MeOH extract (1.98 and 1.02 mg/mL, respectively) [14]. The ethanol extract of aerial parts of O. bracteatum showed significant radical quenching activity in superoxide radical scavenging (EC₅₀: 115.14 μg/mL) and lipid peroxidation (EC₅₀: 199.33 μg/mL) assays [77]. The methanol extracts of O. mutabilis showed higher antioxidant activity than that of water and ethyl acetate fractions, respectively, in which the antioxidant values for methanol extracts were 1.45 ± 0.05, 3.54 ± 0.064, 2.33 ± 0.045, 1.12 ± 0.023, and 1.62 ± 0.079 mg/mL in phosphomolybdenum, DPPH scavenging, ABTS, FRAP, and CUPRAC reducing, respectively [16]. The methanol extract of aerial parts of O. frutescens showed significantly higher antioxidant activity in DPPH (1.14 mg/mL), ABTS (1.04 mg/mL), CUPRAC (0.53 mg/mL), FRAP (0.35 mg/mL), and phosphomolybdenum (1.18 mg/mL) tests than that (1.75,1.50, 0.87, 0.55, 1.97 mg/mL) and (2.18, 1.87, 0.99, 0.63, 1.92 mg/mL) for O. sericea and O. aucheriana, respectively. The ferrous ion chelating assays showed superiority of O. aucheriana (IC₅₀: 2.57 mg/mL) over O. frutescens (4.68 mg/mL) and O. sericea (6.18 mg/mL) [49]. The aqueous extract of O. aucheriana roots showed significant antioxidant activity in radical quenching activity (ABTS, DPPH) with IC50 values as 9.89 and 17.73 μg/mL. Additionally, the same species showed notable lipid peroxidation inhibition, and hydroxyl radical scavenging actions with IC50 values, 23.41 and 31.09 μg/mL, respectively [45]. The methanolic extracts of O. trapezuntea aerial parts showed stronger antioxidant activity (IC₅₀: 3.05 mg/mL in DPPH and 7.19 mg/mL in ABTS) than that (IC₅₀: 2.63 mg/mL in DPPH and 5.23 mg/mL in ABTS) of O. rigidum [50]. The O. argentatum root extracts (0.1% concentration) by n-hexane–dichloromethane mixture (1:1) showed significant 98% antioxidant activity (IC₅₀: 0.0076% w/v) by thiobarbituric acid (TBA) [18]. The methanol extract of aerial parts of O. lycaonica Hub. -Mor. exhibited stronger antioxidant activity in 1,1-diphenyl-2-picrylhydrazyl scavenging activity (2.69 ± 0.10 mg/mL), cupric reducing antioxidant power (1.10 ± 0.01), ferric reducing antioxidant power (0.69 ± 0.01 mg/mL), and ferrous ion chelating activity (2.32 ± 0.16 mg/mL) than that of O. papillosa. However, the O. papillosa showed lower IC₅₀ or EC₅₀ values for phosphomolybdenum (1.90 ± 0.07 mg/mL) when compared to O. lycaonica (2.05 ± 0.07 mg/mL), which could be related to their phytochemical contents as O. lycaonica had higher phenolic contents, with (43.5 ± 1.5 mg (gallic acid equivalent)/g extracts), whereas O. papillosa was higher in flavonoids (32.9 ± 0.3 mg (quercetin equivalent)/g extracts) [48]. The aerial part ethanol extracts of O. hookeri showed the same 2,2-diphenyl-1-picrylhydrazyl (77.77 ± 1.44 μg/mL) scavenging activity as butylated hydroxy toluene (72.70 ± 1.04 μg/mL), but slightly weaker 2,2′-azino-bis-3-ethylbenzthiazoline-6-sulphonic acid (553.56 ± 2.78 μg/mL) scavenging activity and total antioxidant capacity than that of BHT (51.44 ± 1.37 μg/mL), while the ethyl acetate fraction of O. hookeri showed better ABTS scavenger, with IC₅₀ value of 84.83 ± 1.37 μg/mL [66]. The aerial part MeOH extracts of O. sericea significant antioxidant activity in DPPH scavenging (130.23 ± 5.31 mg TE/g extract), ABTS scavenging (235.53 ± 4.62 mg TE/g extract), FRAP (215.65 ± 2.51 mg TE/g extract), CUPRAC (359.63 ± 14.83 mg TE/g extract), total antioxidant capacity (2.46 ± 0.35 mmol TE/g extract), metal chelating activity (24.65 ± 2.21 mgEDTAE/g extract), while O. stenoloba stronger activity with values 53.96 ± 0.78, 95.60 ± 2.30, 76.48 ± 3.26, 142.88 ± 1.49 mg TE/g, 1.16 ± 0.05 mmol TE/g, and 5.51 ± 0.81 mg EDTAE/g in the same essays, respectively [81]. The aerial part extract of O. isauricum exhibited significant antioxidant actions with superiority of its methanol extracts in DPPH (34.75 mg/mL) and CUPRAC (0.643 mg/mL), ferric reducing powers (0.211 mg/mL), ABTS (188.68 mgTE/g extract), superoxide radical scavenging ability (97.50 mgTE/g extract), and total antioxidant ability (86.02 mgAAE/g extract) than that (31.44 mg/mL, 0.471 mg/mL, 0.237 mg/mL, 130.91 mgTE/g, 159.92 mgTE/g, 55.36 mgAAE/g) and (4.69 mg/mL, 0.078 mg/mL, 0.021 mg/mL, 131.94 mgTE/g, 103.23 mgTE/g, 31.17 mgAAE/g extract) for water and ethyl extracts, respectively [83]. The results of antioxidant investigations of O. mollis showed significant radical scavenging actions phosphomolybdenum, DPPH, and ABTS, (2.01, 3.33, 2.30 mg/mL, respectively) while reducing power activity, CUPRAC and FRAP, were found as 1.48 and 0.79 mg/mL, respectively [51].

9.4. Cytotoxicity Activity

For the past decades, several studies have confirmed the traditional usage of the Onosma species as cytotoxic agents, and mammalian cancer cell division was inhibited by its extracts and isolated compounds [45,55,60].

The methanol extract of O. mutabilis aerial parts indicated significant anticancer activity against prostate (DU-145), mammary (MCF-7), and cervical cancer (Hep2c) cells with IC₅₀ values as 35.67 ± 0.15, 28.79 ± 0.23, and 41.83 ± 0.21 μg/mL, respectively [55]. The crude extracts of O. aucheriana showed significant cytotoxicity activity against human rhabdomyosarcoma, human cervix carcinoma Hep2c, and from murine fibroblast (L2OB) cell lines with IC₅₀ values range between 25.54 to 50.57 μg/mL [45]. The isolated compounds acetylshikonin, dimethylacrylshikonin, α-methylbutyrylshikonin, and isovalerylshikonin from the roots of O. paniculata showed appreciable anticancer activity against human CCRF-CEM leukemia, MDA-MB-231 breast cancer, human U251 glioblastoma, HCT 116 colon cancer, and human melanoma (SBcl2, WM35, WM9, WM164) cell lines with IC₅₀ values ranging between 600 nM to 70 μM [60]. The isolated naphtshoquinones α-methylbutyrylshikonin and acetylshikonin compounds from O. visanii roots demonstrated stronger cytotoxic activity against MDAMB-231 cells (IC₅₀: 86.0 μg/mL and 80.2 μg/mL, respectively) than that of 118.9, 204.6, 424.7, 391.6, and 411.5 μg/mL of Deoxyshikonin, β-Hydroxyisovalerylshikonin, Isobutyrylshikonin, 5,8-O-Dimethyl deoxyshikonin, and 5,8-O-Dimethyl isobutyrylshikonin, respectively. Additionally, all compounds except 5,8-O-Dimethyl deoxyshikonin, and 5,8-O-Dimethyl isobutyrylshikonin reduced viability of MDA-MB-231 cells after 48 h of incubation. Furthermore, α-methylbutyrylshikonin demonstrated the higher anticancer activity against HCT116 cells (IC₅₀: 15.2 μg/mL) than that 97.8 μg/mL, 24.6 μg/mL and 30.9 μg/mL of Deoxyshikonin, Acetylshikonin, and β-Hydroxyisovalerylshikonin, respectively [61]. The effect of Onosma bracteatum has been studied against different cancer cell lines and the results showed that various concentrations (0.055, 0.11, 0.22, 0.44, 0.88, 1.7, and 3.52 µg/mL) of O. bracteatum decreased viability of cells in a time- and dose-dependent protocol [84]. Furthermore, the hydrochloric root extracts of O. dichroanthum Boiss. roots have shown significant anticancer actions against gastric cancer cells [11]. Moreover, O. paniculata has shown notable cytotoxicity activity against a number of cancer lines and linked their action with its ability to accelerate apoptosis [60]. The 50 µg/mL ethanolic extract from aerial parts of O. sericeum exhibited significant cytotoxicity activity against the breast cancer cells (MCF-7) with significantly decreased cell viability (28.76 ± 11.31%) [13]. The petroleum ether and aqueous extracts of O. hispidum roots have shown significant anticancer actions against HepG2 liver cancer cell lines [85].

9.5. Enzyme Inhibitory Activity

9.5.1. Antidiabetic Activity

A literature search revealed multiple research works that confirmed the anti-diabetics properties of Onosma species as the in vitro antidiabetic activity of Onosma species was reported based on its inhibitory potentials on α-amylase and glucosidase enzymes. The ethyl acetate extraction of aerial parts of O. gigantea showed higher α-amylase and glucosidase inhibitory activity (15.98 and 1.07 μmol/g) than that (410.50 and 6.75 μmol/g) and (1320.53 and 5.16μmol/g) of methanol and water extracts, respectively [53]. The α-amylase inhibitory activity from MeOH extracts of O. aucheriana and O. sericea were reported higher (2.50 and 2.51 mg/mL, respectively) than that (3.15 mg/mL) of O. frutescens [49]. The ethyl acetate extraction of O. ambigens aerial parts showed stronger α-amylase inhibitory activity (IC₅₀: 2.64 mg/mL) than that (2.98 and 16.34 mg/mL) for methanol and water extracts, respectively [30]. The methanol extracts of O. lycaonica and O. papillosa aerial parts exhibited significant α-amylase inhibitory concentration (IC₅₀: 2.57 and 2.40 mg/mL) and glucosidase inhibition (IC₅₀: 2.60 and 2.61 mg/mL), respectively [48]. The ethyl acetate extract of O. pulchra aerial parts showed higher α-amylase inhibitory activity (2.40 mg/mL) than that (5.47 and 19.23 mg/mL) of methanol and water extracts, respectively [14]. The aerial part extraction of O. rigidum showed higher glucosidase and lower α-amylase enzyme inhibitory activity than that of O. trapezuntea extracts [50]. The MeOH aerial extracts of O. stenoloba exhibited higher α-amylase and lower glucosidase inhibitory activity (0.89 and 43.47 mmol/g) than that (1.26 and 33.38 mmol/g) of O. sericea, respectively [15]. The hydroalcoholic extract of the aerial part of O. Dichroanthum was reported to have anti-diabetic and anti-neuropathy properties based on its ability to down regulation of the MDA and Glutathione levels in homogenized tissues of brain and liver in a rat experiment [86]. The petroleum ether, chloroform, and methanol extracts of O. hispidum wall roots have shown significant anticancer actions with inhibitory percentages reported as 70, 58, and 50%, respectively. Meanwhile, the superiority of petroleum ether extracts has been linked with its higher polyphenolic contents [85].

9.5.2. Alzheimer’s Disease

The protective effect of Onosma species against Alzheimer’s disease was reported depending on its inhibitory activity on acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes. The ethyl acetate extraction of aerial parts of O. gigantea showed higher AChE and BChE inhibitory activity (2.76 and 6.87 μmol/g, respectively) than that (31.57 and 1.82 μmol/g, respectively) of methanol extracts [53]. The isolated hispidone and (2S)-5,2-dihydroxy-7,5-dimethoxyflavanone from methanol extractions of whole plant parts of O. hispida showed significant inhibitory activity against AChE (11.6 and 15.7 mg/mL, respectively) and BChE (28.0 and 7.9 mg/mL, respectively) enzymes [38]. The aerial part extracts of O. lycaonica and O. papillosa exhibited significant AChE inhibition activity (IC₅₀:1.32 and increased BChE inhibitory activity (2.31 ± 0.04 and 2.07 ± 0.1 (2.31 ± 0.04 and 2.07 ± 0.08 mg GALAEs/g extracts), respectively [48]. The MeOH extraction of O. rigidum aerial parts showed higher AChE and lower BChE inhibitory activity than that of O. trapezuntea extracts [50]. O. sericea aerial part extracts showed higher inhibitory activity on AChE (3.74 mg/g) and BChE (0.51 mg/g) than that (4.34 and 3.44 mg/g) for O. stenoloba, respectively [15].

9.5.3. Anti-Tyrosinase Activity

Tyrosinase enzymes are well-known for their participation in melanin biosynthesis, and hypersecretion accompanied by accumulation of melanin pigments may lead to hyperpigmentation disorders and photo carcinogenesis [87]. The ethyl acetate partition of aerial parts of O. gigantea showed higher tyrosinase inhibitory activity (0.15 μmol/g) than that (0.49 and 10.48μmol/g) of methanol and water extracts, respectively [53]. The tyrosinase inhibitory activity of methanol extracts of O. aucheriana aerial parts was higher (2.19 mg/mL) than that (2.23 and 2.40 mg/mL) of O. sericea and O. frutescence, respectively [49]. The methanol partition of aerial parts of O. ambigens showed higher tyrosinase inhibitory activity (2.81 mg/mL) than that (3.79 and 4.45 mg/mL) of water and ethyl acetate extracts, respectively [30]. Onosma lycaonica and O. papillosa aerial extracts have been reported as tyrosinase inhibitors with IC₅₀ values 2.20 and 2.05 mg/mL, respectively [48]. The methanol extracts of O. pulchra aerial parts showed higher tyrosinase inhibitory activity (2.47 mg/mL) than that (3.77 and 4.35 mg/mL) of ethyl acetate and water extracts, respectively [14]. The aerial part extracts of O. rigidum and O. trapezuntea showed comparable tyrosinase inhibitory potentials activity [50]. A previous study also reported modest tyrosinase inhibitory activity (136.35 and 135.68 mg/g) for methanol extracts of aerial parts of O. sericea and O. stenoloba, respectively [15]. The ethyl acetate extracts of O. isauricum showed higher tyrosinase inhibitory activity (19.96 mg/g kojic acid equivalents) than that (15.33 and 14.83 mg/g) of methanol and water extracts, respectively [83].

9.5.4. Anti-Lipoxygenases Activity

Lipoxygenases enzymes are known to catalyze oxidation of polyunsaturated fatty acids (linoleic, linolenic, and arachidonic acid) yielding hydroperoxides. Such reactions may be favorable, but also lipoxygenases may interact undesirably. Aromatic compounds are major yields of lipoxygenase reactions that can interfere with food properties, mainly during long-term storage. Lipoxygenase’s impact on unsaturated fatty acids may lead to off-flavor/off-odor formation, leading to food spoilage. Furthermore, lipoxygenase is considered as an important enzyme in stimulation of inflammatory reactions in the human body by playing as a key factor in the biosynthesis of many bio-regulatory compounds such as hydroxyeicosatetraenoic acids (HETEs), leukotrienes, lipoxins, and hepoxylines that were linked to major diseases such as cancer, stroke, and heart and brain diseases [88]. Therefore, searching for natural products that could target this enzyme has become a continuous scientific mission to prevent such diseases. The onosmins A (2-[(4-methylbenzyl)amino]benzoic acid and B (methyl 2-[(4-methylbenzyl)amino]benzoate) compounds isolated from the n-hexane-soluble fraction of ethanol extracts of O. hispida whole plant showed significant lipoxygenase inhibitory activity (IC₅₀: 24.0 and 36.2 μM) [54].

10. Other Biological Activity

10.1. Parasiticidal Activity

The antileishmanial activities of the crude methanol extract of O. griffithii and its fractions were statistically significant (p < 0.05) against the Leishmania promastigotes, Pakistani isolates in comparison with the standard drug called Pentamidine [17].

10.2. Anti-Inflammatory and Analgesic Activity

The chloroform extracts from roots of O. aucheranum, O. isauricum, and O. tauricum showed 28.0%, 34.3%, and 15.6% inhibitory action in p-benzoquinone-induced abdominal constriction experiment, while the ethanol extracts of O. isauricum and O. sericeum demonstrated inhibition action of 24.6% and 27.5%, respectively, in the same test. The chloroform and ethanol extracts of O. isauricum and ethanol extract of O. sericeum also showed significant inhibitory activity, ranging between 12.3–27.3%, 10.5–25.3%, 8.2–22.6%, respectively, in a carrageenan-induced hind paw edema model at 100 mg/kg dose without gastric damage, and the activity was very comparable to indomethacin (32.0–38.4% inhibition) as a standard sample [73]. The chloroform extracts of O. aucheranum and O. isauricum and ethanolic extracts of O. isauricum and O. sericeum exhibited notable antinociceptive activity; 28.0%, 34.3%, 24.6%, and 27.5% inhibition, respectively, against p-benzoquinone-induced abdominal contractions, without induction of any sign of gastric lesion [73]. The methanol extraction of aerial parts of O. bracteatum showed potent analgesic activity by inducing significant increase in the latency period in a dose-dependent manner at different doses at 1, 2, and 3 h (with superiority of 500 mg/kg i.e., 258.9% (p < 0.05) at 3 h) post feeding, respectively, in a tail flick test. Furthermore, the methanol extract of O. bracteatum showed significant analgesic effect at 500 mg/kg body weight dose by inducing 54% inhibition (p < 0.05) in comparison to 45.9% inhibition activity for standard Diclofenac sodium (5 mg/kg body weight) [89].

10.3. Gastric-Ulcerogenic Activity

The chloroform and ethanol extracts from O. aucheranum, O. isauricum, O. sericeum, and O. tauricum roots did not cause any gastric lesions or bleeding in the stomach of mice in a 48-h experiment [71].

10.4. Treatment and Prevention of COVID-19

The Onosma phytochemicals, deoxyshikonin, 3-hydroxy-isovaleryl shikonin, propionyl shikonin, and acetyl shikonin showed significant binding affinities for the Mpro enzyme based on the molecular docking studies using two distinct approaches, in which a SiteMap module of Maestro was used to detect the possible ligand binding sites for the Mpro enzyme. Docking simulations and molecular mechanics suggest that shikonin derivatives might be effective anti-SARS-CoV-2 compounds [19].

11. Conclusions

Application of natural products and their metabolites as chemically diverse starting building blocks has been a major driving force in drug discovery over the last century. However, the use of natural products is not linked only to the modern era, as most folkloric medicines have plant-derived extracts. Moreover, the technological advancement and new technical development for isolation and identification of the natural bioactive compounds in herbs have motivated scientists to investigate and use them as nutrients and nutraceuticals, as well as curatives.

The genus Onosma, known to be widespread worldwide, has a history of medicinal uses against different diseases in the folk medicine system of several civilizations. In this review, the authors rediscover the genus Onosma by detailing the important isolated and identified chemical compounds and extracts, including naphthoquinone (33), flavonoids (30), hydrocarbon (23), phenolic (22), ester (17), alkaloids (20), terpenoids (10), carboxylic acid (11), fatty acids (9), aromatics (12), and liganin (5). The Onosma phytoconstituents that are considered as potential leads amenable for drug development were reported as rosmarinic acid, apigenin, ferulic acid, protocatechuic acid, chlorogenic acid, caffeic acid, p-coumaric acid, vanillic acid.

Several biological activities were reported from Onosma compounds and extracts, including, Genotoxicity and Mutagenicity, antifungal, antibacterial, antioxidant, anticancer, antidiabetic, anti-Alzheimer, anti-tyrosinase, anti-lipoxygenases, parasiticidal, anti-inflammatory, and gastric-ulcerogenic activities. Finally, despite the fact that rosmarinic acid is reported as the most detectable compound in the Onosma species, it was not found in other species such as O. echioides, O. hookeri, O. heterophylla, and O. erecta, requiring further investigation for more confirmation by profiling many other species for comparison.