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Review

Phytochemistry, Pharmacological Potential, and Ethnomedicinal Relevance of Achillea nobilis and Its Subspecies: A Comprehensive Review

by
Anastassiya Shevchenko
1,2,
Aiman Аkhelova
3,*,
Shamshabanu Nokerbek
4,
Aigul Kaldybayeva
3,
Lyazzat Sagyndykova
5,
Karlygash Raganina
6,
Raushan Dossymbekova
7,
Aliya Meldebekova
8,
Akerke Amirkhanova
6,*,
Yerbol Ikhsanov
2,
Gulzhan Sauranbayeva
3,9,
Manshuk Kamalova
1 and
Aidana Toregeldieva
1
1
Higher School of Medicine, Al-Farabi Kazakh National University, Tole-bi 96, Almaty 050040, Kazakhstan
2
Department of Chemistry and Technology of Organic Substances, Natural Compounds and Polymers, Faculty of Chemistry and Chemical Technology, Al-Farabi Kazakh National University, Almaty 050040, Kazakhstan
3
Department of Pharmaceutical and Toxicological Chemistry, S.D. Asfendiyarov Kazakh National Medical University, Tole-bi 94, Almaty 050012, Kazakhstan
4
School of Pharmacy, S.D. Asfendiyarov Kazakh National Medical University, Tole-bi 94, Almaty 050012, Kazakhstan
5
Department of Pharmaceutical Disciplines, Astana Medical University, Saryarqa Ave., 33, Astana 010000, Kazakhstan
6
Department of Pharmaceutical Technology, S.D. Asfendiyarov Kazakh National Medical University, Tole-bi 94, Almaty 050012, Kazakhstan
7
Department of Biochemistry, S.D. Asfendiyarov Kazakh National Medical University, Tole-bi 94, Almaty 050012, Kazakhstan
8
Department of Biotechnology, Faculty of Biology and biotechnology, Al-Farabi Kazakh National University, Almaty 050040, Kazakhstan
9
Department of Biotechnology and General Chemical Engineering, School of Pharmacy, S.D. Asfendiyarov Kazakh National Medical University, Tole-bi 94, Almaty 050012, Kazakhstan
*
Authors to whom correspondence should be addressed.
Molecules 2025, 30(11), 2460; https://doi.org/10.3390/molecules30112460
Submission received: 20 April 2025 / Revised: 14 May 2025 / Accepted: 14 May 2025 / Published: 4 June 2025
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Versions Notes

Abstract

Achillea nobilis and its subspecies (A. nobilis subsp. neilreichii and A. nobilis subsp. sipylea) have been traditionally used in various ethnomedical systems across Eurasia. However, comprehensive studies on their phytochemical composition and pharmacological properties are still insufficient. This review aims to provide a critical synthesis of current knowledge regarding the botanical characteristics, geographic distribution, traditional applications, chemical constituents, and pharmacological effects of A. nobilis A structured search was conducted using eight scientific platforms, including Scopus, PubMed, Web of Science, Google Scholar, Science.gov, ScienceDirect, JSTOR, and BASE. Keywords related to phytochemistry, pharmacology, and ethnomedicine were applied, and a total of 28,000 records were initially retrieved. After a multi-stage screening process based on inclusion and exclusion criteria, 167 peer-reviewed publications from 1952 to 2023 were selected for detailed evaluation. Findings reveal a diverse range of bioactive compounds, such as flavonoids, monoterpenes, sesquiterpenes, and sesquiterpene lactones, which demonstrate antioxidant, antimicrobial, anti-inflammatory, antinociceptive, antispasmodic, and anticonvulsant activities. Most studies have focused on aerial parts and water-based extracts, while the root chemistry and organ-specific metabolite profiles remain largely unexplored. This review highlights the therapeutic potential of A. nobilis and underscores the need for future studies using multi-omics and advanced analytical techniques to support its development in pharmaceutical and nutraceutical applications.

1. Introduction

The exploration of specific plant species with ethnomedicinal value has proven instrumental in identifying novel bioactive compounds for therapeutic use [1]. Achillea nobilis L. and its subspecies (A. nobilis subsp. sipylea, A. nobilis subsp. neilreichii, and A. nobilis subsp. nobilis) represent a group of aromatic and medicinal plants widely used in traditional medicine systems across Eurasia [2,3,4]. These taxa belong to the Asteraceae family and have been historically used in herbal decoctions, infusions, oils, and topical applications aimed at treating pain, inflammation, gastrointestinal discomfort, respiratory infections, and dermatological conditions [5,6,7,8,9,10]. Their longstanding therapeutic applications are rooted in folk medicine systems from Turkey, Iran, Bosnia and Herzegovina, and Kazakhstan, among others [11,12,13,14,15].
Despite their documented use in traditional medicine, comprehensive scientific analysis of their phytochemical composition and pharmacological properties remains fragmented [16,17]. Reports suggest that A. nobilis and its subspecies contain a diverse array of bioactive secondary metabolites, including flavonoids, flavonoid glycosides, monoterpenes, sesquiterpenes, sesquiterpene lactones, and terpenoid derivatives [18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34]. These compounds have been linked to various biological activities, particularly antimicrobial, anti-inflammatory, antispasmodic, and neuroprotective effects. For example, flavonoids such as apigenin and luteolin glycosides exhibit strong antioxidant and anti-inflammatory properties, while volatile monoterpenes such as α-thujone, cineole, and camphor have shown antimicrobial activity (Figure 1) [21].
Phytochemical investigations from 1978 to 2020 have primarily focused on aerial parts of the plant and water-soluble extracts, often overlooking the phytochemical diversity of underground organs and lipid-soluble fractions. This creates a significant knowledge gap in understanding the complete metabolic profile of the species. Furthermore, studies suggest that the chemical profiles of different plant parts and subspecies vary significantly due to genetic and ecological factors, necessitating chemotaxonomic approaches and organ-specific metabolite profiling [27,28]. Seasonal variations have been reported to influence the concentration of essential oils and flavonoid content, with certain bioactive compounds peaking during flowering or specific phenological stages. Similarly, regional differences, including altitude, soil composition, and climatic conditions, can significantly modulate metabolite accumulation, leading to variability in pharmacological potency across populations [2,20,25]. However, these differences have not yet been fully characterized in a systematic manner.
Although several review articles have addressed the phytochemistry and pharmacological properties of the Achillea genus more broadly [4,35,36,37], none have provided a comprehensive, species-specific focus on Achillea nobilis and its subspecies. Existing reviews such as Barda et al. [4] and Saeidnia et al. [37] compile data primarily for A. millefolium and other well-studied species, while limited attention is given to the distinct phytochemical profiles and ethnomedicinal uses of A. nobilis taxa. Furthermore, no review has yet systematically explored the chemotaxonomic distinctions among A. nobilis subspecies or the variation in lipophilic and underground organ-derived metabolites. This review aims to fill this gap by offering a dedicated analysis of A. nobilis and its subspecies, integrating phytochemical, ethnopharmacological, and pharmacological data, and proposing future research directions using multi-omics and regional comparative approaches.
Recent advances in plant metabolomics, transcriptomics, and chemoinformatics offer the opportunity to resolve these limitations [29,30,31,32,33]. Future research should incorporate integrative multi-omics strategies to explore biosynthetic pathways, quantify metabolite variation across plant parts and environments, and establish pharmacological correlations with specific compounds. Additionally, understanding the influence of geographical and seasonal variability on phytochemical expression will enhance the reproducibility and quality control of derived herbal products. Given these gaps, a focused and comprehensive review is essential to consolidate current knowledge and guide future investigations.
This review aims to offer a thorough and cohesive summary of A. nobilis and its subspecies by consolidating existing information on their botanical traits, geographic distribution, traditional medicinal applications, phytochemical compositions, and pharmacological effects. The objective is to bridge traditional ethnobotanical insights with contemporary phytochemical and pharmacological evidence while identifying research gaps related to underexplored plant parts such as roots. Furthermore, the review proposes future research directions using advanced analytical and systems biology tools to support the safe and effective integration of A. nobilis into pharmaceutical and nutraceutical development.

2. Methods

A comprehensive and systematic literature review was conducted to identify relevant scientific publications pertaining to Achillea nobilis and its subspecies. The search aimed to capture a wide spectrum of studies addressing botanical, phytochemical, ethnomedicinal, and pharmacological aspects. Eight databases were strategically selected to ensure broad and high-quality coverage of the literature. These included bibliographic databases (Scopus, PubMed, Web of Science), academic search engines (Google Scholar, Science.gov), and full-text repositories (ScienceDirect, JSTOR, BASE), which collectively provide access to peer-reviewed journals, open-access materials, institutional repositories, and preprints.
To refine the search and extract relevant literature, targeted keywords were employed, including “A. nobilis”, “A. nobilis phytochemicals”, “A. nobilis compounds”, “A. nobilis pharmacological”, “A. nobilis traditional use”, and “A. nobilis ethnomedicine”. The search strategy incorporated Boolean operators and was applied uniformly across all platforms. The number of search results obtained per keyword from each platform is summarized in Table 1.
The literature review and data collection were conducted between August 2024 and March 2025. Scientific publications in English, Russian, Arabic, and Chinese were included in the review. The primary database searches and article screening were performed by Anastassiya Shevchenko and Akerke Amirkhanova. Other co-authors contributed by verifying the eligibility of the literature, extracting phytochemical and pharmacological data from selected manuscripts, and assisting with data synthesis and final categorization. The review process involved both gradual and parallel stages of search and screening to ensure coverage and accuracy. No conflicts arose during the literature review process.
We compared phytochemical composition data reported in selected studies to assess chemotypic variation across subspecies and plant organs. Specifically, we recorded identified metabolites, extraction solvents, analytical techniques (e.g., GC–MS, LC–MS/MS, NMR), and the corresponding plant parts and subspecies. Studies reporting distinct compound profiles from different subspecies (e.g., A. nobilis subsp. neilreichii vs. A. nobilis subsp. nobilis) or organs (e.g., aerial parts vs. flower heads) were reviewed comparatively to infer chemotypic differences. These patterns were synthesized to identify recurring subspecies-specific chemical signatures. The final synthesis was conducted by categorizing phytochemicals according to chemical class (e.g., flavonoids, terpenes, phenolic acids) and mapping them against plant parts and subspecies. This comparative approach allowed us to infer chemotypic variations and associate them with environmental or genetic factors, as reported by primary authors. Differences in extraction protocols and analytical techniques were also considered to contextualize the findings.
By applying the inclusion and exclusion criteria, papers that met the inclusion criteria were selected for further investigation and content assessment. The inclusion criteria encompassed peer-reviewed articles, biological/pharmacological studies, systematic reviews, and meta-analyses that specifically addressed A. nobilis, its phytochemical composition, pharmacological properties, and ecological significance. Conversely, the exclusion criteria involved omitting gray literature, extended abstracts, presentations, keynotes, book chapters, and inaccessible publications. Additionally, articles discussing Achillea species without specific information on A. nobilis were excluded, as they fell outside the scope of this review, which aims to define the status quo of medicinal and ethnobotanical significance (MES).
The general screening process and the flow of selecting relevant literature are illustrated in Figure 2. Initially, approximately 28,000 records were retrieved from seven platforms. After eliminating non-relevant works, including gray literature, extended abstracts, presentations, keynotes, book chapters, and inaccessible sources, the number of retained articles was reduced to 893 for further title screening. Subsequently, 385 articles met the eligibility criteria for abstract evaluation. Following abstract screening, only 293 articles were deemed relevant for a full-text review. Among them, 167 studies specifically assessed MES, and these articles were downloaded for further detailed screening. Ultimately, 167 publications satisfied all inclusion criteria and were selected for the final analysis (Figure 2). The final set of relevant publications was then used for further evaluation and synthesis.
These terms facilitated the identification of studies related to the phytochemical composition, pharmacological potential, and ethnomedicinal applications of A. nobilis. Moreover, to enhance the accuracy of data retrieval, non-relevant materials were systematically excluded based on their lack of direct relevance to the study’s objectives. This methodological approach ensures the inclusion of high-quality and scientifically rigorous literature, thereby strengthening the reliability and validity of the findings. Additional studies were identified through manual screening of references in the selected articles. Furthermore, books containing high-quality taxonomic, ethnobotanical, and pharmacological information were also reviewed to ensure comprehensive coverage of A. nobilis. In addition to taxonomic and ethnobotanical aspects, particular attention was given to the pharmacological activities of the identified bioactive compounds. This approach provided a broader understanding of the therapeutic potential of A. nobilis, allowing for the identification of key bioactive constituents and their possible mechanisms of action. The literature reviewed spanned from 1952 to 2023.
The process of reviewing scientific articles to identify appropriate materials involves four key actions. First, selecting relevant keywords and developing a precise search strategy using Boolean operators ensures comprehensive database searches. Second, screening article titles and abstracts helps filter studies based on relevance and predefined inclusion/exclusion criteria. Third, full-text evaluation assesses methodological rigor, scientific credibility, and alignment with research objectives. Lastly, reference cross-checking and citation tracking enhance the review by identifying additional relevant studies through backward and forward citation analysis. This systematic approach ensures the selection of high-quality, scientifically relevant materials.

3. Distribution and Botanical Characterization

Based on botanical systematics, Achillea species belong to the Angiosperms, within the Eudicots clade, Campanulates order, Asteraceae family, Tubuliflorae subfamily, and Anthemideae tribe [37]. The Achillea genus comprises approximately 140 perennial herbaceous species worldwide [38]. These species are highly adaptable and thrive in diverse climates, particularly in semi-tropical, temperate, dry, and semi-arid regions [39]. They are commonly found in mountainous forests and steppes, exhibiting resilience in various soil conditions, including degraded lands and roadsides. Their adaptability is largely attributed to their ability to withstand moisture deficiency and direct sunlight, making them versatile in different environmental settings [37,40].
Among these species, A. nobilis is native to Europe, Asia, and parts of North Africa (Figure 3). Additionally, it has been reported to have been introduced into Great Britain, as well as several federal subjects of Russia, including Khabarovsk Krai, Primorye Krai, and Sakhalin. Moreover, its presence has been documented in the United States, specifically in Minnesota and Montana [41].
A. nobilis, commonly known as “noble yarrow”, is a perennial herbaceous plant reaching heights of 15–70 cm, with a rootstock that lacks stolons. Its stems are terete, longitudinally striped, and covered with spreading pilose hairs. The leaves are woolly-pubescent, with basal leaves being 2–3-pinnatipartite, oblong-lanceolate (2–10 × 1–3 cm) with a dentate rachis, while median cauline leaves are ovate-oblong to broadly ovate (2–5 × 1–3 cm), with primary segments regularly 1-pinnatifid to 1-pinnatisect. The species produces 50–150 capitula in dense corymbose inflorescences (2–10 cm wide), each capitulum being broadly obovoid to oblong (3–3.5 × 2–3 mm), with phyllaries ranging from triangular-lanceolate and acute to oblong and obtuse, covered in either sparse hairs or dense woolly-shaggy indumentum. The ligules are pale yellow above and white below (0.8–1.5(–2) mm), with 10–25 disk flowers per capitulum. Flowering occurs from June to August [42].

4. Uses of A. nobilis in Ethnomedicine

Plants constitute the principal healthcare resource in numerous communities globally [43]. They additionally function as vital sources for the advancement of biomedicines, and species traditionally utilized have made substantial contributions to the formulation of biomedical pharmaceuticals [44]. Statistical evidence indicates that traditional remedies, including phytotherapeutic agents, represent the most significant and at times the sole means of therapeutics for nearly 80% of the global population [45]. For example, approximately 85% of the global populace utilizes herbal medicines for both disease prevention and treatment, with demand rising in both developed and developing nations [46,47]. It is estimated that around 500 million individuals in South Asian countries alone seek health security through plant-based resources [44].
A. nobilis widely recognized for its medicinal properties, is one of the most notable examples of a plant extensively utilized in ethnomedicine across diverse cultures, where it has been traditionally employed for its anti-inflammatory, wound healing, and antimicrobial effects (Table 2) [48,49,50,51,52]. For instance, A. nobilis has been traditionally used in Bosnia and Herzegovina for treating bedwetting in children, blood purification, and various skin conditions, including injuries, rashes, and psoriasis. Moreover, its flower tincture has been widely applied, as it is believed to effectively restore the skin to its normal condition. This longstanding use highlights the plant’s significance in ethnomedicine for dermatological and internal health applications [48].
The seminal text Shipagerlik Bayan (“Confessions of a Healer”), authored by the esteemed Kazakh medical practitioner Oteyboydak Tleukabyl during the 15th century AD, provides a comprehensive exposition of the medical paradigms pertaining to pharmacology, anatomy, pathology, immunology, and nutritional care within the framework of Traditional Kazakh Medicine (TKM). Each of these paradigms constitutes a systematic framework comprising six principal components, specifically, kengistik tugyr (space), turak tugyr (earth), suwik tugyr (coldness), ystyk tugyr (heat), zharyk tugyr (light), and karangy tugyr (darkness) [53,54,55]. The foundations of ancient Kazakh folk medicine are rooted in the empirical observations and practical knowledge accrued over numerous generations. Traditionally, the array of medicinal flora utilized by the Kazakh populace was categorized into four primary classifications—fortifying, refreshing, warming, and laxative plants [55,56]—which were adeptly employed to address a variety of ailments, including bronchitis, bronchial asthma, urethritis, chronic rheumatoid arthritis, gastric discomfort, hyperacidity, diarrhea, hemostatic issues, metrorrhagia, envenomations from snake bites, and neoplastic diseases [56,57,58]. Among the diverse Achillea species, A. nobilis has been particularly noted within Kazakh folk medicine for its therapeutic application in treating urethritis and bronchitis. Additionally, its aqueous tincture has been employed in dermatological treatments for psoriasis [52].

5. Phytochemistry

Studying the phytoconstituents of A. nobilis is essential, particularly due to their pharmacological significance. However, a comprehensive literature survey indicates that the majority of phytochemical studies on A. nobilis employing various techniques and methodologies, were conducted between 1978 and 2020 (Table 3) [18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34]. This suggests a limited number of investigations dedicated to the plant’s chemical composition. Furthermore, an analysis of existing studies on A. nobilis and its subspecies (A. nobilis subsp. neilreichii and A. nobilis subsp. sipylea) reveals that most research has focused on water-based extracts. Additionally, studies have predominantly examined the aerial parts of the plant, with no reported investigations of the root composition. Consequently, A. nobilis and its subspecies exhibit a diverse array of phytochemicals, including phenolic compounds (flavonoids and flavonoid glycosides), terpenes (monoterpenes, oxygenated monoterpenes, sesquiterpenes), sesquiterpene lactones, guaianolides, and steroidal compounds (terpenoid derivatives).
Based on the literature, several compounds have been isolated from Achillea nobilis and its subspecies, including apigenin 7-glycoside [18], luteolin 7-glucoside [18], apigenin 7-glucuronide [18], the guaianolide estafiatin [19], hanphyllin [19], anobin [19], 3,5-dihydroxy-6,7,8-trimethoxyflavone [19], anolide [21], tanaparthin-β-peroxide [22], 5-hydroxy-3,6,7,4′-tetramethoxyflavone [22], chrysartemin A [22], canin [22,23], and chrysartemin [23]. These compounds were obtained through phytochemical isolation and characterized using standard techniques such as nuclear magnetic resonance (NMR) spectroscopy and mass spectrometry (MS). In comparison, the remaining compounds discussed in this review, which include phenolic compounds, terpenes and their derivatives, and other biologically active constituents, were identified based on analytical profiling or reported in the literature without direct isolation from A. nobilis.
Flavonoids are one of the primary categories of phytochemicals found in Achillea nobilis L. and its subspecies. Initial research by Solomko et al. [18] employing chromatographic and spectroscopic methods uncovered flavonoid glycosides such as apigenin-7-glucoside, luteolin-7-glucoside, and apigenin-7-glucuronide, from the non-flowering shoots of A. nobilis Follow-up studies by Adekenov et al. [19] and Krenn et al. [24] built upon these discoveries by recognizing flavonoid subclasses like 3,5-dihydroxy-6,7,8-trimethoxyflavone and quercetin-3-o-methyl ether from flower heads and aerial parts, respectively. In a more recent study, Taşkın et al. [33] revealed the existence of phenolic compounds like dicaffeoylquinic acid and several glycosylated derivatives of apigenin and luteolin in A. nobilis subsp. neilreichii, affirming the continued importance of flavonoids and phenolics in the phytochemistry of this group.
Various studies of A. nobilis and its subspecies have consistently reported monoterpenes, oxygenated monoterpenes, and sesquiterpene lactones. Palić et al. [25] discovered oxygenated monoterpenes, including α-thujone (25.7%) and borneol (9.9%), while Karamanendres et al. [26] and Ghani et al. [27] reported elevated concentrations of α-thujone, 1,8-cineole, and fragranol via GC–MS examinations of essential oils. Demirci’s research [28] further highlighted the prevalence of fragranol (24%) and β-eudesmol (8%) in the aerial parts. Additional research (e.g., Azizi et al. [30], Rustaiyan et al. [31], Kazemizadeh et al. [32]) verified the extensive occurrence of monoterpenes like cineole, camphor, and spathulenol. The headspace examination conducted by Ozdemir [34] similarly identified camphor and α-thujone as key volatile compounds. These terpenes are linked to various pharmacological effects, such as antimicrobial and anti-inflammatory properties.
The chemical makeup of A. nobilis differs not just by plant section but also by subspecies. For example, A. nobilis subsp. neilreichii exhibited a diverse range of monoterpenes and sesquiterpenes (e.g., Demirci [28], Ozdemir [34]), while A. nobilis subsp. nobilis and A. nobilis subsp. neilreichii were studied mainly for flavonoids and flavonoid glycosides (Valant-Vetschera [20]). These results indicate the presence of chemotypic variations among subspecies, probably shaped by genetic and environmental influences. These differences hold significant consequences for choosing suitable subspecies for medicinal or industrial uses.
A diverse array of extraction methods and solvents has been used to obtain secondary metabolites from A. nobilis. Previous research utilized comprehensive aqueous extraction (Solomko et al. [18]) and chloroform-based techniques (Adekenov et al. [19]), while subsequent studies embraced more focused methods, such as hydro-distillation (e.g., Ghani et al. [27], Kazemizadeh et al. [32]), headspace solid-phase micro-extraction (Ozdemir [34]), and ethanol-ethyl acetate solvent combinations (Taşkın et al. [33]). Analytical methods evolved over the decades, transitioning from UV and IR spectroscopy to more sophisticated techniques such as GC–MS, LC–MS/MS, and NMR spectroscopy. This methodological advancement indicates a wider movement towards high-resolution, multi-faceted characterization of plant metabolites.
Newer research from 2010 and later shows a distinct emphasis on thorough chemical profiling through contemporary methods. For example, Azizi et al. [30] and Rustaiyan et al. [31] conducted GC–MS analyses on the aerial components, pinpointing significant monoterpenes and sesquiterpenes. Kazemizadeh et al. [32] enhanced this method by examining both leaves and flowers, whereas Taşkın et al. [33] utilized LC–MS/MS to detect phenolic components. Ozdemir’s latest study [34] utilized HS–SPME/GC–MS for identifying volatile compounds in A. nobilis subsp. neilreichii. These investigations highlight a transition towards accurate, quantitative analysis of intricate phytochemical mixtures, with increasing attention on essential oils and phenolics.
Grasping the chemical makeup of A. nobilis and its subspecies has important consequences for the pharmaceutical sciences. Flavonoids such as apigenin and luteolin, found in various studies, display strong antioxidant, anti-inflammatory, and anticancer effects [54]. Likewise, monoterpenes like α-thujone and 1,8-cineole exhibit antimicrobial and neuroprotective properties, positioning them as potential candidates for therapeutic advancement [56]. Additionally, phenolic acids and their derivatives might play a role in cardiovascular protection and metabolic regulation [57]. Therefore, thorough phytochemical analysis bolsters the creation of evidence-backed herbal treatments and increases the significance of traditional medicinal flora in contemporary healthcare.
Although significant advancements have been made, there are still numerous gaps in the chemical profiling of A. nobilis and its subspecies. Interestingly, the plant’s roots remain unexplored, and the majority of research has combined aerial components (leaves, stems, and flowers) without conducting separate assessments. This restricts our comprehension of the biosynthetic abilities specific to organs. Studies indicate that various plant components can generate unique metabolite profiles as a result of different metabolic pathways and ecological roles [58]. Thus, upcoming research should focus on the separate examination of specific organs, such as stems, roots, and flowers, to completely clarify the phytochemical variation of the species.
To thoroughly investigate the chemical profile of A. nobilis and its subspecies, future studies should employ a multi-omics strategy that combines metabolomics, transcriptomics, and chemotaxonomy. Sophisticated methods like UHPLC–HRMS, MALDI–TOF imaging, and molecular networking may reveal new bioactive compounds. Moreover, investigations of seasonal and geographical variations should be carried out to assess the stability of chemotypes in different environments. Partnerships with pharmacologists and bioinformaticians will be crucial for connecting phytochemicals to particular bioactivities. These integrative studies will enhance the phytochemical profile of A. nobilis and promote its thoughtful use in pharmaceuticals and nutraceuticals.

5.1. Phenolic Compounds

Phenolic compounds, including phenolic acids and flavonoids, are widely recognized for their antioxidant and anti-inflammatory characteristics, which may confer protective effects against malignancies, metabolic disorders such as diabetes, and neurodegenerative conditions [59,60,61]. Moreover, flavonoids, classified as a subclass of phenolic compounds, exhibit an extensive array of pharmacological properties, encompassing antioxidant, anti-inflammatory, anticancer, and cardioprotective effects [62]. Flavonol glycosides possess analogous attributes and are particularly investigated for their antioxidant and anti-inflammatory capabilities [63]. Furthermore, they also demonstrate anti-inflammatory, anticancer, and cardiovascular protective properties [64]. These compounds, which are plentiful in the natural environment, present a promising pathway for the innovation of novel therapeutic agents (Table 4, Compounds 1–23) [65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88].
Flavonoid glucuronides such as apigenin-7-O-glucuronide (Compound 11) and luteolin-7-O-glucuronide (Compound 12) derived from A. nobilis demonstrate strong anti-inflammatory and neuroprotective properties. Compound 11 suppresses the production of nitric oxide and tumor necrosis factor-alpha in LPS-activated macrophages, suggesting significant immunomodulatory capabilities [65]. Compound 12 modulates microglial polarization and enhances endogenous antioxidant pathways, offering antidepressant, neuroprotective, and anti-inflammatory benefits [66]. It also displays antibacterial and anticancer effects by inhibiting reactive oxygen species and biofilm formation while modulating critical pathways such as MET/AKT/mTOR [67].
Methoxylated flavones, including 3,5-dihydroxy-6,7,8-trimethoxyflavone (Compound 13) and 5-hydroxy-3,6,7,4′-tetramethoxyflavone (Compound 18) from A. nobilis have shown enhanced anticancer effects, particularly when combined with 5-fluorouracil, resulting in reduced off-target toxicity in colon and pancreatic cancer treatments [71]. C-glycosylflavones such as vitexin (Compound 3, Figure 4), isovitexin (Compound 14), swertisin (Compound 15), orientin (Compound 1, Figure 4), and isoorientin (Compound 2, Figure 4), isolated from A. nobilis subsp. neilreichii, exhibit a wide range of pharmacological effects. These include antioxidant, anti-inflammatory, neuroprotective, cardioprotective, antidiabetic, anticancer, hepatoprotective, and anxiolytic activities [72,73,74,75]. Swertiajaponin (Compound 16), a C-methylated glycoside, has been implicated in the alleviation of metabolic syndromes such as hyperglycemia, hyperlipidemia, and insulin resistance [76], highlighting its therapeutic potential for metabolic disorders.
Flavonoids like quercetin-3-O-rhamnoside-7-O-glucoside (Compound 17) and quercetin-3-O-methylether-7-O-β-glucopyranoside (Compound 9, Figure 4) demonstrate strong antioxidant activities. Quercetin-3-O-rhamnoside-7-O-glucoside (Compound 17) inhibits polyphenol oxidase, preventing enzymatic browning, and enhances food antioxidant properties [77]. Quercetin-3-O-methylether-7-O-β-glucopyranoside (Compound 9, Figure 4) shows protective effects against oxidative stress and in breast cancer models by inducing apoptosis and modulating PI3K/Akt and MAPK/Erk signaling pathways [82,83,84]. Luteolin (Compound 19) and isorhamnetin-3-O-glucoside (Compound 20) obtained from A. nobilis subsp. neilreichii also exhibit potent antioxidant, anti-inflammatory, and antiproliferative activities in endothelial and cancer cells, primarily through the STAT3 pathway and suppression of epithelial–mesenchymal transition (EMT) [85,86]. These compounds collectively enhance the plant’s medicinal potential through their multi-target bioactivities.
Among phenolic acids, dicaffeoylquinic acid (Compound 22) and chlorogenic acid (Compound 23) exhibit significant bioactivities. Compound 22 demonstrates antioxidant, anti-inflammatory, antimicrobial, cardioprotective, hepatoprotective, and antispasmodic properties, proving beneficial in the treatment of respiratory and metabolic disorders [87]. Compound 23, an ester of hydroxycinnamic acid, has a wide range of pharmacological effects, including antibacterial, antiviral, anti-obesity, antihypertensive, antipyretic, and CNS-stimulating activities [88]. It also regulates lipid and glucose metabolism, making it useful in managing cardiovascular disease, diabetes, and obesity.
Several compounds such as luteolin-4-O-β-glucopyranoside (Compound 6, Figure 4), luteolin-6-C-apiofuranosyl-(1”→2”)-glucopyranoside (Compound 7, Figure 4), apigenin-6,8-di-C-glucoside (Compound 21), and quercetin-3-O-[α-arabinopyranosyl-(1”→6”)-β-glucopyranoside] (Compound 10, Figure 4) currently lack comprehensive pharmacological data (Figure 4). However, due to their structural similarity to well-characterized flavonoids such as luteolin and quercetin, they are hypothesized to possess antioxidant, anti-inflammatory, and neuroprotective activities. Studies have shown that C- and O-glycosylation enhance flavone stability and bioactivity, improving their modulatory effects on oxidative stress and inflammatory pathways [65,66,85]. Moreover, glycosidic modifications may enhance solubility and absorption, suggesting favorable pharmacokinetic profiles for future therapeutic applications [89,90,91,92,93,94,95,96,97,98,99,100,101,102,103].

5.2. Terpenes and Derivatives

A literature review revealed that A. nobilis and its subspecies, such as A. nobilis subsp. sipylea and A. nobilis subsp. neilreichii, contain a total of 157 terpene and terpene-derived compounds (Table 5). These substances are divided into various chemical categories: terpenes, terpenoids, sesquiterpenes, and derivatives of sesquiterpenoids. The chemical components were mainly extracted from different plant sections, including flower heads, aerial portions, and leaves, showcasing the plant’s abundant phytochemical diversity and the structural variety of its secondary metabolites. This wide range of terpenoid composition emphasizes the potential of A. nobilis and its subspecies as important sources of bioactive natural compounds.
A significant variety of terpenoids from A. nobilis display marked anti-inflammatory and antioxidant properties. For example, artemetin and caryophyllene oxide exhibit significant anti-inflammatory effects by blocking proinflammatory enzymes and mediators, which helps lower oxidative stress in multiple inflammatory models [105,112]. Carvacrol and thymol are crucial in managing inflammation by inhibiting NF-κB and MAPK pathways, and they have demonstrated effectiveness in decreasing oxidative damage, positioning them as promising options for treating inflammatory diseases [115,117]. Borneol exhibits synergistic anti-inflammatory properties and improves the bioavailability of concurrently administered anti-inflammatory agents [119]. These substances play a major role in the conventional application of A. nobilis for addressing inflammation-related ailments.
Multiple terpenes found in A. nobilis and its subspecies have demonstrated anticancer properties. Significantly, β-caryophyllene and caryophyllene oxide promote apoptosis and hinder cancer cell proliferation by affecting various signaling pathways, such as the PI3K/Akt axis [109,112]. Additionally, thymol and borneol have shown cytotoxic properties against several cancer cell lines, such as liver and breast cancer, with proof indicating their capability to induce cell cycle arrest and apoptosis [117,119]. Camphor, while mainly recognized for its antimicrobial properties, has also demonstrated potential cytostatic effects in cancer studies [120]. These results emphasize the therapeutic potential of A. nobilis terpenes in cancer prevention and therapy.
A significant amount of evidence backs the antimicrobial and antiviral properties of A. nobilis terpenes. Camphor, borneol, thymol, and carvacrol have shown significant antimicrobial properties against Gram-positive and Gram-negative bacteria, along with fungi [115,117,119]. Thymol and carvacrol specifically display membrane-disrupting characteristics that hinder microbial survival and biofilm development. Furthermore, sabinene and β-pinene have demonstrated antiviral properties by disrupting viral replication processes, aligning with the application of essential oils in traditional medicine for addressing respiratory and viral illnesses [113,114]. These terpenoids could function as useful substitutes for synthetic antimicrobial substances.
Certain terpene compounds derived from A. nobilis are noted to exert positive effects on the central nervous system. Thymol has been demonstrated to have anxiolytic and neuroprotective properties by influencing GABAergic neurotransmission and diminishing oxidative damage to neurons [117]. Borneol has shown notable neuroprotective effects, in part because it can traverse the blood–brain barrier and improve drug transport to the brain [119]. In a similar manner, β-caryophyllene engages with cannabinoid receptors and demonstrates anxiolytic, antidepressant, and neuroprotective effects [109]. These results indicate a possible function for A. nobilis terpenoids in the treatment of neurodegenerative diseases and mental health therapies.
Besides the primary therapeutic areas mentioned earlier, various terpenoids exhibit a range of bioactivities. For instance, thujone and sabinene have shown insecticidal and antifeedant properties that are beneficial in pest control [122]. Myrtenol and camphene show gastroprotective and antispasmodic properties, which could be helpful for gastrointestinal issues [110,121]. Additionally, α-pinene and β-pinene exhibit bronchodilatory and mucolytic properties, aiding their application in respiratory disorders [113]. While certain compounds like aristolone and germacrene D remain inadequately researched, their structural resemblance to active terpenes implies probable antioxidant and anti-inflammatory functions. These adaptable pharmacological characteristics endorse the multifunctional capabilities of A. nobilis terpenes in clinical and ethnopharmacological uses.

5.3. Other Biologically Active Compounds

Other biologically active compounds identified in A. nobilis and its subspecies include simple hydrocarbons, fatty alcohols, fatty acids, heterocyclic compounds, and simple ketones, all of which contribute to the plant’s diverse pharmacological potential (Table 6). Among these, 1-octadecanol (Compound 26) stands out due to its antibacterial, anti-inflammatory, emollient, and mucosal-protective characteristics, which support its use in vaginal drug delivery systems and various mucosal therapeutic formulations [159,160]. Hexadecanoic acid (Compound 27), commonly referred to as palmitic acid, has been shown to promote the growth of bone marrow mesenchymal stem cells and displays various pharmacological properties, such as antimicrobial, antioxidant, anti-inflammatory, anticancer, hypocholesterolemic, and skin-protective effects. This establishes it as a significant bioactive lipid for therapeutic advancements [161]. Likewise, dillapiol (Compound 29) has demonstrated antimicrobial and antifungal properties, indicating its relevance in the development of antimicrobial medications and natural preservation methods [162]. Additional compounds extracted from A. nobilis also show specific pharmacological effects. For instance, isovaleric acid (Compound 30) has been reported to improve ovariectomy-induced osteoporosis by suppressing osteoclast differentiation, suggesting its potential use in managing bone health after menopause [163]. This supports the inclusion of isovaleric acid among clinically significant bioactives for bone metabolism and osteoporosis-related conditions.
On the other hand, several compounds found in A. nobilis such as tricosane (Compound 24), hexadecanol (Compound 25), indipone (Compound 28), adamantane-1,3-dimethyl (Compound 31), 3-chloro-4-tert-butyl-6-phenylpyridazin (Compound 32), and pentadecanone (Compound 33), currently do not have documented pharmacological activity according to the existing literature. Although these compounds have not been extensively studied, their structural features and chemical classifications suggest potential biological activity. For example, alkanes such as tricosane and ketones like pentadecanone frequently occur in essential oils recognized for their insect-repellent or antimicrobial properties, while pyridazine derivatives are being explored for their anti-inflammatory and anticancer effects. Therefore, future bioactivity-oriented studies are needed to determine the medicinal relevance of these lesser-known compounds.

6. Pharmacological Effects Studies on A. nobilis and Its Subspecies

Achillea nobilis L. and its subspecies (A. nobilis subsp. neilreichii and A. nobilis subsp. sipylea) have garnered growing scientific interest owing to their extensive array of bioactive compounds and varied pharmacological characteristics, establishing them as a potential natural shield against a broad range of pathological issues, as demonstrated by their various pharmacological effects (Figure 4). Notably, the ethanolic extract of A. nobilis demonstrated significant anticonvulsant potential in preclinical models. In a comparative study using maximal electroshock (MES), pentylenetetrazole (PTZ), and strychnine nitrate (STN)-induced seizure models in rats, A. nobilis extract exhibited dose-dependent anticonvulsant effects, particularly at 200 and 300 mg/kg doses. Specifically, in the MES and PTZ-induced convulsion tests, the extract delayed the onset of seizures and reduced seizure duration, indicating central nervous system depressant activity. Moreover, at a dose of 300 mg/kg, A. nobilis provided 60% protection against STN-induced seizures, suggesting its potential role in modulating glycine-mediated neurotransmission. However, lower doses (100 and 200 mg/kg) did not show significant protection in the STN model, highlighting a possible threshold for efficacy. Consequently, these findings support the potential of A. nobilis as a natural source of anticonvulsant agents and warrant further investigation into its active constituents and mechanisms of action [164].
Another study revealed that the ethanol extract of A. nobilis subsp. neilreichii has noteworthy antinociceptive and anti-inflammatory effects, highlighting its possible therapeutic importance in managing pain and inflammation. The extract produced a significant antinociceptive response during the later phase of the formalin test at doses of 100, 200, and 400 mg/kg (i.p.), demonstrating its efficacy in alleviating inflammatory pain. Furthermore, it demonstrated anti-inflammatory effects in the carrageenan-induced paw edema model, especially at 100 and 200 mg/kg, indicating the suppression of acute inflammatory reactions. Nonetheless, no notable antinociceptive effect was noted in the tail-flick test, suggesting restricted effectiveness in altering spinal reflexes to thermal stimuli. Importantly, the administration of 400 mg/kg lengthened the latency on the hot-plate test at 60 and 90 min, indicating possible central analgesic effects without impairing sensory motor function. Additionally, the extract showed a significant safety margin, exhibiting an intraperitoneal LD50 value of 4456 mg/kg in mice. As a result, these results emphasize the anti-inflammatory and mild analgesic effects of A. nobilis subsp. neilreichii, endorsing its continued investigation in pain management studies [165].
Additionally, the research examined the antispasmodic properties of the total extract from A. nobilis subsp. sipylea on isolated rat duodenum, offering pharmacological support for its historical use in treating gastrointestinal spasms. The extract was assessed via a range of experiments that included cumulative dose–response curves for acetylcholine (ACh) and calcium chloride (CaCl2), conducted both without and with established spasmolytic agents like atropine, papaverine, and verapamil. The findings showed that the extract had a concentration-dependent inhibitory effect on contractions induced by ACh and CaCl2, noticeably decreasing the maximum contractile responses of the duodenal tissue. Significantly, this effect resembled that of papaverine and verapamil, but was different from atropine, indicating a mechanism of action that does not depend on muscarinic receptor antagonism and is more likely related to direct relaxation of smooth muscle or modulation of calcium channels. Additionally, the extract reduced K+-induced contractions, highlighting its muscle-relaxing properties. As a result, these results suggest that A. nobilis subsp. sipylea has significant antispasmodic properties, probably through the disruption of calcium influx and smooth muscle contractions, and may offer potential therapeutic benefits for gastrointestinal issues marked by hypermotility or spasms [166].
The protective benefits of Achillea species indigenous to Turkey, such as A. nobilis subspecies, have been studied regarding oxidative stress caused by hydrogen peroxide (H2O2) in human erythrocytes and leucocytes. This research assessed the antioxidant capacity of infusions made from 15 Achillea species, which are commonly used in traditional Turkish medicine, by measuring their effect on vital antioxidant enzymes—catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GPx)—along with lipid peroxidation (LPO) and glutathione (GSH) concentrations. The findings revealed that all Achillea infusions provided considerable protective benefits against oxidative damage induced by H2O2 by boosting the function of antioxidant defense systems in both erythrocytes and leucocytes. Significantly, A. falcata was the most potent in improving CAT, SOD, and GPx activities in red blood cells. Among the infusions tested, A. crithmifolia and A. nobilis subsp. neilreichii showed the greatest stimulation of CAT activity in leukocytes, while A. millefolium subsp. pannonica was the most effective for SOD, and A. teretifolia for GPx. Moreover, A. nobilis subsp. sipylea and A. setacea exhibited the most significant protective effects on LPO levels in leucocytes, while A. millefolium subsp. pannonica and A. falcata showed the least LPO levels in erythrocytes. As a result, these results indicate that Achillea species, especially the A. nobilis subspecies, serve as a valuable source of natural antioxidants that may be useful in the prevention and management of diseases linked to oxidative stress [167].
The essential oils extracted from A. nobilis subsp. sipylea and A. nobilis subsp. neilreichii show different levels of antibacterial and antifungal effects against various clinically significant microorganisms, with A. nobilis subsp. sipylea displaying the strongest antimicrobial capability. This subspecies exhibited significant antifungal properties against Candida albicans, resulting in an inhibition zone of 41 mm, and also demonstrated considerable antibacterial effects against Escherichia coli, Staphylococcus aureus, and Salmonella typhimurium, with inhibition zones varying from 12 to 15 mm. Conversely, essential oils obtained from A. nobilis subsp. neilreichii, gathered from various geographic sites, showed diminished antimicrobial properties; however, there was still some activity, especially against Gram-positive bacteria like Staphylococcus epidermidis and S. aureus. None of the essential oils evaluated were successful against Pseudomonas aeruginosa, renowned for its significant inherent resistance [27]. While the antimicrobial effectiveness of these essential oils was typically less than that of standard antibiotics like amoxicillin and sulbactam/ampicillin, the findings still indicate significant biological activity [141,164]. These results back the possible application of A. nobilis, especially subsp. sipylea, as a hopeful natural source of antimicrobial compounds, with regional differences in chemical makeup probably explaining variations in effectiveness [26,27]. Another study assessed the antibacterial properties of various extracts from A. nobilis subsp. neilreichii against S. aureus ATCC 25923, emphasizing how the extraction method and solvent type influence antimicrobial effectiveness. The Soxhlet extracts, especially those derived from ethyl acetate and chloroform, exhibited the strongest activity, showing minimum inhibitory concentrations (MICs) of 3.1 µg/mL and 3.87 µg/mL, respectively. Conversely, extracts obtained via ultrasonic bath with chloroform and maceration with n-hexane, chloroform, or ethanol exhibited lesser effects, resulting in MIC values surpassing 5 µg/mL and exceeding 6.25 µg/mL in certain instances. These findings indicate that Soxhlet extraction using semi-polar solvents improves the extraction of antibacterial compounds from the plant material. Furthermore, while the plant extracts were not as effective as the standard antibiotic meropenem (MIC, 0.012 µg/mL), they still suggest that A. nobilis subsp. neilreichii could be a valuable source of natural antibacterial compounds, especially when suitable extraction techniques are utilized [33].
While the cited pharmacological studies on A. nobilis and its subspecies provide valuable insights into their biological activities, several limitations should be acknowledged. Most experiments have been conducted using in vivo rodent models or basic in vitro assays, with limited mechanistic investigations to identify specific molecular targets. Additionally, many studies rely on crude extracts rather than purified compounds, which makes it difficult to determine which constituents are responsible for the observed effects. The sample sizes and control designs are sometimes insufficiently described, and variations in extraction methods may lead to inconsistent results across studies.
Importantly, a comprehensive literature review using multiple scientific databases (as detailed in the methodology section) found no published human clinical studies investigating A. nobilis or its subspecies. This significant gap indicates that the species is underexplored in clinical research, and highlights the need for rigorous human trials to validate its safety, efficacy, and therapeutic relevance. Furthermore, comprehensive toxicity and pharmacokinetic evaluations are lacking, and most studies do not assess long-term safety. These limitations underscore the need for standardized experimental protocols and advanced preclinical and clinical research to support the integration of A. nobilis and its bioactive components into evidence-based pharmaceutical and nutraceutical applications.

7. Conclusions

This review highlights the ethnomedicinal importance of A. nobilis and its subspecies (A. nobilis subsp. neilreichii and A. nobilis subsp. sipylea), which have been esteemed for ages in conventional medical practices. These plants have been extensively used to address a range of issues, such as inflammation, pain, infections, spasms, and convulsions. Their application in decoctions, oils, and infusions showcases the vibrant cultural history related to their therapeutic uses. Although there is extensive traditional usage, scientific investigation into their pharmacological mechanisms and bioactive components is still incomplete.
Existing phytochemical investigations show that A. nobilis comprises a variety of compounds, particularly flavonoids, flavonoid glycosides, monoterpenes, sesquiterpenes, sesquiterpene lactones, and terpenoid derivatives. These substances are associated with noteworthy pharmacological impacts, including antioxidant, antibacterial, antifungal, anti-inflammatory, antinociceptive, antispasmodic, central analgesic, and anticonvulsant effects. The existence of these bioactive compounds not only confirms traditional applications but also establishes the plant as a strong contender for drug development. Nonetheless, the majority of research has focused on water-based extracts and above-ground portions, with minimal emphasis on the chemistry specific to roots or variations within organs.
As indicated in the summarized pharmacological profile, A. nobilis and its varieties display a wide range of bioactivities. However, these effects differ based on subspecies, part of the plant, and extraction technique. Significant chemotypic variation is impacted by environmental and genetic influences, necessitating accurate chemotaxonomic and organ-specific evaluations. Incorporating multi-omics strategies, including metabolomics, transcriptomics, and sophisticated analytical methods (e.g., UHPLC–HRMS, MALDI–TOF), will be crucial for thoroughly charting the metabolite profile of this species and linking it to pharmacological results.
In summary, this review emphasizes the medical potential and overlooked research prospects related to A. nobilis and its subspecies. Future research should focus on examining underexplored plant components such as roots, assess seasonal and geographical impacts on phytochemical variations, and create solid pharmacological connections through interdisciplinary teamwork. Such initiatives will yield important understanding for the evidence-driven use of these plants in contemporary pharmacology and nutraceutical development.

Author Contributions

Conceptualization, A.A. (Akerke Amirkhanova), A.A. (Aiman Аkhelova), A.S., S.N., A.M., A.K., R.D., K.R. and Y.I.; methodology, L.S.; software, M.K. and A.T.; data curation, G.S., A.K. and A.A. (Akerke Amirkhanova); writing—original draft preparation, A.S., A.A. (Akerke Amirkhanova), A.A. (Aiman Аkhelova), A.S., S.N., A.M. and M.K.; writing—review and editing, A.S., R.D., K.R., Y.I., A.T., A.K. and A.A. (Akerke Amirkhanova); supervision, A.S. and A.A. (Akerke Amirkhanova). All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

No new data were created or analyzed in this study. Data sharing is not applicable to this article.

Conflicts of Interest

The authors declare no conflicts of interest.

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Molecules 30 02460 g001
Figure 1. Pharmacological effects of A. nobilis and its subspecies.
Figure 1. Pharmacological effects of A. nobilis and its subspecies.
Molecules 30 02460 g001
Molecules 30 02460 g002
Figure 2. Schematic representation of the database search process for identifying and selecting publications in a systematic review (MES: medicinal and ethnobotanical significance).
Figure 2. Schematic representation of the database search process for identifying and selecting publications in a systematic review (MES: medicinal and ethnobotanical significance).
Molecules 30 02460 g002
Molecules 30 02460 g003
Figure 3. The distribution of A. nobilis (Green indicates the native distribution) [41]. The map was created using Microsoft Excel based on publicly available distribution data.
Figure 3. The distribution of A. nobilis (Green indicates the native distribution) [41]. The map was created using Microsoft Excel based on publicly available distribution data.
Molecules 30 02460 g003
Molecules 30 02460 g004
Figure 4. Chemical structures of selected flavone and flavonol glycoside derivatives identified in Achillea nobilis L. and its subspecies [24]. Compound 1: orientin; Compound 2: isoorientin; Compound 3: vitexin; Compound 4: isoschaftoside; Compound 5: luteolin-7-O-β-glucuronide; Compound 6: luteolin-4-O-β-glucopyranoside; Compound 7: luteolin-6-C-apiofuranosyl-(1 → 2)-glucopyranoside; Compound 8: quercetin-3-O-methyl ether; Compound 9: quercetin-3-O-methylether-7-O-β-glucopyranoside; Compound 10: quercetin-3-O-[α-arabinopyranosyl-(1 → 6)-β-glucopyranoside].
Figure 4. Chemical structures of selected flavone and flavonol glycoside derivatives identified in Achillea nobilis L. and its subspecies [24]. Compound 1: orientin; Compound 2: isoorientin; Compound 3: vitexin; Compound 4: isoschaftoside; Compound 5: luteolin-7-O-β-glucuronide; Compound 6: luteolin-4-O-β-glucopyranoside; Compound 7: luteolin-6-C-apiofuranosyl-(1 → 2)-glucopyranoside; Compound 8: quercetin-3-O-methyl ether; Compound 9: quercetin-3-O-methylether-7-O-β-glucopyranoside; Compound 10: quercetin-3-O-[α-arabinopyranosyl-(1 → 6)-β-glucopyranoside].
Molecules 30 02460 g004
Table 1. The number of searches for each keyword.
Table 1. The number of searches for each keyword.
Platforms Keywords Total
A. nobilisA. nobilis
Phytochemicals 		A. nobilis
Compounds 		A. nobilis
Pharmacological 		A. nobilis
Traditional use 		A. nobilis
Ethnomedicine
Scopus300000030
Pubmed171851133
Google Scholar14,200238035702100337070426,324
Web of Science73123150103
ScienceDirect9671355214320371093
JSTOR121013070141
Science.gov202122241701468762
BASE43315813162523
“0” means not found.
Table 2. Ethnomedicinal use of A. nobilis in different cultures.
Table 2. Ethnomedicinal use of A. nobilis in different cultures.
CountryPlant PartEthnomedicinal Use(s)Ref.
Bosnia and Herzegovinaflowermanaging nocturnal enuresis in children, cleansing the blood, and addressing a range of dermatological issues (wounds, irritations, and psoriasis)[48]
Iranabove-ground partantiparasitic, wound-healing and anti-infective agent[49]
Turkeyabove-ground partabdominal pain and flatulence[50]
Chinaroottreating hypertension [51]
Kazakhstanabove-ground parttreating urethritis, bronchitis, and psoriasis[52]
Table 3. Phytochemical composition studies of A. nobilis and its subspecies.
Table 3. Phytochemical composition studies of A. nobilis and its subspecies.
YearSpeciesPlant of PartMethods of ExtractionExtractTechniques/MethodsIdentified Chemical ClassesMajor CompoundsRef.
1978A. nobilisNon-Flowering ShootshydrodistillationwaterChromatographic analysis, UV and IR spectraflavonoidsapigenin-7-glycoside (cosmosiin), luteolin-7-glucoside (cynaroside)[18]
1984A. nobilisFlower Headscolumn chromatographychloroformIR, PMR, MSterpenes, flavonoidsanobin, estafiatin, hanphyllin, 3,5-dihydroxy-6,7,8-trimethoxyflavone[19]
1987A. nobilis subsp. nobilis, A. nobilis subsp. nedrelchllLeavesN/SN/STLC, UV, NMRflavonoid glycosidesvitexin, orientin, isoorientin, di-C-glycosylapigenins, isovitexin, swertiajaponin, di-C-glycosylluteolins, C-glycosylflavone[20]
1994A. nobilisAerial ParthydrodistillationwaterIR, UV, PMR, NMR, X-raysesquiterpene lactonesanolide[21]
1995A. nobilisFlower Headscolumn chromatographyN/SMS, 1H-NMR, 13C-NMR, 2D-NMRguaianolides, monoterpenestanaparthin-β-peroxide, 5-hydroxy-3,6,7,4′-tetramethoxyflavone[22]
1999A. nobilisAerial Partaqueous extraction, silica gel chromatographyhexane-ethyl acetateIR, PMRsesquiterpene lactoneschrysartemin a, canin[23]
2003A. nobilisAerial Partmethanol extractionmethanolUV, 1H-NMR, 13C-NMR, ESI–MSflavonoidsluteolin-6-c-apiofuranosyl-(1′′′ --> 2′′)-glucoside, orientin, quercetin-3-o-methyl ether[24]
2003A. nobilisFlower HeadshydrodistillationwaterGC–MSmonoterpenes, oxygenatedα-thujone (25.7%), artemisia ketone (14.8%), borneol (9.9%) and camphor (8.2%)[25]
2007A. nobilis subsp. sipylea, A. nobilis subsp. neilreichiiFlower HeadshydrodistillationwaterGC–MSmonoterpenes, oxygenated monoterpenes, sesquiterpenesfragranol, dihydro-eudesmol, linalool, chrysanthenone[26]
2008A. nobilisAerial ParthydrodistillationN/SGC, GC–MSmonoterpenes, sesquiterpenesα-thujone (34.06%), 1,8-cineole (14.14%) and β-cedren epoxide (9.63%)[27]
2009A. nobilis subsp. nobilis, A. nobilis subsp. neilreichiiAerial Parthydrodistillation (Clevenger-type apparatus)N/SGC, GC–MSmonoterpenes, sesquiterpenesfragranyl acetate (32%), fragranol (24%), and β-eudesmol (8%)[28]
2010A. nobilisAerial Parthexane extraction, column chromatographyhexaneIR, PMR, 13C-NMRsteroidal compoundsacetyleucanbin[29]
2010A. nobilisAerial ParthydrodistillationdichloromethaneGC–MSmonoterpenes, sesquiterpenesα-thujone, 1,8-cineole, artemisia ketone[30]
2011A. nobilisAerial ParthydrodistillationmethanolGC, GC–MSoxygenated monoterpenes,artemisia ketone, 1,8-cineole, yomogi alcohol, spathulenol[31]
2011A. nobilisLeaves, Flowershydrodistillation (Clevenger-type apparatus)N/SGC, GC–MSmonoterpenes, sesquiterpenes1,8-cineole, geranyl isovalerate, trans-verbenol[32]
2018A. nobilis subsp. neilreichii (Kerner)Aerial Partethanol and ethyl acetate extractionethanol, ethyl acetateHPLC–DAD, LC–MS/MSphenolic compoundsdicaffeoylquinic acid, luteolin-7-o-glucoside, apigenin-6,8-di-c-glucoside[33]
2019A. nobilis subsp. neilreichiiAerial Partsolid-phase micro-extractionN/SHS–SPME/GC–MSmonoterpenes, sesquiterpenescamphor, germacrene d, 1,8-cineole, α-thujene[34]
Here, UV: Ultraviolet Spectroscopy; IR: Infrared Spectroscopy; PMR: Proton Magnetic Resonance (another term for 1H-NMR); MS: Mass Spectrometry; TLC: Thin-Layer Chromatography; NMR: Nuclear Magnetic Resonance; 1H-NMR: Proton Nuclear Magnetic Resonance; 13C-NMR: Carbon-13 Nuclear Magnetic Resonance; 2D-NMR: Two-Dimensional Nuclear Magnetic Resonance; ESI-MS: Electrospray Ionization Mass Spectrometry; GC–MS: Gas Chromatography–Mass Spectrometry; GC: Gas Chromatography; HPLC-DAD: High-Performance Liquid Chromatography with Diode-Array Detection; LC–MS/MS: Liquid Chromatography–Tandem Mass Spectrometry; HS-SPME/GC-MS: Headspace Solid-Phase Microextraction Gas Chromatography–Mass Spectrometry; HPLC: High-Performance Liquid Chromatography; HS-SPME: Headspace Solid-Phase Microextraction; N/S: not specified.
Table 4. Phenolic compounds found in A. nobilis and its subspecies.
Table 4. Phenolic compounds found in A. nobilis and its subspecies.
No.CompoundsPlant Species Investigated Plant Part Chemical Class (Subclass) Chemical Structure Known Pharmacological Activities
1Apigenin 7-glucuronide [18]A. nobilisLeaves/flowersFlavonoid (Flavone glucuronide)Molecules 30 02460 i001Compound 11significantly inhibited nitric oxide (NO) production in LPS-stimulated macrophages (RAW264.7) (at 1 μg/mL, NO inhibition was 30.7%; at 10 μg/mL, NO inhibition reached 97.1%); also reduced tumor necrosis factor-alpha (TNF-α) production (at 5 μg/mL, TNF-α inhibition was 26.2%, at 10 μg/mL, TNF-α inhibition was 83.8%) [65,68,69,70]
2Luteolin 7-glucoside (cynaroside) [18]A. nobilisLeaves/flowersFlavonoid (Flavone glycoside)Molecules 30 02460 i002
Compound 12		exhibits antidepressant, anti-inflammatory, anti-ferroptotic, and neuroprotective effects by modulating microglial M1 polarization and the IRF1/SLC7A11/GPX4 signaling pathway in LPS-stimulated BV-2 cells and CUMS-induced mice [66]; shows antibacterial, antifungal, antileishmanial, antioxidant, hepatoprotective, antidiabetic, anti-inflammatory, anticancer, and anti-apoptotic activities, including inhibition of ROS, biofilm formation, and the MET/AKT/mTOR pathway [67]
33,5-Dihydroxy-6,7,8-Trimethoxyflavone [19]A. nobilisLeaves/flowers Flavonol Molecules 30 02460 i003
Compound 13		synergizes with 5-fluorouracil, allowing for dose reduction and reduced off-target toxicity in the treatment of colonic and pancreatic cancers [71]
4Vitexin [20,24]A. nobilis subsp. nobilis, A. nobilis subsp. neilreichiiLeavesFlavonoid (C-glycosylflavoneSee Figure 3
Compound 3		exhibits antioxidant, anti-inflammatory, neuroprotective, cardioprotective, anticancer, anxiolytic, antidiabetic, hepatoprotective, antimicrobial, antithyroid, analgesic, and anti-osteoporotic activities [72]
5Isovitexin [20]A. nobilis subsp. nobilis, A. nobilis subsp. neilreichiiLeavesFlavonoid (C-glycosylflavone)Molecules 30 02460 i004
Compound 14		exhibits antioxidant, anti-inflammatory, neuroprotective, anticancer, antidiabetic, cardioprotective, hepatoprotective, antimicrobial, and anti-anxiety activities [73]
6Swertisin [20]A. nobilis subsp. nobilis, A. nobilis subsp. neilreichiiLeavesFlavonoid (C-glycosylflavone)Molecules 30 02460 i005
Compound 15		exhibits antioxidant, anti-inflammatory, anticancer, hepatoprotective, antidiabetic, neuroprotective, and anti-obesity activities [74]
7Orientin [20,24]A. nobilis subsp. nobilis, A. nobilis subsp. neilreichiiLeavesFlavonoid (C-glycosylflavone)See Figure 3
Compound 1		exhibits anticancer, antioxidant, neuroprotective, cardioprotective, antiallergic, and anti-inflammatory [75]
8Isoorientin [20,24]A. nobilis subsp. nobilis, A. nobilis subsp. neilreichiiLeavesFlavonoid (C-glycosylflavone)See Figure 3
Compound 2		exhibits antioxidant and anti-inflammatory activities and plays a key role in ameliorating metabolic complications such as hyperglycemia, hyperlipidemia, and insulin resistance [76]
9Swertiajaponin [20]A. nobilis subsp. nobilis, A. nobilis subsp. neilreichiiLeavesFlavonoid (C-methylated glycoside)Molecules 30 02460 i006
Compound 16		exhibits potent antioxidant activity, inhibits enzymatic browning by inactivating polyphenol oxidase, and enhances the flavonoid content and antioxidant capacity of foods [77]
10Quercetin 3-O-rhamnoside-7-O-glucoside [20]A. nobilis subsp. nobilis, A. nobilis subsp. neilreichiiLeavesFlavonoid (O-glycoside)Molecules 30 02460 i007
Compound 17		possesses high anti-inflammatory activity by binding with interleukin-6 [78]
115-Hydroxy-3,6, 7,4′ -tetramethoxyfla- vone [22]A. nobilisFlower headsFlavonoid (O-methylated flavone)Molecules 30 02460 i008
Compound 18		known for its anticancer properties [79]
12Isoschaftoside [24]A. nobilisAerial part Flavonoid (C-glycosylflavone)See Figure 3
Compound 4		inhibits lipopolysaccharide-induced inflammation in microglia through regulation of HIF-1 α-mediated metabolic reprogramming [80]; reverses nonalcoholic fatty liver disease via activating autophagy in vivo and in vitro [81]
13Luteolin-7-O-β-glucuronide [24]A. nobilisAerial part Flavonoid (O-glucuronide)See Figure 3
Compound 5		 NS
14Luteolin-4-O-β-glucopyranoside [24]A. nobilisAerial part Flavonoid (O-glucoside)See Figure 3
Compound 6		 NS
15Luteolin-6-C-apiofuranosyl-(1′′′→2″)-glucopyranoside [24]A. nobilisAerial part Flavonoid (C,O-diglycoside)See Figure 3
Compound 7		NS
16Quercetin-3-O-methyl ether [24]A. nobilisAerial part Flavonoid (O-methylated flavone)See Figure 3
Compound 8		protects FL83B cells from copper induced oxidative stress through the PI3K/Akt and MAPK/Erk pathway [82]; inhibits lapatinib-sensitive and -resistant breast cancer cell growth by inducing G (2)/M arrest and apoptosis [83]; protects FL83B cells from copper-induced oxidative stress through the PI3K/Akt and MAPK/Erk pathway [84]
17Quercetin-3-O-methylether-7-O-β-glucopyranoside [24]A. nobilisAerial part Flavonoid (O-methylated glucoside)See Figure 3
Compound 9		NS
18Quercetin-3-O-[α-arabinopyranosyl-(1′′′→6″)-β-glucopyranoside] [24]A. nobilisAerial part Flavonoid (Diglycoside)See Figure 3
Compound 10		NS
19LuteolinA. nobilis subsp. neilreichiiAerial part [33]Flavonoid (Flavone (aglycone))Molecules 30 02460 i009
Compound 19		blocks cancer development in vitro and in vivo by inhibition of proliferation of tumor cells, protection from carcinogenic stimuli, and activation of cell cycle arrest; reverses epithelial–mesenchymal transition (EMT) through a mechanism that involves cytoskeleton shrinkage, induction of the epithelial biomarker E-cadherin expression [86]
20Isorhamnetin 3-O-glucosideA. nobilis subsp. neilreichiiAerial part [33]Flavonoid (Flavonoid glycoside)Molecules 30 02460 i010
Compound 20		 NS
21Apigenin-6,8-di-C-glucosideA. nobilis subsp. neilreichiiAerial part [33]Flavonoid (Flavonoid glycoside)Molecules 30 02460 i011
Compound 21		 NS
22Dicaffeoylquinic acidA. nobilis subsp. neilreichiiAerial part [33]Phenolic compound (Polyphenol (ester of caffeic acid and quinic acid))Molecules 30 02460 i012
Compound 22		exhibits antioxidant, anti-inflammatory, antimicrobial, hypoglycemic, cardioprotective, neuroprotective, hepatoprotective, antitussive, and antispasmodic activities, supporting their potential role in the treatment of respiratory diseases [87]
23Chlorogenic acidA. nobilis subsp. neilreichiiAerial part [33]Phenolic compound (Hydroxycinnamic acid ester (caffeic acid + quinic acid))Molecules 30 02460 i013
Compound 23		exhibits a wide range of pharmacological activities, including antioxidant, anti-inflammatory, antibacterial, antiviral, neuroprotective, hepatoprotective, cardioprotective, antipyretic, anti-obesity, antihypertensive, antimicrobial, CNS-stimulating, hypoglycemic, and hypocholesterolemic effects, with significant roles in regulating lipid and glucose metabolism [88]
Here, “NS” means not studied.
Table 5. Terpenes and derivatives found in A. nobilis and its subspecies.
Table 5. Terpenes and derivatives found in A. nobilis and its subspecies.
No.CompoundsPlant SpeciesInvestigated Plant Part Chemical Class Known Pharmacological Activities
1Anobin [19]A. nobilisLeaves/flowers Sesquiterpene lactone NS
2Estafiatin [19]A. nobilisLeaves/flowers Sesquiterpene lactone exerts anti-inflammatory effects on macrophages and protects mice from sepsis induced by LPS and cecal ligation puncture [104]
3Anolide [21]A. nobilisAerial partSesquiterpene lactone, anolide type NS
44-Hydroperoxy-2R,3R-isopropyliden-hex-5-en-1-ol acetat [22]A. nobilisFlower headsAcyclic monoterpenoid NS
54-Hydroperoxy-2S,3R-isopropyli-den-hex-5-en-1-ol acetat [22]A. nobilisFlower headsAcyclic monoterpenoid NS
6Tanaparthin-β-peroxide [22]A. nobilisFlower headsSesquiterpene lactone peroxide NS
7Clarysartemin [23]A. nobilisAerial partSesquiterpene lactone NS
8Canin [23]A. nobilisAerial partSesquiterpene lactone NS
9Sabinene [25,26,30]A. nobilis [25,27,30], A. nobilis subsp. sipylea, A. nobilis subsp. neilreichii [26]Aerial part [25,27], flower heads [26], leaves [30]Bicyclic terpeneprevents skeletal muscle atrophy by Inhibiting the MAPK-MuRF-1 pathway in rats [105]
10Yomogi alcohol [25,30,32]A. nobilis [25,30,32]Aerial part [25,32], leaves [30]Monoterpene alcohol NS
11α-Terpinene [25,26,27,30,32]A. nobilis [25,27,30,32], A. nobilis subsp. sipylea, A. nobilis subsp. neilreichii [26]Aerial part [25,27,32], flower heads [26], leaves [30]Monoterpene, cyclic diene NS
12p-Cymene [25,26,27,30,32]A. nobilis [25,27,30,32], A. nobilis subsp. sipylea, A. nobilis subsp. neilreichii [26]Aerial part [25,27,30,32], flower heads [26]Monoterpene aromatic hydrocarboncarvacrol and ρ-cymene established a strong synergistic antimicrobial effect against planktonic cultures of Gardnerella spp. [106]
131,8-Cineole [25,26,27,28,30,32]A. nobilis [25,27,28,32], A. nobilis subsp. sipylea, A. nobilis subsp. neilreichii [26]Aerial part [25,27,28,32], flower heads [26], leaves [30]Cyclic terpene ether, oxideshows anti-inflammatory and antioxidant mainly via the regulation on NF-κB and Nrf2 [107]
14Artemisia ketone [25,32]A. nobilisAerial partMonoterpene ketone NS
15Artemisia alcohol [25,30,31,32]A. nobilisAerial part [25,31,32], leaves [30]Monoterpene alcohol NS
16α-Thujone [25,26,27,30,32]A. nobilis [25,27,30,32], A. nobilis subsp. sipylea, A. nobilis subsp. neilreichii [26]Aerial part [25,27,32], flower heads [26], leaves [30]Monoterpene ketone, bicyclic NS
17β-Thujone [25,27,30]A. nobilis [25,27]Aerial part [25,27],
Leaves [30]		Monoterpene ketone, bicyclic NS
18Camphor [25,26,27,30,32]A. nobilis [25,27,30,32], A. nobilis subsp. sipylea, A. nobilis subsp. neilreichii [26]Aerial part [25,27,32], flower heads [26],
leaves [30]		Monoterpene ketone, bicyclicpotential anti-orthopoxvirus agent [108]
19Pinocarvone [25,26,32,34]A. nobilis [25,32,34], A. nobilis subsp. sipylea, A. nobilis subsp. neilreichii [26]Aerial part [25,32,34], flower heads [26]Monoterpene ketone NS
20Borneol [25,26]A. nobilis [25], A. nobilis subsp. sipylea, A. nobilis subsp. neilreichii [26]Aerial part [25], flower heads [26]Monoterpene alcohol, bicyclicpotential anti-orthopoxvirus agent [108]
21Terpinen-4-ol [25,26,28,30,31]A. nobilis [25,28,30,31], A. nobilis subsp. sipylea, A. nobilis subsp. neilreichii [26]Aerial part [25,28,31], flower heads [26],
leaves [30]		Monoterpene alcoholantibacterial and antibiofilm agent against Staphylococcus aureus [109]
22α-Terpineol [25,26,27,30,31,32]A. nobilis [25,27,30,31,32], A. nobilis subsp. sipylea, A. nobilis subsp. neilreichii [26]Aerial part [25,27,31,32], flower heads [26],
leaves [30]		Monoterpene alcoholsuppresses glioblastoma aggressive behavior and downregulates KDELC2 expression (anti-tumor) [110]
23Myrtenal [25,34]A. nobilisAerial partMonoterpene aldehydeshows antimicrobial, antifungal, antiviral, anticancer, anxiolytic, and neuroprotective properties [111]
24Myrtenol [25,34]A. nobilisAerial partMonoterpene alcoholshows anti-inflammatory, anticancer, antimicrobial effects [112]
25trans-Carveol [25,31]A. nobilisAerial part [25,31]Monoterpene alcohol NS
26cis-Carveol [25]A. nobilisAerial partMonoterpene alcohol NS
27Cuminaldehyde [25]A. nobilisAerial partTerpene (Phenylpropanoid aldehyde)ameliorates hyperglycemia [113]
28Carvone [25]A. nobilisAerial partMonoterpene ketoneshows antimicrobial, antispasmodic, anti-inflammatory, antioxidant, antinociceptive, anticonvulsant [114]
29Bornyl acetate [25,26,32]A. nobilis [25,32], A. nobilis subsp. sipylea, A. nobilis subsp. neilreichii [26]Aerial part [25,32], flower heads [26]Monoterpene estera promising agent for immune modulation and inflammation [115]
30Carvacrol [25]A. nobilisAerial partMonoterpene phenolcarvacrol and ρ-cymene established a strong synergistic antimicrobial effect against planktonic cultures of Gardnerella spp. [116]
31Thymol [25]A. nobilisAerial partMonoterpene phenolexhibits antimicrobial, antioxidant, anticarcinogenesis, anti-inflammatory, and antispasmodic activities [116]
32Eugenol [25,26,28,32]A. nobilis [25,28,32], A. nobilis subsp. sipylea, A. nobilis subsp. neilreichii [26]Aerial part [2,25,32], flower heads [26]Terpene (Phenylpropanoid (allylbenzene))shows antibacterial; antifungal; antioxidant [117]
33trans-Myrtenol acetate [25]A. nobilisAerial partMonoterpene ester NS
34β-caryophyllene [25,30,31,32]A. nobilisAerial part [25,31,32], leaves [30]Sesquiterpene hydrocarbonexhibits anticancer and analgesic properties [118]
35Linalool butyrate [25]A. nobilisAerial partMonoterpene ester NS
36(E)-β-farnesene [25]A. nobilisAerial partSesquiterpene hydrocarbon, acyclic NS
37β-selinene [25,31]A. nobilisAerial part [25,31]Sesquiterpene hydrocarbon, bicyclic NS
38β-himachalene [25]A. nobilisAerial partSesquiterpene hydrocarbon, tricyclic NS
39δ-Cadinene [25,28,31,32]A. nobilisAerial part [25,28,31,32]Sesquiterpene hydrocarboninhibits the growth of ovarian cancer cells [119]
40Ledol [25,32,34]A. nobilisAerial part [25,32]Sesquiterpene alcohol, tricyclic NS
41Spathulenol [25,28,30,32,34]A. nobilisAerial part [25,28,32,34],
leaves [30]		Sesquiterpene alcohol NS
42Viridiflorol [25,26]A. nobilis [25], A. nobilis subsp. sipylea, A. nobilis subsp. neilreichii [26]Aerial part [25], flower heads [26]Sesquiterpene alcohol, tricyclicinhibits the growth of ovarian cancer cells [120]
43α-eudesmol [25]A. nobilisAerial partSesquiterpene alcohol, tricyclic NS
44α-Cadinol [25,27]A. nobilisAerial part [25,27]Sesquiterpene alcohol, tricyclic NS
45Patchouli alcohol [25]A. nobilisAerial partSesquiterpene alcoholdemonstrates diverse pharmacological activities, including antiviral, antidepressant, antinociceptive, vasorelaxant, lung- and neuroprotective, anti-ulcer, anti-colitis, prebiotic-like, anti-inflammatory, anticancer, and metabolic disease-protective effects [121]
46β-bisabolol [25,26,28]A. nobilis [25,28], A. nobilis subsp. sipylea, A. nobilis subsp. neilreichii [26]Aerial part [25,28], flower heads [26]Sesquiterpene alcohol, acyclic NS
47trans-α-Bergamotol [25]A. nobilisAerial partSesquiterpene alcohol, monocyclic NS
48α-Thujene [26,30,32]A. nobilis subsp. sipylea, A. nobilis subsp. neilreichii [26], A. nobilis [30,32]Flower heads [26], leaves [30], aerial part [32]Monocyclic monoterpene hydrocarbon NS
49α-Pinene [26,30,32]A. nobilis subsp. sipylea, A. nobilis subsp. neilreichii [26], A. nobilis [30,32]Flower heads [26], leaves [30], aerial part [32]Bicyclic monoterpene hydrocarbonantitumor agent for the treatment of T-cell tumors [122,123]
50Camphene [26,27,30,32]A. nobilis subsp. sipylea, A. nobilis subsp. neilreichii [26], A. nobilis [27,30,32]Flower heads [26], aerial part [27,32], leaves [30]Bicyclic monoterpene hydrocarbon NS
51β-Pinene [26,27,28,30,32]A. nobilis subsp. sipylea, A. nobilis subsp. neilreichii [26], A. nobilis [27,28,30,32]Flower heads [26], aerial part [27,28,32], leaves [30]Bicyclic monoterpene hydrocarbonexhibits antibiotic resistance, anticoagulant, antitumor, antimicrobial, antimalarial, antioxidant, anti-inflammatory, anti-Leishmania, and analgesic properties [123]
52Myrcene [26]A. nobilis subsp. sipylea, A. nobilis subsp. neilreichiiFlower headsAcyclic monoterpene hydrocarbonexhibits anxiolytic, antioxidant, anti-ageing, anti-inflammatory, analgesic properties [124]
53α-Campholenal [31]A. nobilisAerial part [31] Monoterpene aldehyde (bicyclic) NS
54Limonene [26]A. nobilis subsp. sipylea, A. nobilis subsp. neilreichiiFlower headsMonocyclic monoterpene hydrocarbonantioxidant, antidiabetic, anticancer, anti-inflammatory, cardioprotective, gastroprotective, hepatoprotective, immune modulatory, anti-fibrotic, anti-genotoxic [125]
55γ-Terpinene [26,27,30,32,34]A. nobilis subsp. sipylea, A. nobilis subsp. neilreichii [26,34], A. nobilis [27,30,32]Flower heads [26], aerial part [27,32,34], leaves [30]Monocyclic monoterpene hydrocarbon NS
56TricycleneA. nobilis subsp. neilreichiiAerial part [34]Tricyclic monoterpene hydrocarbon NS
57δ-3-CareneA. nobilis subsp. neilreichiiAerial part [34]Bicyclic monoterpene hydrocarbon NS
58Terpinolene [26,30,32,34]A. nobilis subsp. sipylea, A. nobilis subsp. neilreichii [26,34], A. nobilis [30,32]Flower heads [26], leaves [30], aerial part [32]Monocyclic monoterpene hydrocarbon NS
59trans-Sabinene hydrate [30,32]A. nobilisLeaves [30], Aerial part [32]Monocyclic monoterpene hydrocarbon NS
60cis-Sabinene hydrate [26,30,32]A. nobilis subsp. sipylea, A. nobilis subsp. neilreichii [26], A. nobilis [30,32]Flower heads [26], leaves [30], aerial part [32]Monocyclic monoterpene hydrocarbon NS
61Linalool [26,28,32]A. nobilis subsp. sipylea, A. nobilis subsp. neilreichii [26], A. nobilis [28,32]Flower heads [26], aerial part [28,32]Acyclic monoterpene alcoholexhibits sedative, anxiolytic, antimicrobial, anti-inflammatory, antinociceptive, and anticancer effects [126]
62Chrysanthenone [26]A. nobilis subsp. sipylea, A. nobilis subsp. neilreichiiFlower headsBicyclic monoterpene ketone NS
63Camphene hydrate [26]A. nobilis subsp. sipylea, A. nobilis subsp. neilreichiiFlower headsBicyclic monoterpene alcohol NS
64Fragranol [26,28]A. nobilis subsp. sipylea, A. nobilis subsp. neilreichii [26], A. nobilis [28]Flower heads [26], aerial part [28]Monoterpene alcohol (isomer of linalool) NS
65Tetrahydro-linalool acetate [26]A. nobilis subsp. sipylea, A. nobilis subsp. neilreichiiFlower headsSaturated monoterpene ester (acetate of a linalool derivative) NS
66Piperitone [26]A. nobilis subsp. sipylea, A. nobilis subsp. neilreichiiFlower headsMonoterpene ketone NS
67Sabinyl acetate [26]A. nobilis subsp. sipylea, A. nobilis subsp. neilreichiiFlower headsMonoterpene acetate esterexhibits antioxidant, antimicrobial, and anti-implantation activities [127]
68Geranyl acetate [26,31]A. nobilis subsp. sipylea, A. nobilis subsp. neilreichii [26], A. nobilis [31]Flower heads [26], aerial part [31]Acyclic monoterpene esterantibacterial, anti-inflammatory, and larvicidal activity; inhibits enzymes involved in bacterial cell wall synthesis [128]
69p-Menth-1-en-8-ol [32]A. nobilisAerial part Monocyclic monoterpene alcohol NS
70Lavendulol [27]A. nobilisAerial partMonoterpene alcohol (acyclic or monocyclic)antibacterial, insecticidal, and anti-inflammatory effects [129]
71Terpinene-4-ol [27,32]A. nobilisAerial partMonocyclic monoterpene alcoholantibacterial, antibiofilm, anti-inflammatory, anticancer, and antifungal activities
72Cuminyl aldehyde [27,34]A. nobilisAerial partAldehyde derivative of aromatic monoterpene[130]
73cis-Chrysanthenyl acetate [28]A. nobilisAerial partMonoterpene ester (acetate of chrysanthenol)antidiabetic, antimicrobial, anti-inflammatory, and anticancer properties [131]
74Lavandulyl acetate [28,30,31,32]A. nobilisAerial part [28,32], leaves [30,31]Acyclic monoterpene ester NS
754-Terpinenyl acetate [28]A. nobilisAerial partMonocyclic monoterpene ester NS
76Fragranyl formate [28]A. nobilisAerial partEster of fragranyl alcohol NS
77Fragranyl acetate [28]A. nobilisAerial partEster of fragranyl alcohol NS
78Fragranyl isobutyrate [28]A. nobilisAerial partEster of fragranyl alcohol NS
79Fragranyl butyrate [28]A. nobilisAerial partTerpenoid derivative NS
80Fragranyl 2-methylbutyrate [28]A. nobilisAerial partTerpenoid derivative (Ester of fragranyl alcohol) NS
81Fragranyl 3-methylbutyrate [28]A. nobilisAerial partTerpenoid derivative (Ester of fragranyl alcohol) NS
82Fragranyl valerate [28]A. nobilisAerial part Terpenoid (Monoterpene ester) NS
83Fragranyl hexanoate [28]A. nobilisAerial partTerpenoid (Ester of fragranyl alcohol and hexanoic (caproic) acid) NS
84Artemisiaketone [30]A. nobilisLeavesMonoterpene ketoneantimicrobial and antifungal activities [132]
85cis-Sabinol [30]A. nobilisLeavesMonocyclic monoterpene alcohol (oxygenated sabinene)exhibits antibacterial and antifungal properties [133]
86Lavandulol [30,31]A. nobilisLeaves [30], aerial part [31]Acyclic monoterpene alcohol NS
87Bornylacetate [30]A. nobilisLeavesBicyclic monoterpene esteranti-inflammatory, analgesic, anticoagulant, and hepatoprotective activities [134,135]
88Lavandulyl propionate [30]A. nobilisLeavesAcyclic monoterpene ester NS
89Lavandulyl isobutanoate [30]A. nobilisLeavesAcyclic monoterpene ester NS
90Lavandulyl-isovalerate [30]A. nobilisLeavesAcyclic monoterpene ester NS
91Longipinocarvone [30]A. nobilisLeavesOxygenated bicyclic monoterpeneexhibits antimicrobial and cytotoxic properties [136]
92VeridiflorolA. nobilisAerial part [32]Acyclic monoterpene esterdemonstrates antibacterial, antifungal, anti-inflammatory, and cytotoxic effects [137]
93Neryl acetateA. nobilisAerial part [31]Acyclic monoterpene esterShows anti-inflammatory, antifungal, and neuroprotective activities [138,139]
94Bornyl angelateA. nobilisAerial part [31]Bicyclic monoterpene ester NS
95Linalool oxideA. nobilisAerial part [32]Acyclic monoterpene epoxideanxiolytic, anticonvulsant, and antinociceptive effects [140]
96α-CyclocytralA. nobilisAerial part [32]Monoterpene aldehydeNS
97p-Mentha-2-en-1-olA. nobilisAerial part [32]Monocyclic monoterpene alcoholNS
98IsicyclocytralA. nobilisAerial part [32]Monoterpene aldehyde (isomer of cyclocitral)NS
99trans-3(10)-Carene-4-olA. nobilisAerial part [32]Bicyclic monoterpene alcoholNS
100cis-VerbenolA. nobilisAerial part [32]Bicyclic monoterpene alcoholantibacterial and acaricidal activity [141]
101trans-VerbenolA. nobilisAerial part [32]Bicyclic monoterpene alcoholantimicrobial and insecticidal activity [142]
102LavandolulA. nobilisAerial part [32]Acyclic monoterpene alcohol NS
1034-TerpineolA. nobilisAerial part [32]Monocyclic monoterpene alcoholantifungal, antibacterial, and anti-inflammatory properties [143]
1042-Pinene-10-olA. nobilisAerial part [32]Bicyclic monoterpene alcohol NS
105E-3(10)Caren-2-olA. nobilisAerial part [32]Bicyclic monoterpene alcohol NS
106trans-Crystantenyl acetateA. nobilisAerial part [32]Monoterpene ester NS
107cis-Crystantenyl acetateA. nobilisAerial part [32]Monoterpene ester NS
108Geranyl isovalerateA. nobilisAerial part [32]Acyclic monoterpene ester NS
109Lavandulyl acetateA. nobilisAerial part [32]Acyclic monoterpene esterantimicrobial and sedative properties [144]
110Limonene-6-ol-pivalateA. nobilisAerial part [32]Monoterpene ester NS
111Geranyl propionateA. nobilisAerial part [32]Acyclic monoterpene ester NS
112β-Bisabolene [26]A. nobilis subsp. sipylea, A. nobilis subsp. neilreichiiFlower headsAcyclic sesquiterpene hydrocarbon)anti-inflammatory, antimicrobial, and anticancer activities [145]
113γ-Cadinene [26]A. nobilis subsp. sipylea, A. nobilis subsp. neilreichiiFlower headsBicyclic sesquiterpene hydrocarbonantioxidant and anti-inflammatory effects [146]
114Bicyclogermacrene [27,34]A. nobilisAerial partBicyclic sesquiterpene hydrocarbonantibacterial, anti-inflammatory, and cytotoxic activities [147]
115trans-β-Guaiene [27]A. nobilisAerial partBicyclic sesquiterpene hydrocarbonNS
116α-Copaene [28]A. nobilisAerial partBicyclic sesquiterpene hydrocarbonantifungal and cytotoxic effects [148]
117cis-α-Bergamotene [28]A. nobilisAerial partMonocyclic sesquiterpene hydrocarbonanti-inflammatory and insecticidal activities [149]
118Sesquisabinene [28]A. nobilisAerial partTricyclic sesquiterpene hydrocarbon NS
119γ-Curcumene [28]A. nobilisAerial partAromatic sesquiterpene hydrocarbonanti-inflammatory and anticancer properties [150]
120ar-Curcumen [28]A. nobilisAerial partAromatic sesquiterpene hydrocarbon NS
121Santolina triene [30,32]A. nobilisAerial partTricyclic sesquiterpene hydrocarbon with three double bonds NS
122Germacrene D [30,32,34]A. nobilisLeaves [30], aerial part [32,34]Bicyclic hydrocarbonantimicrobial, anti-inflammatory, and cytotoxic properties [151]
123α-SelineneA. nobilisAerial part [31,34]Eudesmane-type sesquiterpene hydrocarbon NS
124(E,E)-α-FarneseneA. nobilisAerial part [31]Acyclic sesquiterpene hydrocarbonantifungal, and anti-inflammatory effects [152]
125Geranyl isobutyrate [31,32]A. nobilisAerial part [31,32]Acyclic monoterpene ester NS
126α-CalacoreneA. nobilisAerial part [31]Tricyclic sesquiterpene hydrocarbonantimicrobial and antioxidant properties [153]
127β-ChamigreneA. nobilisAerial part [32]Tricyclic sesquiterpene hydrocarbonantimicrobial and cytotoxic activities [153]
128CedreneA. nobilis subsp. neilreichiiAerial part [34]Bicyclic sesquiterpene hydrocarbonNS
129β-Eudesmol [26,28,31]A. nobilis subsp. sipylea, A. nobilis subsp. neilreichii [26], A. nobilis [28,31]Flower heads [26], aerial part [28,31]Oxygenated sesquiterpene alcoholNS
130Dihydro-eudesmol [26]A. nobilis subsp. sipylea, A. nobilis subsp. neilreichiiFlower headsSaturated form of eudesmolNS
131α-Bisabolol [26]A. nobilis subsp. sipylea, A. nobilis subsp. neilreichiiFlower headsOxygenated sesquiterpene alcoholNS
132Germacrene D-4-ol [27,28]A. nobilisAerial partSesquiterpene alcoholNS
133Cedrene-β-epoxide [27]A. nobilisAerial partEpoxide derivative of cedreneNS
172Helifolenol [27]A. nobilisAerial partOxygenated sesquiterpeneNS
134trans-Sesquisabinene hydrate [28]A. nobilisAerial partHydroxylated sesquiterpeneNS
135Caryophyllene oxide [28,30,32,34]A. nobilisAerial part [28,32,34], leavesEpoxidized sesquiterpeneNS
136Salvial-4(14)-en-1-one [28]A. nobilisAerial partKetone-type sesquiterpenoidNS
137cis-Sesquisabinene hydrate [28]A. nobilisAerial partHydroxylated sesquiterpeneNS
138γ-Eudesmol [28,30]A. nobilisAerial part, leavesSesquiterpene alcoholNS
139Eremoligenol [28]A. nobilisAerial partHydroxylated sesquiterpeneNS
140ar-Turmerol [28]A. nobilisAerial partAromatic sesquiterpene alcoholNS
141neo-Intermedol [30]A. nobilisLeavesHydroxylated sesquiterpeneNS
142Intermedeol [28]A. nobilisAerial partGuaiane-type sesquiterpene alcohol)NS
143Torilenol [28]A. nobilisAerial partHydroxylated sesquiterpeneNS
144Eudesma-4(15),7-dien-4β-ol [28]A. nobilisAerial partEudesmane-type sesquiterpene alcoholNS
145γ-Costol [28]A. nobilisAerial partOxygenated sesquiterpeneNS
146Cadin-4-en-7-ol [30]A. nobilisLeavesSesquiterpenoid (Cadinane-type alcohol)NS
147Epi-α-CadinoA. nobilisAerial part [31]Sesquiterpenoid (Cadinane-type sesquiterpene alcohol)NS
148Selin-11-en-4-α-olA. nobilisAerial part [31]Hydroxylated selinane-type sesquiterpeneNS
149KhusinolA. nobilisAerial part [31]Oxygenated sesquiterpene alcoholNS
150AristoloneA. nobilisAerial part [31]Tricyclic sesquiterpene ketoneantimicrobial and anti-inflammatory activities [154]
151NerolydolA. nobilisAerial part [32]Acyclic sesquiterpene alcoholantimalarial, antiparasitic, antifungal, and antioxidant effects [155]
152Murolan-3,9(11)-diene-10peroxyA. nobilisAerial part [32]Oxygenated sesquiterpene peroxide NS
153CubenolA. nobilisAerial part [32]Tricyclic sesquiterpene alcoholantifungal, cytotoxic, and antioxidant activities [156]
1543β-Cadin-4-en-10-oA. nobilisAerial part [32]Sesquiterpenoid (Cadinane-type sesquiterpene alcohol) NS
155Aromadenderen epoxideA. nobilisAerial part [32]Oxygenated sesquiterpeneantibacterial and anti-inflammatory activities [157,158]
156Eudesm-7(11)-en-4-olA. nobilisAerial part [32]Eudesmane-type sesquiterpene alcohol NS
157Hanphyllin [19]A. nobilisLeaves/flowersSequiterpene (Sesquiterpene lactones, germacranolide) NS
Here, “NS” means not studied.
Table 6. Other biologically active compounds found in A. nobilis and its subspecies.
Table 6. Other biologically active compounds found in A. nobilis and its subspecies.
No.CompoundsPlant SpeciesInvestigated Plant Part Chemical Class Chemical Structure Known Pharmacological Activities
1TricosaneA. nobilis subsp. neilreichiiAerial part [34]AlkaneMolecules 30 02460 i014
Compound 24		 NS
2HexadecanolA. nobilisAerial partFatty alcoholMolecules 30 02460 i015
Compound 25		 NS
31-OctadecanolA. nobilisAerial partFatty alcohol Molecules 30 02460 i016
Compound 26		exhibits antibacterial, anti-inflammatory, emollient, and mucosal-protective properties, supporting its use in vaginal drug-delivery hydrogels [159,160]
4Hexadecanoic acidA. nobilisAerial part [30] Fatty acid Molecules 30 02460 i017
Compound 27		induces proliferation of bone marrow mesenchymal stem cells, antimicrobial, antioxidant, anti-inflammatory, anticancer, hypocholesterolemic, and skin-protective effects [161]
5IndiponeA. nobilisLeaves [30]Aromatic ketoneMolecules 30 02460 i018
Compound 28		 NS
6DillapiolA. nobilisAerial part [31]PhenylpropanoidMolecules 30 02460 i019
Compound 29		antimicrobial and antifungal [162]
7Isovaleric acidA. nobilisAerial part [32]Carboxylic acidMolecules 30 02460 i020
Compound 30		ameliorates ovariectomy-induced osteoporosis by inhibiting osteoclast differentiation [163]
8Adamantane,1,3-dimethylA. nobilisAerial part [32]Polycyclic hydrocarbonMolecules 30 02460 i021
Compound 31		 NS
93-chloro-4-t-buthyl-6-phenyl pyridazinA. nobilisAerial part [32]Heterocyclic compoundMolecules 30 02460 i022
Compound 32		 NS
10PentadecanoneA. nobilis subsp. neilreichiiAerial part [34]Aliphatic ketoneMolecules 30 02460 i023
Compound 33		 NS
Here, “NS” means not studied.
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Shevchenko, A.; Аkhelova, A.; Nokerbek, S.; Kaldybayeva, A.; Sagyndykova, L.; Raganina, K.; Dossymbekova, R.; Meldebekova, A.; Amirkhanova, A.; Ikhsanov, Y.; et al. Phytochemistry, Pharmacological Potential, and Ethnomedicinal Relevance of Achillea nobilis and Its Subspecies: A Comprehensive Review. Molecules 2025, 30, 2460. https://doi.org/10.3390/molecules30112460

AMA Style

Shevchenko A, Аkhelova A, Nokerbek S, Kaldybayeva A, Sagyndykova L, Raganina K, Dossymbekova R, Meldebekova A, Amirkhanova A, Ikhsanov Y, et al. Phytochemistry, Pharmacological Potential, and Ethnomedicinal Relevance of Achillea nobilis and Its Subspecies: A Comprehensive Review. Molecules. 2025; 30(11):2460. https://doi.org/10.3390/molecules30112460

Chicago/Turabian Style

Shevchenko, Anastassiya, Aiman Аkhelova, Shamshabanu Nokerbek, Aigul Kaldybayeva, Lyazzat Sagyndykova, Karlygash Raganina, Raushan Dossymbekova, Aliya Meldebekova, Akerke Amirkhanova, Yerbol Ikhsanov, and et al. 2025. "Phytochemistry, Pharmacological Potential, and Ethnomedicinal Relevance of Achillea nobilis and Its Subspecies: A Comprehensive Review" Molecules 30, no. 11: 2460. https://doi.org/10.3390/molecules30112460

APA Style

Shevchenko, A., Аkhelova, A., Nokerbek, S., Kaldybayeva, A., Sagyndykova, L., Raganina, K., Dossymbekova, R., Meldebekova, A., Amirkhanova, A., Ikhsanov, Y., Sauranbayeva, G., Kamalova, M., & Toregeldieva, A. (2025). Phytochemistry, Pharmacological Potential, and Ethnomedicinal Relevance of Achillea nobilis and Its Subspecies: A Comprehensive Review. Molecules, 30(11), 2460. https://doi.org/10.3390/molecules30112460

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