Phytochemicals are plant natural products that possess numerous therapeutic properties. Traditional medicines have utilised the beneficial properties associated with these compounds for centuries, highlighting their potential to become novel drug candidates [
1]. Modern scientific approaches such as structural and computational biology offer unprecedented opportunities to study these natural products further. Analysis conducted via structural biology techniques has revealed three-dimensional structures of phytochemicals that can aid investigations with molecular docking or virtual screening to find new pharmacologically active molecules [
2]. This literature review will explore the role of phytochemicals in modern-day drug discovery. The review highlights essential findings and trends in this field from 1995, focusing on the methodologies used, the challenges encountered, and future research prospects.
1.1. The Role of Phytochemicals in Traditional Medicine
Traditional medicine encompasses approaches from indigenous knowledge systems and is heavily influenced by phytochemicals derived from plants that have both cultural and historical significance [
3]. Plant-based remedies have shaped modern pharmacology through the identification of valuable therapeutic agents present within them. With its interdisciplinary approach, ethnopharmacology seeks to understand how these specific phytochemicals function as part of traditional healing methods [
1].
Approximately 70−80% of the global population uses traditional medicines to treat diseases [
4]. For those living in rural regions across the globe with limited access to advanced Western medical practices and technology, traditional medications continue to be an essential aspect of inclusive healthcare solutions [
5]. Phytomedicines are derived from centuries-old healing traditions from the natural resources surrounding them. Moreover, these medicines often emphasise curing disease beyond the physical symptoms alone; they maintain a patient’s overall psychological and ethical balance as integral determinants of health, making phytomedicines beneficial amongst community members who value holistic recovery [
6]. Many such preparations are extracted directly from plants; some can be modified by structural transformation. Given the natural diversity of plants globally, there are many unidentified phytochemicals whose biological actions are yet to be discovered [
7]
In recent years, traditional Chinese and African medicine have been used against diseases, including COVID-19. For instance, the National Administration of Traditional Chinese Medicine organised a study to identify potential treatments against COVID-19, and the Lung Cleansing and Detoxifying Decoction (LCDD) was widely used and studied through clinical trials. LCDD contains 21 ingredients, including
Ephedra sinica, Atractylodes macrocephala, and
Scutellaria baicalensis, which likely counteract COVID-19 through synergistic activities[
8]. The first trial showed that LCDD was effective on 90% of the 214 COVID-19 patients. Further trials were carried out on a more extensive trial group with 1262 patients, including 57 with severe symptoms. The results showed that 99.28% of the patients recovered, and none developed severe symptoms during the treatment [
8]. In Africa, an elixir based on
Artemisia annua extract, known as "covid-organics," was used as a potential cure for COVID-19, and studies are still ongoing [
9]. Plant-based antimalarials like artemisinin from
Artemisia spp. have also been tested against the SARS-CoV-2 virus [
10].
Panax ginseng has been widely used as a healing plant in Asian traditional medicine. This species contains many natural products, including ginsenosides, that exert qualities such as improving immune health, reducing inflammation, and having anticancer effects [
11]. Similarly, turmeric, or
Curcuma longa, a plant in the ginger family
Zingiberaceae, which is prominent in Ayurvedic culture, contains curcumin and has wound-healing abilities and antioxidant and anti-inflammatory activities [
12]. Moreover,
Echinacea from North America is effective against respiratory disorders [
13].
Echinacea possesses phytochemicals such as phenolics, including caftaric acid, chicoric acid, cynarin, chlorogenic acid and echinacoside. Volatile terpenes, such as germacrene D and polyacetylene, are also present and possess antimicrobial and antioxidant activities. Ascorbic acid is also present, and it aids in immune augmentation. The polysaccharides and glycoproteins in the plant, including arabinogalactans, inulin and heteroxylans, possess immunostimulatory and anti-inflammatory activities that aid in immune modulation, thus reducing inflammation often experienced during illness episodes [
14,
15,
16].
Plant-derived compounds have also been used to treat diarrhoea, a major global health issue. Several scientific studies have found that herbal extracts act as antisecretory agents, have antiperistaltic effects, antimicrobial and antispasmodic properties. Apigenin and friedelin have been identified as antidiarrhoeal agents because of their antisecretory and antimotility activity [
17].
Arctostaphylos uva-ursi and
Vaccinium macrocarpon have been used to treat urinary tract infections, and the essential oils from
Allium sativum, Melaleuca alternifolia, and
Melissa officinalis have been extensively used to treat respiratory, GI, urinary, and skin infections [
18].
The examples above show that plant-derived phytochemicals may play a role in traditional medicine, offering potential remedies for various health conditions. With the integration of modern and traditional medical systems and the exploration of the world’s under-explored biodiversity, there is immense potential to discover novel phytochemicals and drug leads.
1.2. Examples of Approved Commercial Phytochemical Drugs
Several plant-derived drugs on the market have been developed to treat various diseases (
Figure 1), e.g., apomorphine (
1) is made semisynthetically from morphine isolated from
Papaver somniferum L. While initially investigated as a potential non-addictive morphine replacement, the pharmacology of
1 is distinct, acting as a dopamine receptor agonist and it is now approved for the treatment of Parkinson’s disease [
19]. Arteether (
2) is a semisynthetic drug derived from artemisinin from
Artemisia annua and is used to treat malaria. Arteether is oil soluble, has a long elimination half-life, and is more stable than artemisinin [
20]. Galantamine (
3) is an Amaryllidaceae alkaloid from
Galanthus woronowii and an acetylcholinesterase inhibitor used in Alzheimer’s treatments [
18]. Tiotropium is a muscarinic receptor antagonist from
Atropa belladonna that has been used to treat asthma and chronic obstructive pulmonary disease (COPD) [
21]. Other examples include anthocran, cysticlean and monoselect macropcarpon from
Vaccinium spp., which are being used to treat urinary tract infections. GutGuard is a standard product that was derived from
Glycyrrhiza glabra extract, and Parodontax is a product that was developed from
Commiphora myrrha,
Echinacea purpurea,
Krameria triandra, and
Matricaria recutita extracts.
Mentha arvensis,
M. piperita and
Salvia officinalis essential oils have all been used to treat oral infections [
22].
Even in recent times, natural products play a role in drug development, with 6 of 53 new products approved by the FDA in 2023 have been inspired from natural products (
Figure 2) [
23]. Examples of small molecules approved include bexagliflozin (
4) (Brenzavvy
TM) and sotalgliflozin (
5) (Inpefa
TM), sodium-glucose co-transporter inhibitors that are synthetic analogues of the natural product phlorizin isolated initially from apple trees. Brenzavvy
TM has been authorized for glycemic control in adults with type 2 diabetes, and Inpefa
TM has been approved as a cardiovascular therapeutic. The synthetic steroids zuranolone (
6) (Zurzuvae
TM) and vamorolone (
7) (Agamree
TM) were respectively approved for the treatment of postpartum depression and Duchenne muscular dystrophy.
Filsuvez
TM is an extract of birch terpenoids that was approved in 2023. The topical gel consists of pentacyclic triterpenes (
Figure 3), namely, betulin (
8) (72–88%), lupeol (
9) (2.4–5.7%), betulinic acid (
10) (2.6–4.2%), erythrodiol (
11) (0.5–1.2%), and oleanolic acid (
12) (0.3–0.8%). The gel treats partial-thickness wounds with Junctional and Dystrophic Epidermolysis Bullosa (JEB and DEB). This is the first treatment approved for wounds associated with the rare disease JEB [
23].