**4. Folkloric usage of secondary metabolites based on reliable sources of information and genuine scientific investigations**

The fact that animals and humans have been in existence before the advent of orthodox medicine is a proof that plants have been quite effective in treating diseases. The folkloric use of plant medicine has a long history [95]. From the earliest times, man acquired knowledge of the adverse and beneficial effects of plants from observations on animals. To distinguish edible from poisonous plants, grazing animals were observed and the plants not eaten were considered poisonous [96]. About 80% of the rural population today depends largely on medicinal plants for primary health care [97]. About 25% of all prescription drugs in developed countries are obtained directly or indirectly from plants [98].

Plants produce valuable organic compounds, some of which have potentials in treating ailments in both animals and humans [99]. Of the 252 drugs considered as basic and essential by the WHO, 11% are exclusively of plant origin and a significant number are synthetic drugs obtained from natural precursors [100]. In 1997, the world market for phytomedicinal products was estimated at US\$10 billion [101]. This prompted the WHO to consider phytotherapy in its alternative or complementary health program. Locally produced plant medicines can be cheaper than imported synthetic drugs. One striking example is an herbal wound powder (Himax®) in Sri Lanka that was found to be as effective as an imported powder (Neomex®) and comparatively 80–90% cheaper [102].

The most easily accessible, affordable, and inexpensive sources of treatment in the primary healthcare system throughout the world are medicinal plants; there is a long history for the therapy of various disease conditions traditionally in various regions of the world [103].

Natural products' earliest records were depicted on clay tablets from Mesopotamia (2600 BC) in cuneiform; there are documented evidences of the folkloric of the use of oils derived from *Commiphora species* and *Cupressus sempervirens* that are still in use today to treat inflammation, coughs, and colds [104]. The Egyptian pharmaceutical record "the Ebers Papyrus" (2900 BC) documented over 700 drugs of plant origins; these agents include infusions, gargles, ointments, and pills. The Chinese folkloric record books such as the Materia Medica (1100 BC) with 52 prescriptions, the Tang Herbal (659 AD) with 850 drugs, and the Shennong Herbal (100 BC) with 365 drugs provide records of natural products' uses [104]. Theophrastus (300 BC), the Greek natural scientist and philosopher, is an expert in dealing with medicinal herbs, while Dioscorides (100 AD), the Greek physician, documented the uses and storage of medicinal herbs [104]. The monasteries in Germany, England, France, and Ireland preserved this knowledge during the Dark and Middle Western Ages. Preservation of the Greek and Roman knowledge was done by the Arabs. They also expanded of their own resources; this is done with the Indian and Chinese unfamiliar herbs to the Greek and Roman world [104]. In the eighth century, it was the Arabs who privately

own pharmacies. Avicenna, a Persian physician, pharmacist, poet, and philosopher, contributed a lot to the science of medicine and pharmacy through his notable work such as the "Canon Medicine" [104].

#### **4.1 Some reported medicinal uses of secondary metabolites**

#### *4.1.1 Alkaloids*

Alkaloids have a wide range of pharmacological effects including antimalarial (quinine), antiasthma (ephedrine), anticancer (homoharringtonine), vasodilatory (vincamine), antiarrhythmic (quinidine), analgesic (morphine), antibacterial (chelerythrine), and antihyperglycemic activities (e.g., piperine) [37].

#### *4.1.2 Anthraquinones*

Huang et al. [105] and other teams clearly demonstrated that anthraquinones, such as emodin, aloe-emodin, and rhein, inhibit the growth and proliferation of various cancer cells, such as lung adenocarcinoma, myelogenous leukemia, neuroblastoma, hepatocellular carcinoma, bladder cancer, and others through cell death and survival's modulation. Several anthraquinones are able to inhibit the replication of viruses or even directly kill enveloped or unenveloped strains [106]. Senna, cascara, frangula, rhubarb, and aloe are commonly used for their laxative effects [107].

#### *4.1.3 Flavonoids*

Flavonoids have various health-promoting effects such as antioxidative, anti-inflammatory, anticarcinogenic, and antimutagenic. Flavonoids have antioxidant effects associated with various diseases such as Alzheimer's disease, cancer, atherosclerosis [108].

#### *4.1.4 Cardiac glycosides*

The most important use of the cardiac glycosides is its effects in treatment of cardiac failure. In cardiac failure, or congestive heart failure, heart cannot pump sufficient blood to maintain body needs. During each heart contraction, there is an influx of Na<sup>+</sup> and an outflow of K<sup>+</sup> . Before the next contraction, Na<sup>+</sup> , K+ -ATPase must reestablish the concentration gradient pumping Na+ into the cell against a concentration gradient. This process requires energy, which is obtained from hydrolysis of ATP to ADP by Na+ , K+ -ATPase. Cardiac glycosides inhibit Na<sup>+</sup> , K+ -ATPase, and consequently increase the force of myocardial contraction [109].

#### *4.1.5 Saponins*

Saponins exhibit a biological role and medicinal properties such as anti-inflammatory [110], antibacterial, antifungal, antiviral, insecticidal, anticancer, cytotoxic, and molluscicidal action [111].

#### *4.1.6 Terpenes and steroids*

Terpenes include substances such as floral fragrances, which serve as insect attractants, pine oil, growth inhibitors, plant hormones (gibberellic acid and abscisic acid), and some of which are insecticidal. About 30,000 terpenes have been identified; they all possess repeating five-carbon isoprene units (a five-carbon ring) [112].

Artemesinin is a sequiterpene, which originated from the Chinese medicinal plant Quinhao (*Artemisia annua*). It was used to treat fever medicine for over two millennia. It was mentioned in the 52 Remedies recovered from the Mawangdui Tomb dating from the Han Dynasty 206 BC – 221 BC located in Henan Province [113]. Placitaxol (a diterpene) is quite effective in treating against ovarian, breast, colon, non-small-cell lung cancer, and malignant melanoma [114]. Terpenoids (diterpenoids, sesquiterpenoids, triterpenoids) and lignoids also have antiviral activities. A number of them inhibit replication of inhibit coronaviruses, including SARS-Corona Virus. Betulinic acid and savinin are competitive inhibitors of a protease (an enzyme that breaks down proteins) produced by the SARS-CoV 3CL virus [114]. It will be worthwhile testing the effect of these terpenoids on SARs-CoV 2, the cause of recent Covid-19 pandemic.
