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impact on the therapeutic activity of potent biological molecules. Implementation of drug
delivery systems improves the bioavailability, solubility as well as the pharmacological
potential of bioactive molecules. In addition, NDDS also help in the enhancement of target
specicity and permeability of a bioactive molecule. Natural products incorporated into
NDDS have been reported to have signicant potential in treating ailments like diabetes,
cancer, and neurodegenerative diseases (Chopra and Dhingra, 2021). The complex
chemical structure of natural products is very important in the formulation, for the delivery
of drugs/bioactive molecules. The formulation should be synthesized in a way that active
molecules should be released precisely on a targeted site. Subsequently, the vehicle must
simultaneously help to enhance the solubility of the drug, inhibit the degradation of the
drug, and also reduce its toxicity (Bonifacio et al., 2014).
Pharmacological and phytochemical sciences have developed the constitution and
biological properties of various medicinal plant products. The majority of the active
constituents of plant extracts like avonoids, tannins, and terpenoids have high water
solubility, yet exhibit a lower absorption rate as they are not able to penetrate lipid
membranes. Moreover, they have a higher molecular size and show poor absorption which
brings about a decrease in bioavailability and potency (Bonifacio et al., 2014).
Nanotechnological drug delivery systems have attempted to break the aforementioned
barriers. They permit molecules with different characteristics to be used in the same
formulation and help to alter the molecule’s characteristics and behavior in a biological
environment (Bonifacio et al., 2014). Even though nanotechnology implementations are
benecial for a variety of natural products in an effective way, it is important to highlight
the disadvantages associated with it. There are some negative factors of nanotechnology,
which have been reported by clinical researchers and scientists, including signicant
expense, trouble in scaling up processes, and the accessibility of inhalation of nanoparticles
which can lead to severe lung diseases and frequently result in other diseases causing
alterations in homeostasis or even death (Bonifacio et al., 2014).
1.4 NATURAL PRODUCTS AS A GUIDE IN DRUG DESIGN AND SYNTHESIS
Natural products and biotherapeutics present a wider asset for the development of new
drugs. Nevertheless, several parameters such as the cost and duration for the achievement
of drug discovery and importantly the financial support from the pharmaceutical industries remain the major retarding factors in the development of new effective therapeutics
(Obeid et al., 2017).
Natural products and their derivatives have been perceived for many years as the major
source of therapeutic agents with versatile structures (Lahlou, 2013). As per previous
records, more than 70% of novel chemical molecules are approved as drugs available in the
market originated from a natural origin whereas only 27% of approved drugs were based
on pure synthesis (Lautie et al., 2020). The exploration of new potent chemical moieties
from natural origin is still recognized as the best way to search for drug discovery and
to preserve the natural ora for future drug discoveries. However, the strategies for drug
discovery intentions should be reassessed. These strategies include:
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1. Systematic access to compounds from plant parts by a scalable culture of plant
cells, capable of producing a specific chemical compound.
2. Utilization of the inventory of natural product sources for the phytochemical
constitution of known plants.
3. Application of synthetic biology methods to synthesize the potent compound in a
laboratory.
Natural product-inspired synthetic compounds play a vital role in dealing with drug
design challenges by providing feasible and innovative solutions. According to a study
on the natural product-inspired synthetic compound, reported by Hergenrother and
team (Parkinson et al., 2015), deoxynybomycin- inspired chemical entity demonstrated
powerful antibacterial activity against Staphylococcus aureus and better aqueous solubility (Rodrigues et al., 2016). Rosuvastatin is another example of a natural productinspired drug. The drug evolved from a synthetically accessible mimetic of the natural
product mevastatin, produced by the fungus Penicillium citrinum. Similarly , Gademann
and colleagues (Schmid et al., 2013) shortened militarinone and derivatized the natural
product-inspired compound as an effective inducer of neurite outgrowth (Rodrigues
et al., 2016). Numerous natural product-inspired compounds have been reported by
various researchers. These compounds blend physicochemical characteristics from
both the drug and the natural product, thus, conceivably leading to further development
(Rodrigues et al., 2016).
Moreover, computational software helps to extenuate the progression of natural
product-inspired synthetic compounds. In a more precise manner, fragment-like natural
products with innovative scaffolds may be exploited as the seed for chemical biology
and medicinal chemistry research with assured success (Rodrigues et al., 2016). Articial
intelligence has further inspired various disciplines of science which include computer-
aided drug discovery. Deep learning approaches, utilizing articial intelligence provide
multiple applications in drug discovery. Such approaches are based on an articial neural
network with secret handling layers and gained huge contemplation attributed to the
capability of automatic feature elicitation from input data and acquiring the input-output
relationship. These approaches have already been utilized to restore the novel modeling in
drug discovery. Among different applications of articial intelligence in drug discovery,
ligand-based quantitative structure-activity/property relationship, novel modeling based on
structure, de novo molecular design, and synthesis prediction are in the limelight (Jiménez-
Luna et al., 2021).
1.5 NATURAL PRODUCTS AS PROMISING DRUG CANDIDATES
1.5.1 ANTIVIRAL DRUG CANDIDATES
Emerging viral infections have been recorded as the highest threat to human health and
well-being. Millions of people are killed by different viral infections each year, which
mainly include severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), hepatitis
B virus (HBV), hepatitis C virus, human immunodeficiency virus, and influenza virus.
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The threat of these viral infections keeps on growing because of the lack of potent vaccines
and drugs against many viral infections (Musarra-Pizzo et al., 2021).
Natural products continue to be the best source as well as inspiration for us in the
discovery of novel drugs. The variety and intricacy of natural products provide exceptional
adequacy to target viral infections with efcacy and specicity and serve as a potential
source of antiviral therapeutics. However, the discovery and specic production of novel
antiviral agents are still considered a strenuous approach because of the limited antiviral
agents. However, novel approaches, which mainly include biosynthetic pathways could be
mediated in the production of these effective antiviral agents to overcome these limitations
(Ma et al., 2020).
The majority of viruses own a limited set of coding genes and they rely on the host
for the completion of their lifecycles and generation of viral progeny. On that account,
two major pathways to be considered in antiviral treatments are direct-acting antivirals
and host-acting antivirals (HAAs). The HAAs are generally wide-range antivirals with
multiple benets such as targeting various viruses, hindering the occurrence of new
resistant viral strains, and decreasing drug-drug interactions. Therefore, natural products
with diversied structures are considered an excellent source of antiviral agents which
exhibit different mechanisms of action. For instance, inuenza neuraminidase inhibitors,
known as “oseltamivir” are derived from the natural product, shikimic acid (Ma et al.,
2020). Hesperidin and hesperetin, two avonoids present in citrus fruits as the major
constituents, have shown a prophylactic effect in coronavirus disease-2019 infections
by preventing the binding of SARS-CoV-2 virus to angiotensin-converting enzyme 2 of
the host cell (Agrawal et al., 2021). Similarly, numerous plant extracts and compounds
have been reported as effective antiviral agents against SARS-CoV-2 including lectins,
diaminopropane, essential oil, polyphenols, silvestrols, and extracts of Houttuynia cordata,
Isatisindigotica, Rheum ocinale, Artemisis annua, Pyrrosia lingua, and Lycoris radiata.
These novel natural products demonstrated antiviral activity through different mechanisms
of action such as inhibition of viral attachment, inhibition of viral replication cycle, binding
to RNA-dependent RNA polymerase, tar geting spike proteins, inhibition of ATPase activity
of SARS-CoV-2 helicase and inhibition of 3C-like protease.
Hepatitis virus is innately a hepatotropic virus responsible for causing chronic and acute
hepatitis, targeting about 33% of the total world population. Many of these chronically
infected people die due to liver cirrhosis, liver failure, and hepatocellular cancer. Despite
the availability of effective vaccines, viral mutations in certain populations lead to
treatment failure. Derivatives of nucleos(t)ide like lamivudine, adefovir, and entecavir
have been reported as an effective treatment of hepatitis B and hepatitis C, but long-term
therapy is associated with the development of drug resistance. Natural products are blessed
with diversied and complex chemical structures and provide effective and promising
therapeutic agents. A wide range of phytoconstituents including vogonin (avonoid),
artemisinin (terpene), oxymatrine (alkaloid), geraniin (polyphenols), astragaloside
(saponins) and helioxanthin (lignans) have been isolated and evaluated in vitro as well as in
vivo for anti-HBV activities. These compounds have varied and overlapping mechanisms
of action by either inhibiting viral antigens secretion or suppressing DNA replication
(Parvez et al., 2016).
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1.5.2 ANTIPARASITIC DRUG CANDIDATES
Neglected tropical diseases such as leishmaniasis and trypanosomiasis are common diseases
in sub-tropical regions of Asia, Africa, and America, and are mainly caused by protozoa.
These diseases are a major cause of mortality and morbidity around the globe and also affect
the world economy . The treatments for some of these diseases are available but have variable
efficacy , long durations, and toxicity and are barely available for poor people. Over the last
decade, various natural products have been isolated and reported as effective antiparasitic
and antibiotic agents (Carter et al., 2021). For instance, antiparasitic imidazole alkaloids,
paenidigyamycin A and G, derived from Ghanaian Paenibacillus polyxma were reported
to inhibit Leishmania major, Leishmania donovanii, and Trypanosoma brucei. Similarly,
natural indolocarbazole, staurosporine, and oxostaurosporine extracted from Streptomyces
sanyensis were found to be effective against Leishmania donovani and Trypanosoma
cruzi (Cartuche et al., 2020). A novel diterpene, bifurcatriol isolated from alga Bifurcaria
bifurcate exhibited antiprotozoal activity against Leishmania donovanii and Trypanosoma
brucei rhodesiens. Another study on furanocembranoid diterpene isolated from Plumarella
delicatissima reported antileishmanial activity against Leishmania donovanii (Nweze et al.,
2021). A novel cyclic peptide, janadolide isolated from cyanobacterium showed potent
activity against Trypanosoma brucei. Hoshinolactam, isolated from Oscillatoria sp. also
demonstrated strong inhibitory effects against Trypanosoma brucei (Ogawa et al., 2017).
Novel anthraquinone isolated from Actinokineospora spheciospongaie named Fridamycin
H exhibited significant antiparasitic activity against Trypanosoma brucei. Surprisingly
the sesquiterpenes from the sponge, Dysideaavara, avarone, and its thiazinoquinone
derivative, thiazoavarone exhibited potential activity against different pathogenic strains
of Leishmania including Leishmania infatum and Leishmania tropica (Imperatore et al.,
2020). Another compound, harzialactone A, isolated from the fungus Paecilomyces sp.
was found to be active against Leishmania amazonensis (Nweze et al., 2021). Quercetin,
a polyphenolic flavonoid found in green leafy vegetables, citrus fruits and green tea, is
reported to have potential antileishmanial activity targeting various pathogenic strains of
Leishmania sp. including Leishmania amazonensis, Leishmania donovani, Leishmania
infatumchagasi, Leishmania tropica, and Leishmania braziliensis (Carter et al., 2021).
1.5.3 NEUROPROTECTIVE AGENTS
Alzheimer’s disease (AD) and Parkinson’s disease (PD) are the most prevalent
neurodegenerative diseases around the world. These neurodegenerative diseases are
characterized by a progression of neuronal loss at a slower rate along with the presence
of general pathological mechanisms such as misfolding of proteins, oxidative stress,
neuronal inflammation, mitochondrial dysfunction, and neuronal death (Feng et al., 2019).
AD is clinically recognized as age-associated dementia, cognitive decline, and behavioral
derangement whereby PD is associated with muscular stiffness, bradykinesia, rest tremor,
impairment of movement, and nonmotor symptoms. A limited number of drugs have been
discovered to treat mild and severe cases of AD and PD. To date, no drug is available yet
to cure these diseases completely and those available are also associated with side effects.
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So, therapeutic agents having significant antioxidant activity could be of great potential in
dealing with neurodegenerative disorders like AD and PD (Habtemariam, 2019). Numerous
experimental studies have been conducted on natural products with significant anti-PD and
anti-AD properties. There are several phenols which are reported as promising and effective
neuroprotective agents. Flavonoids and phenols have been isolated from both plants and
fungi, which possess high antioxidant potential. Epigallocatechin, a phenolic bioflavonoid,
which is abundantly found in green tea has been reported to possess a neuroprotective action
and is authorized to prove that it has clinical application in PD therapeutics (Singh et al.,
2020). Another flavonoid, baicalein, commonly isolated from the Chinese herb Scutellaria
baicalensis has demonstrated potential neuroprotective properties and anti-inflammatory
properties (Sowndhararajan et al., 2017). Resveratrol is a type of natural nonflavonoid
polyphenol, derived from the skin of grapes, blueberries, peanuts, and mulberries. It has
shown potent neuroprotective properties against multiple toxins such as rotenone, neurotoxin
6-hydroxydopamine, and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced
parkinsonism in animal models (Singh et al., 2020). Findings of resveratrol have been
reported as a neuroprotective agent. Quercetin, the main flavonoid, isolated from flowers,
leaves, and fruits of several plants also demonstrated significant neuroprotective activity in
animal models. It is proposed that PD dietary modifications may provide neuroprotection
in PD patients (Singh et al., 2020). Luteolin, a type of flavonoid isolated from various
medicinal plants, fruits, and vegetables has shown neuroprotective effects on primary
neuronal cells against oxidative damage (Singh et al., 2020). Moreover, luteolin is also
advantageous in improving memory cells. Curcumin, a nonflavonoid polyphenol isolated
from turmeric has been reported to possess neuroprotection under in-vivo studies, by
showing a potential reduction in the level of proinflammatory agents, transcription factor
NF-κB and activator protein-1 (Singh et al., 2020). Puerarin, derived from the Chinese
herb Pueraria lobata showed neuroprotective effects by protecting dopaminergic neurons.
Similarly, genistein, an isoflavone isolated from soy products has demonstrated promising
neuroprotective potential, especially in neurodegenerative diseases in animal studies
(Zhou et al., 2014; Singh et al., 2020). Naringin, a flavonoid originating from tomatoes,
grapefruits, and citrus fruits has shown neuroprotective properties through the activation
of antioxidant machinery, antiapoptotic pathways, and neurotrophic factors (Singh et al.,
2020). A phenolic compound, mangiferin, isolated from various plants including Mangifera
indica L. has been implicated in the neuroprotection against oxidative stress, mitochondrial
dysfunction, neuroinflammation, and cellular apoptosis. It has also shown effectiveness in
the enhancement of memory and cognition in rat models (Feng et al., 2019). In addition,
several natural products including myricetin, morin, kaempferol, catechin, and tannin have
also been reported to target neurotoxicity (Habtemariam, 2019). These natural products
could be utilized in PD/AD therapeutics.
1.6 CONCLUSION
Natural products are still considered the inspiration for the development of effective and
novel drugs to target numerous diseases. Novel computational methods mingled with
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advanced isolation and biosynthetic techniques could be utilized to deal with complications in the development of novel drugs from natural origin. Natural products derived from
microbes and plants have always been appreciated for the treatment of various diseases and
continue to be one of the most valuable and effective sources in the development of new
natural product-derived moieties as clinical candidates for future world-class drugs.
KEYWORDS
• natural products
• medicinal plants
• antimicrobial agents
• nanodrug delivery systems
• host-acting antivirals
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