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A review on the Phytochemistry and Pharmacological properties of Picralima nitida Durand and H. (Apocynaceae family): A potential antiCovid-19 medicinal plant species

In this mini-literature review, the traditional use, nutritional value, phytochemistry and biological properties of P. nitida, a plant used as a conventional African medicine is described. The literature discussed in this investigation established that extracts from P. nitida were very efficient in the treatment of several diseases including malaria. Hence we anticipate that it may be effective against Covid-19 virus also. We suggest that in vitro and in vivo assays should be conducted to confirm the activity of the plant against SARS-CoV-2.


Introduction
The world is confronted with a new coronavirus epidemiccalled COVID- 19. This novel incipient disease is initiated by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [1]. A genetic study has revealed that SARS-CoV-2 belongs to the Beta coronavirus family and is very similar to SARS-CoV-1 [1]. Despite the biosafety and hygiene measures to limit the large-scale spread of this pandemic, there is currently no antiCovid-19 drug approved by the World Health Organization (WHO). Therefore, traditional medicines can play a pivotal role in the management of this pandemic. Indeed, medicinal plants have been used in folk medicine for generations in most of the cultures throughout the world and are the primary form of treatment in many areas today [2]. However, among the 250,000-500,000 species of plants on earth, only a relatively small percentage (1-10 %) is used for food by humans and animals [3]; however, more may serve medicinal purposes. Medicinal plants are an important source of molecules with various pharmacological properties. These medicinal values of plants have been claimed to lie in their phytochemical components including alkaloids, tannins, flavonoids, and other phenolic compounds [4]. According to the World Health Organization, more than 80% of the population in Africa uses traditional medicine to solve the primary health problems. The traditional medicines have the advantage of being safe, effective, less expensive, and less risky, with significantly reduced side effects compared to modern medicines [5][6][7][8][9]. Picralima nitida Durand  The seed has a light brown color, obovoid in shape, and smooth texture [12].

Microscopy features
Osuala et al., [12] reported that microscopy of the powdered seeds revealed the presence of sclereids, parenchyma and epidermal cells, calcium oxalate crystal, and fat globules.

Nutrient composition of P. nitrida
The seeds contain vital essential amino acids such as leucine, phenylalanine, tyrosine, and nonessential amino acids.  The ground seeds contain more unsaturated fatty acids than saturated fatty acids and possess considerable amount of macro and micro-elements with iron, zinc, and manganese. The ground seeds also have vitamins A and E [29]. The results of the proximate composition of this species indicated that P. nitida peels contains an appreciable amount of nutrients: lipid, protein, and carbohydrate as well as moisture and ash [14]. Another study on mineral analysis revealed that the plant contains metals such as Ca++, Mg++, and K+ ions and non-metals, such as Cl-ions [12].

Pharmacological activities Anticancer activity
The anticancer activity of P. nitida root bark against human epithelial MCF-7 cells has been reported by Engel et al., [45]. Studies have confirmed the presence of alkaloids, tannins, polyphenols, and steroids in P. nitida, and these components are associated with the anticancer property of this species.

Free radical scavenging activities
The in vitro antioxidant evaluation of methanol extract of P. nitida and its fractions using the DPPH free radical scavenging method showed that its crude extract has IC-50 value of 5μg/mL for radical scavenging activity which is significantly higher than that of ascorbic acid (2.55μg/mL). Picralima nitida has the potential for use as a natural plant antioxidant in preventing the free radical damage [2]. In another study on determining the antioxidant capacity of ethanol, ether, ethyl acetate, butanol, and aqueous extracts of plant seeds using free radical, it was noted that P. nitida seed extract exhibits highest antioxidant capacity [40].

Antimalarial activity
The in vitro antimalarial activity of P. nitida extracts has been investigated. Iwu et al., [23] indicated that the alkaloid extracts of the fruits of this species exhibit activity against drug-resistant and drugsensitive malarial strains of Plasmodium falciparum and these alkaloids show significant inhibitory activity against both clones of P. falciparum at IC50 values of 0.0.1-09 g/ml. In another study, the significant inhibitory activity of the methanol fruit extract was obtained on multi-drug resistant human Plasmodium falciparium with IC50 value of 1.75 µg/mL [30]. Extracts of different parts (seed, fruit rind, and stem bark) of P. nitida showed remarkable inhibitory activity against drug resistant clones of P. falciparum at doses of 1.23-32 µg/mL [46]. The results in vitro antiplasmodial activity of the ethanol seed extract of the plant in chloroquine-sensitive Plasmodium berghei infected mice showed that the ethanol seed extract of this plant exhibited a significant in vivo antiplasmodial activity in both early (4-Day chemo-suppressive test) and established infections (Curative test). Ethanolic seed extract of P. nitida produced a dose-dependent chemo-suppressive effect of 65.5%, 70.4% and 73.0% respectively for 35, 70 and 115 mg/kg/day doses [31]. Methanol seed extract of P. nitida demonstrated significant activity against the chloroquine-resistant Plasmodium falciparum W2 strain with IC50 value of (10.9, 1.1) µg/mL [33]. The root, stem bark and fruit rind extracts displayed significant inhibitory activities against the asexual erythrocytic form of Plasmodium falciparum with IC50 values of 0.188, 0.545, and 1.581 µg/mL respectively [32].

Uterotonic effects
Uterotonic effect of aqueous ethanolic fruit extract of P. nitida on uterine contractility was investigated using the rat model [41]. The results of this study revealed that the extract was found to induce a dose-dependent myometrial contraction at concentrations ranging from 0.035-0.28 mg/ml, whereas concentrations above this range caused a progressive relaxative effect on the uterine muscle tissue. The effective concentrations (EC50) were 0.056 mg/ml and 1.06 mg/ml for contractile and the relaxative responses respectively. These results demonstrated that the extract did not elicit any contractile response in a physiological salt solution devoid of calcium ions. The contractile response   evoked by a fixed concentration of the extract (0.07 mg/ml) decreased as the concentration of verapamil (0.02-0.2 µmol) increased. The extract (0.07 mg/ml) did not restore the spontaneous myometrial contraction previously abolished by adrenaline (9.1 nmol) and a selective β-adrenergic receptor agonist, salbutamol (0.2 µmol) respectively. However, about 26.3% contraction was observed when a non-selective β-adrenergic stimulant, isoprenaline (0.1 µmol) was added simultaneously with the extract. Also, propranolol (0.3 µmol) potentiated the contractile response of this extract.   Ezeamuzie et al.,[30] demonstrated the antipyretic activity of methanol fruit extract of P. nitida. The result of the present study revealed that the methanol fruit extract at a dose of 50 mg/kg produced a mean percentage antipyrexia of 38.7% on lipopolysaccharide induced pyrexia in rabbits, which was comparable to aspirin (29.0% at 200 mg/kg). Extracts of the plant have been shown to possess significant analgesic activity in the rat pedal model [23].

Antidiabetic activity
Teugwa et al., [39] reported that the hydroethanolic extract of whole plants (150 mg/Kg) and methanol leave extract of the plant (300 mg/Kg) exhibited significant antidiabetic activities with 39.40% and 38.48% glycemia reduction, respectively. Inya-Agha et al., [47] investigated the hypoglycemic effect of the methanol extracts of seed, and fruit rind of P. nitida in rats. The result of this study showed a significant (P<0.01) hypoglycemic effect of all extracts at 300 and 900 mg/kg in alloxan-induced diabetes in rats. In another study, Aguwa et al., [48] confirmed the hypoglycemic effect of the aqueous seed extract of P. nitida in alloxan-induced diabetic rabbits.

Microbial activities
Studies on P. nitida indicate that extracts from this plant have an action against Staphylococcus aureus, Enterococcus faecalis, Bacillus cereus, Escherichia coli, Salmonella typhi, and Proteus mirabilis [14,27]. These results give credence to the use of the extract in herbal medicines for the treatment of   [39] diseases and infections. Ubulom et al., [15] reported that both the aqueous and ethanol leaf extracts of P. nitida exerted an antifungal effect on Aspergillus flavus and C. albicans in a dosedependent manner, but no antifungal effect was exhibited against Microsporum canis. The basic fraction of the methanol extract of the stem bark of this species has been shown to exhibit significant antimicrobial activity against a wide range of Gram-positive bacteria and fungi, but limited activity against Gram-negative bacteria [49].

Anti-leishmanial activity
The chloroform extract of the seed of P. nitida was evaluated for possible antileishmanial activity using a radiorespirometric micro-test technique and the result of this study confirmed its activity against Leishmania donovani at 50 µg/mL [34]. Okonta et al.,[43] demonstrated the antiulcer activity of P. nitida extracts. In this study, oral administration of the methanol extract, chloroform fraction and methanol fraction at 1000 mg/kg reduced gastric ulcer by 56.4%, 40.0%, and 56.3%, respectively; and the fractions of the extract significantly (P<0.05) reduced gastric emptying time when compared to the control. Gastric acidity was significantly decreased when compared with saline group, 40.25 mEq/L in methanol extract, 50.0 mEq/L in methanol fraction but had no significant effect on gastric secretion volume.

Hepatoprotective activity
Results of Idu et al., [42] showed that the treatment with P. nitida extracts had no adverse effect on the body weight of Wistar rats. Biochemical analysis showed increase in CAT and GSH which are good antioxidant agents. Photomicrographs show moderate amelioration from steatosis caused by Carbon tetrachloride in the treatment groups.

Toxicopathological and acute toxicity
Taofik et al., [50] reported that the extract had no significant effect on all kidney function indices assayed but caused a significant reduction (P < 0.05) in the activities of liver enzymes accompanied by a significant decrease in the liver to body weight ratio, serum total protein, and globulin concentrations. No significant alteration was observed in the serum levels of albumin and conjugated bilirubin, whereas the extract brought about a significant increase (P < 0.05) in serum total bilirubin concentration. In this study, the hematological analysis revealed no significant effect on erythrocyte indices in contrast to white blood cell count and its differentials which were significantly elevated (P < 0.05) following the extract administration. The acute toxicity of seeds aqueous decoction from P. nitida was assessed after giving the crude decoction to mice in increasing doses ranging from 600 to 3000 mg/kg of body weight (b.w.). The use of the herbal medicine, through oral route (or), at different doses, does not cause some clinical signs. The results made it possible to obtain the dose at bordering on solubility which squares with the tolerated maximal dose or TMD (3000 mg/kg/b.w./or). This toxicological parameter (tolerated maximal dose) is by far higher than 94.885 mg/kg b.w./or, the recommended daily dose bytraditional healers. Therefore, the dose prescribed by traditional healers is not toxic, justifying the use of the plant in traditional conditions of preparation and oral administration.

Conclusion and future prospects
The Covid-19 pandemic is a major health crisis of the 21st century for which no cure is currently available and which requires an alternative solution based on the endogenous knowledge. P. nitida medicinal plant species owing to its valuable properties have been used traditionally in folk medicines to treat various ailments including malaria, which make it the best candidate in the fight against the current dread disease. The current study aimed to review the literature on the traditional use, nutritional value, phytochemistry, and biological properties of this valuable plant species. The results of the bibliographic investigation showed that P. nitida treats several diseases including diabetes mellitus and malaria, etc. Concerning the phytochemistry, several compounds have been identified including several alkaloids, as the major class of compounds of these species whose properties make this plant a potential anti-COVID-19 candidate. Molecular docking studies are, emergent Life Sciences Research Inkoto et al. therefore, necessary to evaluate the binding reaction of alkaloids with the major SARS-COV-2 target enzymes. emergent Life Sciences Research Inkoto et al.