INTRODUCTION:

Plant produces a valuable source of medicines. There are remarkable progresses in synthetic medicinal chemistry, still over 25% of the advised drugs are derived directly or indirectly from plants¹.Medicinal plants have been used in folk medicine in Asian and African populations for thousands of years, and many plants are consumed in developed nations for their health benefits^2,3.It is estimated that 70-95% of the population in developing countries are using traditional medicine⁴. Because of unmatched availability of chemical diversity, natural products, such as plant extract, either as pure compounds or as standardized extracts, provide unlimited opportunities for new drug discoveries⁵. Strong antioxidant such as plant polyphenols protect cell constituents against oxidative damage, thus averting the deleterious on nucleic acid, proteins and lipids in cells⁶.

Flavonoids, the largest and most widely studied polyphenols, are gaining interest as antioxidants due to their high ability to destroy free radicals. Flavonoids prevent hydroxy radical-induced damage by donating electrons to neutralize 10 species^7,8,9,10,11.

Sonneratia apetala is a mangrove tree belonging to the family of Lythraceae, it is found in the coastal areas in India, Bangladesh, Malaysia, Australia, etc. It is a rapid growing mangrove used in the reforestation of salinity affected areas. According to Bandaranayake¹². It is commonly called kandal. This tree reaches a height of 20 meters. The leaves are simple, opposite and leathery, while the flowers are green and fleshy. The leaves are reported to have antibiotic and antifungal activity¹³.

The present study was carried out to identify phytochemicals present in the methanolic extract of Sonneratia apetala with the aid of HPLC, FTIR, UV-Visible and Swiss ADME techniques which may provide an insight in its use in traditional medicine.

MATERIALS AND METHODS:

Plant Preparation:

Sonneratia apetala was collected from mangroves habitat in Raigad district. Then wash leaves with tap water. The clean leaves then dried under shade, after that the dried leaves placed inside the oven for couples of hours. The dried leaves grinded by using electric blender.

Plant Extraction:

Take 5.0gm sample of Sonneratia apetala leaves and dissolved it in 50ml of methanol and kept it for 24hours. Filter this solution after 24hours. Add 50ml of methanol to the residue again and boil it in a boiling water bath till half the solution remains. Then combine this filtrate and initial filtrate and kept it in water bath for complete evaporation of methanol, the extract is finally obtained.

High Performance Liquid Chromatography (HPLC):

The HPLC for the methanolic extract of Sonneratia apetala leaves was performed by Shimadzu-LC20AR. They carried out by using the following conditions According to previously reported method^14-16 (Table 1).

Table 1: HPLC parameters for analysis

Mobile Phase	Methanol
Column	C18 5μ (4.6mm*250.0 )
Detector	Photo Diode Array- 254nm
Sample Injection Loop	20 μL
Flow Rate	1.0 mL/min
Run time	20 min.

Fourier Transform Infrared Spectroscopy (FTIR):

FTIR is largely used technique to identifying the types (functional groups) of chemical bonds in compounds. The particular chemical bond absorbed light of particular wavelength. By observing the infrared absorption spectrum, we can determine the chemical bonds in a molecule^17,18. A small amount of extract of Sonneratia apetala loaded in FTIR spectroscopy (Shimadzu, IR Affinity-1S WL, Japan) with scan range from 500 to 4000 cm^-1.

UV-visible spectroscopy: 1.0g sample of Sonneratia apetala was diluted in 100ml of methanol. The aliquote was transferred to a quartz cell (1cm pathway) and analyzed by Shimadzu Corporation, Japan (UV-1800 240V). The extract was scanned from 200nm to 800nm to create a characteristic absorption spectrum of the sample^19,20,21,22.

Physicochemical Properties, Lipophilicity, Water Solubility, Pharmacokinetics, Druglikeness and Medicinal Chemistry Friendliness Prediction of Phytochemicals:

The approximate study of pharmacokinetics, especially ADME, physicochemical properties, lipophilicity, water solubility, drug-likeness and medicinal chemistry of mangroves plant like Sonneratia apetala were carried out by using Swiss ADME online tool^23,24. The canonical SMILES string for each chemical was incorporated in this tool for the computational simulation. This tool predicts bioavailability radar as per six physicochemical properties such as lipophilicity, size, polarity, solubility, flexibility and saturation to detect drug-likeness. The ADME properties e.g. passive human gastrointestinal absorption (HIA) and blood-brain barrier (BBB) permeation as well as substrate or non-substrate of the permeability glycoprotein (P-gp) as detected positive or negative in the BOILED-Egg model²⁵. Estimation of lipophilicity (Log p/w) parameters such as iLOGP was calculated by n-octanol and water on free energies of solvation as per the generalized-born and solvent accessible surface area (GB/SA) model²⁶, XLOGP3 is an atomistic method including corrective factors and knowledge-based library²⁷, WLOGP has implemented for a purely atomistic method is relying on the fragment system²⁸, M-LOGP is an archetype of topological method based on a linear relationship with 13 molecular descriptors implemented as per researchers^29,30 and SILICOS-IT is an hybrid method, based on 27 fragments and 7 topological descriptors.

The Lipinski (Pfizer) filter is included in the Pioneer Rule-of-Five has Incorporated in this tool from and this tool has also been included for prediction of drug-likeness³¹. Bioavailability radar for oral bioavailability prediction as per distinct physico-chemical parameters has been developed by SwissADME tool^23,24.

Predicting medicinal chemistry techniques has based on the root of structural alert³², the pan assay interference compounds or PAINS structural alert³³ or the Lilly MedChem³⁴ filters applied to cleansing chemical libraries of compounds most likely unstable, reactive, toxic, or prone to interfere with biological assays because non-specific frequent hitters, dyes or aggregators³⁵. The synthetic accessibility (SA) score has based primarily on the assumption that the frequency of molecular fragments in ‘really’ obtainable molecules correlates with the ease of synthesis. The developed and standardized method is characterized by molecular synthetic accessibility scores, which are found between 1 and 10 (easy to make and very difficult to make)³⁶.

RESULT AND DISCUSSION:

In this research, methanolic extract of Sonneratia apetala was screening for its properties and its chemical structure by using different method such as HPLC, FTIR, and UV-Visible techniques.

The results obtained from HPLC were shown in the figure 1. In table (2) shown that the methanol extract of Sonneratia apetala leaves have more than one retention time. The HPLC analysis of Sonneratia apetala leaves gave 8 peaks with maximum height at 2.346 min. of retention time.

Table 2: HPLC peak table of Sonneratia apetala leaves

Peak	Retention Time	Area	Height
1	2.346	216061	21894
2	2.821	254710	14332
3	3.380	110376	12299
4	3.900	25307	1654
5	4.279	6032	558
6	4.227	3402	381
7	5.059	4617	490
8	7.652	7636	600
Total		688142	52208

The FTIR spectrum of the methanol leaves extract of Sonneratia apetala indicates the presence of different functional groups. The result is shown in Figure 2 and Table (3). The peak near 3250 cm^-1 is O-H stretch (alcohol). Also, the peak near 2924 cm^-1 is C-H stretch (Alkanes compound) and peak near 1691 cm^-1 is C=O stretch (Carboxylic acid). The result of near 1442 cm^-1 is C-C stretch (in-ring) (Aromatic compound) and also the peak near 1315 cm^-1, 1242 cm^-1, 1220 cm^-1, 1186 cm^-1 and 1028.06 cm^-1is C-O stretch (Ester, Ethers or Carboxylic acid).

Figure 2: FTIR Spectrum of methanolic extract of Sonneratia apetala leaves

Table 3: FTIR Spectrum Peak Value and Functional Group obtain from methanolic extract of Sonneratia apetala leaves

S. No.	Peak Value	Functional group assignment	Phyto compound Identified
1	3250.05	O-H stretch	Alcohol
2	2924.09	C-H stretch	Alkanes compound
3	1691.57	C=O stretch	Carboxylic acids
4	1442.75	C-C stretch (in-ring)	Aromatic compound
5	1315.45	C-O stretch	Ester, Ethers or Carboxylic acid
6	1242.75	C-O stretch	Ester, Ethers or Carboxylic acid
7	1220.94	C-O stretch	Ester, Ethers or Carboxylic acid
8	1186.22	C-O stretch	Ester, Ethers or Carboxylic acid
9	1028.06	C-O stretch	Ester, Ethers or Carboxylic acid

The qualitative UV-Visible spectrum profile of methanol extract of Sonneratia apetala leaves was selected from wavelength 200 to 800nm due to sharpness of the peaks and proper baseline. The profile showed the peaks at 656, 600, 624 and 584nm with the absorbance of 0.296, 0.196, 0.171 and 0.189 respectively shown in Table (3). The maximum absorbance is 0.296 at 656nm²⁸.

Table 4: UV-Visible Spectrum Peak values of methanolic extract of Sonneratia apetala leaves

S. No	Wavelength in nm	Absorbance
1	656	0.296
2	600	0.196
3	346	4.000
4	235	4.000
5	624	0.171
6	584	0.189
7	342	3.684

The result on predictive data for Physicochemical properties, Lipophilicity, Water solubility, Pharmacokinetics, Drug likeness and Medicinal Chemistry Friendliness of established 8 Phytochemicals such as Gibberellin, Betulinic acid, Lupeol, Lupeone, Stigmast-5-ene-3beta, 5β-cholestane-3α,7α-diol, β-amyrin hexadecaneate, Physcoion (Table 5-10). In table 5, molecular formula and molecular weight are obtained. Gibberellin (C₁₉H₂₂O₆, 346.37g/mol), Betulinic acid (C₃₀H₄₈O₃, 456.70), Lupeol (C₃₀H₅₀O, 426.72), Lupeone (C₃₀H₄₈O, 424.70), Stigmast-5-ene-3beta (C₃₁H₅₄O, 442.76), 5β-cholestane-3α,7α-diol (C₂₇H₄₈O₂, 404.67), β-amyrin hexadecaneate (C₄₆H₈₂O, 651.14), Physcoion (C₁₆H₁₂O₅, 284.26).

Table 5: General Characteristic of Phytoconstituents of Sonneratia apetala leaves

SI. No	Small Molecule	Molecular Formula	Canonical SMILES	Molecular Weight (in g/mol)
1	Gibberellin	C₁₉H₂₂O₆	OC(=O)[C@H]1[C@H]2[C@]3([C@H]4[C@]51CC(=C)[C@](C5)(O)CC4)C=C[C@@H]([C@@]2(C)C(=O)O3)O	346.37
2	Betulinic acid	C₃₀H₄₈O₃	CC(=C)[C@@H]1CC[C@]2([C@H]1[C@H]1CC[C@H]3[C@@]([C@]1(C)CC2)(C)CC[C@@H]1[C@]3(C)CC[C@@H](C1(C)C)O)C(=O)O	456.70
3	Lupeol	C₃₀H₅₀O	CC(=C)C1CCC2(C1C1CCC3C(C1(C)CC2)(C)CCC1C3(C)CCC(C1(C)C)O)C	426.72
4	Lupeone	C₃₀H₄₈O	CC(=C)C1CCC2(C1C1CCC3C(C1(C)CC2)(C)CCC1C3(C)CCC(=O)C1(C)C)C	424.70
5	Stigmast-5-ene-3beta	C₃₁H₅₄O	CC[C@@H](CC(C)C)CC[C@H]([C@H]1CC[C@@H]2[C@]1(C)CC[C@H]1[C@H]2[C@H](O)C=C2[C@]1(C)CC[C@@H](C2)C)C	442.76
6	5β-cholestane-3α,7α-diol	C₂₇H₄₈O₂	CC(CCC[C@H]([C@H]1CC[C@@H]2[C@]1(C)CCC1[C@H]2[C@H](O)C[C@H]2[C@]1(C)CC[C@H](C2)O)C)C	404.67
7	β-amyrin hexadecaneate	C₄₆H₈₂O	CCCCCCCCCCCCCCCCO[C@H]1CC[C@]2([C@H](C1(C)C)CC[C@@]1(C2CC=C2C1CC[C@@]1([C@@]2(C)CC(C)(C)CC1)C)C)C	651.14
8	Physcoion	C₁₆H₁₂O₅	COc1cc(O)c2c(c1)C(=O)c1c(C2=O)c(O)cc(c1)C	284.26

Table 6: Lipophilicity of the Phytoconstituents of Sonneratia apetala leaves

SI. No.	Small Molecule	iLOGP	XLOGP3	WLOGP	MLOGP	SILICOS-IT	Consensus Log P_o/w
1	Gibberellin	1.69	0.24	1.03	1.66	1.31	1.18
2	Betulinic acid	3.81	8.21	7.09	5.82	5.75	6.14
3	Lupeol	4.68	9.87	8.02	6.92	6.82	7.26
4	Lupeone	4.54	9.56	8.23	6.82	7.41	7.31
5	Stigmast-5-ene-3beta	5.58	10.55	8.66	7.12	7.58	7.90
6	5β-cholestane-3α,7α-diol	4.55	6.18	6.44	5.56	5.52	5.65
7	β-amyrin hexadecaneate	8.65	17.44	14.67	9.72	13.73	12.84
8	Physcoion	2.45	3.04	2.19	0.61	3.07	2.27

In table 7, two topological approaches included in SwissADME to predict water solubility. First one is the application of the ESOL model. The water solubility data obtained for soluble compound, e.g., Gibberellin and Physcoion and moderately soluble compound e.g., 5β-cholestane-3α,7α-diol and poorly soluble compound e.g., Betulinic acid, Lupeone, Lupeol, Stigmast-5-ene-3beta and insoluble compound e.g., β-amyrin hexadecaneate. Second one is Ali. The water solubility data obtained for very soluble compound e.g., Gibberellin and moderately soluble compound e.g., Physcoion and poorly soluble compound e.g., Betulinic acid, Lupeone, 5β-cholestane-3α,7α-diol and insoluble compound e.g., Lupeol, β-amyrin hexadecaneate. The third predictor of SwissADME was developed by SILICOS-IT. The water solubility data obtained for soluble compound e.g., Gibberellin and moderately soluble compound e.g., Betulinic acid, 5β-cholestane-3α,7α-diol, Physcoion and poorly soluble compound e.g., Lupeone, Lupeol, Stigmast-5-ene-3beta and insoluble compound e.g., β-amyrin hexadecaneate.

Table 7: Water solubility of the Phytoconstituents of Sonneratia apetala leaves

Small Molecule

ESOL

Ali

SILICOS-IT

Log S

(ESOL)

Solubility

Class

Log S

(ESOL)

Solubility

Class

Log S

(ESOL)

Solubility

Class

mg/ml

mol/L

mg/ml

mol/L

mg/ml

mol/L

Gibberellin

-2.07

2.93e+00

8.64e-03

Soluble

-1.99

3.58e+00

1.03e-02

Very soluble

-1.46

1.19e+01

3.44e-02

Soluble

Betulinic acid

-7.71

8.87e-06

1.94e-08

Poorly soluble

-9.28

2.40e-07

5.26e-10

Poorly soluble

-5.70

9.09e-04

1.99e-06

Moderately soluble

Lupeol

-8.64

9.83e-07

2.30e-09

Poorly soluble

-10.22

2.58e-08

6.05e-11

Insoluble

-6.74

7.69e-05

1.80e-07

Poorly soluble

Lupeone

-8.43

1.58e-06

3.72e-09

Poorly soluble

-9.83

6.28e-08

1.48e-10

Poorly soluble

-7.44

1.54e-05

3.63e-08

Poorly soluble

Stigmast-5-ene-3beta

-8.77

7.53e-07

1.70e-09

Poorly soluble

-10.92

5.28e-09

1.19e-11

Insoluble

-6.72

8.40e-05

1.90e-07

Poorly soluble

5β-cholestane-3α,7α-diol

-5.91

4.95e-04

1.22e-06

Moderately soluble

-6.81

6.21e-05

1.54e-07

Poorly soluble

-4.97

4.30e-03

1.06e-05

Moderately soluble

β-amyrin hexadecaneate

-13.81

1.08e-11

1.55e-14

Insoluble

-17.84

9.36e-16

1.44e-18

Insoluble

-13.67

1.40e-11

2.15e-14

Insoluble

Physcoion

-3.84

3.80e-02

1.34e-04

Soluble

-4.47

9.72e-03

3.42e-05

Moderately soluble

-4.60

7.07e-03

2.49e-05

Moderately soluble

Table 8: Pharmacokinetic Parameters of the Phytoconstituents of Sonneratia apetala leaves

Small Molecule	GI absorption	BBB permeant	P-gp substrate	CYP1A2 inhibitor	CYP2C19 inhibitor	CYP2C9 inhibitor	CYP2D6 inhibitor	CYP3A4 inhibitor	Log K_p(cm/s)
Gibberellin	High	No	Yes	No	No	No	No	No	-8.24
Betulinic acid	Low	No	No	No	No	Yes	No	No	-3.26
Lupeol	Low	No	No	No	No	No	No	No	-1.90
Lupeone	Low	No	No	No	No	No	No	No	-2.10
Stigmast-5-ene-3beta	Low	No	No	No	No	No	No	No	-1.51
5β-cholestane-3α,7α-diol	High	No	No	No	No	No	No	No	-4.38
β-amyrin hexadecaneate	Low	No	Yes	No	No	No	No	No	2.11
Physcoion	High	No	No	Yes	No	Yes	No	Yes	-5.88

Table 9: Drug likeness of the Phytoconstituents of Sonneratia apetala leaves

Small Molecule	Lipinski	Ghose	Veber	Egan	Muegge	Bioavailability score
Gibberellin	Yes; 0 violation	Yes	Yes	Yes	Yes	0.56
Betulinic acid	Yes; 1 violation: MLOGP>4.15	No; 3 violations: WLOGP>5.6, MR>130, #atoms>70	Yes	No; 1 violation: WLOGP>5.88	No; 1 violation: XLOGP>5	0.85
Lupeol	Yes; 1 violation: MLOGP>4.15	No; 3 violations: WLOGP>5.6, MR>130, #atoms>70	Yes	No; 1 violation: WLOGP>5.88	No; 2 violations: XLOGP3>5, Heteroatoms<2	0.55
Lupeone	Yes; 1 violation: MLOGP>4.15	No; 3 violations: WLOGP>5.6, MR>130, #atoms>70	Yes	No; 1 violation: WLOGP>5.88	No; 2 violations: XLOGP3>5, Heteroatoms<2	0.55
Stigmast-5-ene-3beta	Yes; 1 violation: MLOGP>4.15	No; 3 violations: WLOGP>5.6, MR>130, #atoms>70	Yes	No; 1 violation: WLOGP>5.88	No; 2 violations: XLOGP3>5, Heteroatoms<2	0.55
5β-cholestane-3α,7α-diol	Yes; 1 violation: MLOGP>4.15	No; 2 violations: WLOGP>5.6, #atoms>70	Yes	No; 1 violation: WLOGP>5.88	No; 1 violation XLOGP3>5	0.55
β-amyrin hexadecaneate	No; 2 violations: MW>500, MLOGP>4.15	No; 4 violations: MW>480, WLOGP>5.6, MR>130, #atoms>70	No; 1 violation: Rotors>10	No; 1 violation: WLOGP>5.88	No; 4 violations: MW>600, XLOGP>5, heteroatoms<2, Rotors>15	0.17
Physcoion	Yes; 0 violation	Yes	Yes	Yes	Yes	0.55

Table 10: Medicinal Chemistry Properties of the Phytoconstituents of Sonneratia apetala leaves

SI. No.	Small Molecule	Pains	Brenk	Leadlikeness	Synthetic accessibility
1	Gibberellin	0 alert	1 alert: isolated_alkene	Yes	6.69
2	Betulinic acid	0 alert	1 alert: isolated_alkene	No; 2 violations: MW>350, XLOGP3>3.5	5.63
3	Lupeol	0 alert	1 alert: isolated_alkene	No; 2 violations: MW>350, XLOGP3>3.5	5.49
4	Lupeone	0 alert	1 alert: isolated_alkene	No; 2 violations: MW>350, XLOGP3>3.5	5.38
5	Stigmast-5-ene-3beta	0 alert	1 alert: isolated_alkene	No; 2 violations: MW>350, XLOGP3>3.5	6.56
6	5β-cholestane-3α,7α-diol	0 alert	0 alert	No; 2 violations: MW>350, XLOGP3>3.5	5.42
7	β-amyrin hexadecaneate	0 alert	1 alert: isolated_alkene	No; 3 violations: MW>350, Rotars>7, XLOGP3>3.5	8.13
8	Physcoion	1 alert: quinone_A	0 alert	Yes	2.69

CONCLUSION:

Sonneratia apetala is an edible mangrove plant which contain many medicinal properties. Sonneratia apetala leaves has diverse biological effects, including Antioxidant, Anti-inflammatory, Antimicrobial, Anticancer, Anti-diabetic. The success of isolation and purification of Gibberellin from Sonneratia apetala leaves, which considered as less toxic.

CONFLICT OF INTEREST:

The authors have no conflicts of interest regarding this investigation.

ACKNOWLEDGEMENT:

The authors express sincere gratitude towards Management, Principal, Anekant Education Society’s Tuljaram Chaturchand College Baramati. Head, and P.G. Coordinator Department of Chemistry and ARC T.C. College for facility and financial support. The authors are also grateful to coordinator, CFC for HPLC and FTIR analysis.

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Received on 26.05.2022 Modified on 13.06.2022

Res. J. Pharmacognosy and Phytochem. 2022; 14(3):155-162.

DOI: 10.52711/0975-4385.2022.00029