Phytochemical investigation of Magnolia grandiflora green seed cones: Analytical and phytoceutical studies

Abstract Phytochemicals are inevitable part of human civilization. It is impossible to say exactly when menfolk started to take plant portions to cure various diseases. Phytochemical investigation of diethyl ether and ethanol extracts of Magnolia grandiflora green seed cones has been carried out. Extraction, isolation, and identification of the phytochemicals were carried out. Structures were determined by various analytical methods including extensive nuclear magnetic resonance, gas chromatography‐mass spectroscopy, and X‐ray crystallographic analyses. Structures of the three compounds viz. 5,5′‐diallyl‐[1,1′‐biphenyl]‐2,2′‐diol (I), 3′,5‐diallyl‐[1,1′‐biphenyl]‐2,4′‐diol (II), and (3S,3aS,8S,9aS,10aR,10bS,E)‐8‐hydroxy‐3,6,9a‐trimethyl‐3a,4,5,8,9,9a,10a,10b‐octahydrooxireno[2′,3′:9,10]cyclodeca[1,2‐b]furan‐2(3H)‐one (III) were confirmed by X‐ray crystallographic analysis. GS‐MS studies of the isolated oil, eluted with hexanes, revealed the presence of eight compounds including two highly bio‐privileged molecules 5,5′‐diallyl‐2′‐methoxy‐[1,1′‐biphenyl]‐2‐ol (IV) and 1‐(4‐isopropylbenzyl)‐1,3‐dihydro‐2H‐benzo[d]imidazol‐2‐one (V). The druggability of the five compounds has also been determined by in silico studies. The isolated compounds and/or their semi‐synthetic products may find application in natural drug development research.

are pharmacologically/medicinally relevant molecules that produce therapeutic effects (positive health effect); addictives have negative health effects, whereas toxins cause fatal health effect (Bandyopadhyay, 2014a(Bandyopadhyay, ,2014b. The utilization of natural products and/or their novel cores, in order to discover and develop the final drug entity, is still an interesting and highly promising area of drug discovery research. For example, in the area of cancer, from around the 1940s to the end of 2014, 175 small molecules were approved by the US Federal Drug Administration (FDA) or its similar organizations worldwide. Out of these 175 small molecule anticancer drugs, 131 (74.85%) are completely nonsynthetic molecules. Presently, about 25% of medicines are directly derived from nature. About 61% of new chemical entity (NCE) can be traced to a natural product origin.
In certain therapeutic areas, this impact is even higher. For example, about 75% of anticancer drugs and 78% of antibacterial drugs are either natural products or chemically modified natural products or semi-synthetic natural products. The rapidly evolving recognition that a significant number of drugs/leads/hits are produced by Mother Nature, and therefore it is considered that this area of natural resources should be expanded significantly (Giddings & Newman, 2015a,2015b,2015cNewman & Cragg, 2016). Accordingly, chemical investigation of natural compounds is one of the most reliable and traditional routes to discover new and novel natural drugs.
Magnolias (belong to the family Magnoliaceae) are known worldwide for their beautiful flowers with intense fragrance. Many species of the genus Magnolia are grown around the world, and out of all these different species, Magnolia grandiflora is the most attractive one because of its large size, gorgeous color, and fragrance (Avonto, Chittiboyina, Sadrieh, Vukmanovic, & Khan, 2018;Ding et al., 2018;Lata et al., 2017). This article deals with the phytochemical investigation of the diethyl ether and ethanol extracts derived from the Magnolia grandiflora green seed cones. Along with other compounds, five medicinally privileged compounds have been isolated and identified as drug-like molecules through in silico evaluation. Appropriate chemical modifications of these molecules aiming to synthesize suitable semi-synthetic compounds for drug-protein interactions might lead to develop novel therapeutics. These compounds ( Figure   1) were characterized through various analytical techniques including gas chromatography-mass spectroscopy (GC-MS) and X-ray crystallographic analyses.  (Sheldrick, 2015), and SHELXTL v6.10 (Sheldrick, 2008). All the solvents were purchased from Fisher-Scientific throughout the investigation. Deionized water was used for the preparation of all aqueous solutions.

| General experimental
F I G U R E 1 Compounds obtained from Magnolia grandiflora green seed cones | 1763

| RE SULTS AND D ISCUSS I ON
The melting points of the compounds (1) 137.55, 133.32, 131.35, 129.91, 124.17, 116.75, 115.86, 39.39. In FT-IR spectrum, the broad peak at 3,132 cm -1 identified the phenolic O-H stretching, whereas the presence of terminal double bonds was determined by 1D-NMR experiments. The structure of the compound (I) was further confirmed by X-ray crystallographic analysis. The ORTEP projection of the compound (I) is presented in Figure 2.
The structure was solved with the program SHELXS-2014/7 and was refined on F 2 with SHELXL-2014/7 (Sheldrick, 2015). Numerical absorption correction based on Gaussian integration over a multifaceted crystal model was applied using CrysAlisPro. The temperature of the data collection was controlled using the system Cryojet (manufactured by Oxford Instruments). The H atoms were placed at calculated positions using the instructions AFIX 23, AFIX 43, AFIX 93, or AFIX 137 with isotropic displacement parameters having values 1.2 or 1.5 Ueq of the attached C atoms. The structure is ordered and the details are shown in Table 1.  137.81, 136.01, 132.28, 131.17, 130.25, 129.65, 128.85, 128.58, 127.75, 126.40, 116.96, 116.60, 115.63, 115.59, 39.43, 35.17. In FT-IR spectrum, the broad peak at 3,293 cm -1 identified the phenolic O-H stretching, whereas the presence of terminal double bonds was determined by 1D-NMR experiments. APT and DEPT F I G U R E 2 X-ray crystallographic analysis of compound (I) experiments revealed the presence of three aromatic methine carbons, one aliphatic methine carbon, two methylene carbons, and three quaternary carbons in the molecule. The structure of the compound (II) was further confirmed by X-ray crystallographic analysis.

| Characterization of compound (III)
In FT-IR spectroscopy, the alcoholic -OH hydrogen appeared at 3,492 cm -1 and the lactone carbonyl appeared at 1,760 cm -1 . The presence of three methyl groups was confirmed by APT and DEPT experiments. The three methylene carbons appeared at δ 46.20, 40.98, and 28.86. The structure and stereochemistry of the compound (III) were determined by 2D-NMR spectroscopy and further confirmed by X-ray crystallographic analysis. The ORTEP projection of the compound (III) is presented in Figure 4.
The structure of (III) was solved following the method stated earlier, and the details are shown in Table 3. The structure is ordered and the absolute configuration was established by anomalous-dispersion effects in diffraction measurements on the crystal, and the Flack and Hooft parameters refine to −0.08(6) and −0.08(5), respectively. The structure has chirality S, S, S, S, R, R at C1, C6, C7, C9, C10, and C11, respectively.   In the next step, the druggability of the compounds (I-V, Figure 1) was validated following Lipinski's rule-of-five (RO5) (Lipinski, 2004;Lipinski, Lombardo, Dominy, & Feeney, 1997). Compounds I, III, and V showed no violation, whereas other two compounds (II and IV)

| GC-MS studies of the oil
showed only one violation each. Accordingly, all the five compounds can be considered as "drug-like" molecules and semi-synthetic products derived from these molecules (with appropriate chemical modification) have high promise to become effective drug(s). The  TA B L E 4 Druggability validation a of the compounds (I-V)