Plant-Based Bioactive Phthalates Derived from Hibiscus rosa-sinensis: As In Vitro and In Silico Enzyme Inhibition

Hibiscus rosa-sinensis is an attractive, ever-blossoming, and effortlessly available plant around the globe. The fabulous flowers of H. rosa-sinensis enjoy a significant status in folk medicine throughout the world and comprise a range of phyto constituents due to which this splendid flower owns numerous biological and pharmaceutical activities like antioxidant, antifungal, antimicrobial, anti-inflammatory, antipyretic, antidiabetic, and antifertility activity. Considering this, column chromatographic isolation of the phytoconstituents of ethyl acetate fraction of the flowers of H. rosa-sinensis was performed. A series of five phthalates including Di-n-octyl phthalate (HR1), ditridecyl phthalate (HR2), 1-allyl 2-ethyl phthalate (HR3), diethyl phthalate (HR4), and bis (6-methylheptyl) phthalate (HR5) were isolated. The structures of the isolated phthalates were elucidated by gas chromatography–mass spectrometry, 1H NMR, and 13C NMR. In silico and in vitro antidiabetic and antioxidant potential and DFT studies of isolated phthalates were carried out. In our study, isolated ligands were explored as potent antidiabetic as well as antioxidant agents as they exhibited good binding affinity (in in vitro and in silico experiments) against all selected protein targets. Compounds HR1–HR5 showed that the binding affinity value ranged from −5.9 to −5.2 kcal/mol, −5.5 to −4.3 kcal/mol, and −5.0 to −4.1 kcal/mol for target proteins 1HNY, 2I3Y, and 5O40, respectively. Among all isolated phthalates, HR5 can be a lead compound as it showed the best binding affinity with human pancreatic α-amylase (ΔG = −5.9 kcal/mol) and displayed a minimum inhibition concentration (IC50) of 11.69 μM among all phthalates. Compound HR1 was the best docked and scored compound for inhibiting glutathione peroxidase; however, HR2 possessed the lowest binding score of −5.0 kcal/mol, thus indicating the highest potential among isolated phthalates for inhibiting the superoxide dismutase. Furthermore, the top-ranked docked ligand–protein complex for each protein was assessed for stability of protein and complex mobility by molecular dynamics simulation using the IMOD server.

[1]  Chandni Hayat,et al.  Immunoinformatics and Reverse Vaccinology Driven Predication of a Multi-Epitope Vaccine Against Borrelia burgdorferi and Validation Through in silico Cloning and Immune Simulation. , 2023, Current pharmaceutical design.

[2]  S. Maiti,et al.  Molecular dynamic simulation suggests stronger interaction of Omicron-spike with ACE2 than wild but weaker than Delta SARS-CoV-2 can be blocked by engineered S1-RBD fraction , 2022, Structural Chemistry.

[3]  G. Zyryanov,et al.  In Silico Evaluation of Antifungal Compounds from Marine Sponges against COVID-19-Associated Mucormycosis , 2022, Marine drugs.

[4]  T. Mehmood,et al.  Structure-Based Designing, Solvent Less Synthesis of 1,2,3,4-Tetrahydropyrimidine-5-carboxylate Derivatives: A Combined In Vitro and In Silico Screening Approach , 2021, Molecules.

[5]  N. Shafiq,et al.  Copper-catalyzed one-pot relay synthesis of anthraquinone based pyrimidine derivative as a probe for antioxidant and antidiabetic activity , 2021 .

[6]  Z. Nazli,et al.  Phytochemical Profiling of Medicinal Plants Extracts and Their Antioxidant and Anticancer Potentialities Against Human Liver Cancer (Hep G2) Cell Lines , 2021 .

[7]  Ashish Ranjan Sharma,et al.  A Novel Multi-Epitopic Peptide Vaccine Candidate Against Helicobacter pylori: In-Silico Identification, Design, Cloning and Validation Through Molecular Dynamics , 2021, International journal of peptide research and therapeutics.

[8]  A. Chinnathambi,et al.  Evaluating the potency of Sulawesi propolis compounds as ACE-2 inhibitors through molecular docking for COVID-19 drug discovery preliminary study , 2020, Journal of King Saud University - Science.

[9]  Soumya Krishnamurthy,et al.  GC–MS analysis of phytoconstituents from Amomum nilgiricum and molecular docking interactions of bioactive serverogenin acetate with target proteins , 2020, Scientific Reports.

[10]  R. Roy.  Bioactive natural derivatives of phthalate ester , 2020, Critical reviews in biotechnology.

[11]  M. Bouachrine,et al.  Moroccan Medicinal plants as inhibitors against SARS-CoV-2 main protease: Computational investigations , 2020, Journal of biomolecular structure & dynamics.

[12]  V. Pande,et al.  Molecular docking and molecular dynamics simulation approach to screen natural compounds for inhibition of Xanthomonas oryzae pv. Oryzae by targeting peptide deformylase , 2020, Journal of biomolecular structure & dynamics.

[13]  A. Harrath,et al.  New pyrazolo-triazolo-pyrimidine derivatives as antibacterial agents: Design and synthesis, molecular docking and DFT studies , 2020 .

[14]  D. Mcclements,et al.  Effect of rice glutelin-resveratrol interactions on the formation and stability of emulsions: A multiphotonic spectroscopy and molecular docking study , 2019 .

[15]  I. Ferreira,et al.  Isolation of secondary metabolites from Geranium molle L. with anticancer potential , 2019, Industrial Crops and Products.

[16]  Z. Duan,et al.  Five individual polyphenols as tyrosinase inhibitors: Inhibitory activity, synergistic effect, action mechanism, and molecular docking. , 2019, Food chemistry.

[17]  S. Pattanayak,et al.  Structure Based Multitargeted Molecular Docking Analysis of Selected Furanocoumarins against Breast Cancer , 2019, Scientific Reports.

[18]  M. Brestič,et al.  Isolation of Phytochemicals from Bauhinia variegata L. Bark and Their In Vitro Antioxidant and Cytotoxic Potential , 2019, Antioxidants.

[19]  S. K. Baderden,et al.  Pharmacognostical and phytochemical studies of Iraqi Hibiscus rosa-sinensis , 2019 .

[20]  A. Prabakaran,et al.  Synthesis, characterization, spectroscopic studies, DFT and molecular docking analysis of N, N′-dibutyl-3, 3′-diaminobenzidine , 2019, Journal of Molecular Structure.

[21]  A. Oyebamiji,et al.  Theoretical Investigation on Biological Activity of Phenacetin and Its Derivatives via DFT and Docking Approach , 2019, Chemical Science International Journal.

[22]  Estibaliz Sansinenea,et al.  Di-2-ethylhexylphthalate May Be a Natural Product, Rather than a Pollutant , 2018, Journal of Chemistry.

[23]  G. Jayaraman,et al.  In vitro inhibition potential of mono‐n‐octyl phthalate on Mycobacterium tuberculosis H37Ra: Possibility of binding to mycobacterial PknB—An in silico approach , 2018, Biotechnology and applied biochemistry.

[24]  S. Ichwan,et al.  In silico analysis of molecular interactions between the anti-apoptotic protein survivin and dentatin, nordentatin, and quercetin , 2018, Journal of Physics: Conference Series.

[25]  K. Sayın,et al.  Investigation of anticancer properties of caffeinated complexes via computational chemistry methods. , 2018, Spectrochimica acta. Part A, Molecular and biomolecular spectroscopy.

[26]  S. Sawai,et al.  Phytochemical Screening and Evaluation of Cytotoxic Effect and Antioxidant Activity of Fractions Isolated from Stenochlaena palustri (Burm.f.) Bedd. Leaves , 2017 .

[27]  Hagir G. Abd Elaleem,et al.  Potential Antibacterial Activity of Hibiscus rosasinensis Linn Flowers Extracts , 2017 .

[28]  Shahzad Ahmad,et al.  Molecular docking reveals the potential of phthalate esters to inhibit the enzymes of the glucocorticoid biosynthesis pathway , 2017, Journal of applied toxicology : JAT.

[29]  K. Ayub,et al.  Synthesis, structural studies and biological activities of three new 2-(pentadecylthio)-5-aryl-1,3,4-oxadiazoles , 2017 .

[30]  P. Anusooriya,et al.  Isolation, Structural Characterization of Oleic Acid from Zaleya decandra Root Extract , 2016 .

[31]  S. Poda,et al.  Bioactive metabolites produced by Streptomyces Cheonanensis VUK-A from Coringa mangrove sediments: isolation, structure elucidation and bioactivity , 2016, 3 Biotech.

[32]  D. Villemin,et al.  Molecular Structure, HOMO-LUMO, MEP and Fukui Function Analysis of Some TTF-donor Substituted Molecules Using DFT (B3LYP) Calculations , 2016, International Research Journal of Pure and Applied Chemistry.

[33]  S. Tekin,et al.  Alkyl sulfonic acide hydrazides: Synthesis, characterization, computational studies and anticancer, antibacterial, anticarbonic anhydrase II (hCA II) activities , 2015 .

[34]  P. Chavatte,et al.  Docking study: PPARs interaction with the selected alternative plasticizers to di(2-ethylhexyl) phthalate , 2015, Journal of enzyme inhibition and medicinal chemistry.

[35]  B. Honarparvar,et al.  Pentacycloundecane lactam vs lactone norstatine type protease HIV inhibitors: binding energy calculations and DFT study , 2015, Journal of Biomedical Science.

[36]  Bernhard Rupp,et al.  Models of protein–ligand crystal structures: trust, but verify , 2015, Journal of Computer-Aided Molecular Design.

[37]  S. Kumar,et al.  A comparative theoretical study on the biological activity, chemical reactivity, and coordination ability of dichloro-substituted (1,3-thiazol-2-yl)acetamides , 2014 .

[38]  M. Abdollahi,et al.  Are medicinal plants polluted with phthalates? , 2013, DARU Journal of Pharmaceutical Sciences.

[39]  S. Visht,et al.  Isolation of Natural Products , 2012 .

[40]  D. Lachenmeier,et al.  Determination of Diethyl Phthalate and Polyhexamethylene Guanidine in Surrogate Alcohol from Russia , 2011, International journal of analytical chemistry.

[41]  S. Zinjarde,et al.  Potent α-amylase inhibitory activity of Indian Ayurvedic medicinal plants , 2011, BMC complementary and alternative medicine.

[42]  B. Akinpelu,et al.  Studies on the chemical constituents, antioxidants and membrane stability activities of Hibiscus rosa sinensis , 2010 .

[43]  J. Rauha,et al.  Natural products in the process of finding new drug candidates. , 2004, Current medicinal chemistry.

[44]  A. Missoum.  Hibiscus rosa sinensis phytochemistry and medicinal uses , 2018 .

[45]  M. Czaplicka,et al.  Determination of phthalates in polymer materials - comparison of GC/MS and GC/ECD methods , 2013 .

[46]  Hao-Yu Shen,et al.  Simultaneous determination of seven phthalates and four parabens in cosmetic products using HPLC-DAD and GC-MS methods. , 2007, Journal of separation science.