Phytochemical study and pharmacological activity of Terminalia chebula fruit extracts activity as Dihydrofolate Reductase enzyme inhibitors associated with antioxidant effect: In vitro study

Authors

  • Marwah Mohammed Salih Ali Department of Pharmacology and Toxicology/ College of Pharmacy/ Mustansiriyah University, Baghdad, Iraq
  • Mayssaa Essam Abdalah Department of Clinical Laboratory Sciences/ College of Pharmacy/ Mustansiriyah University, Baghdad, Iraq
  • Bahir Abdul-Razzaq Mshimesh Department of Pharmacology and Toxicology/ College of Pharmacy/ Mustansiriyah University, Baghdad, Iraq

DOI:

https://doi.org/10.32947/ajps.v22i4.948

Keywords:

Dihydrofolate reductase (DHFR), Terminalia chebula, phytochemical analysis, antioxidant activity.

Abstract

Dihydrofolate reductase (DHFR) is a fundamental enzyme in producing the precursor of purines and pyrimidines for biosynthesis of DNA, RNA and amino acids at various stages. It is considered the key target for both anticancer and antimicrobial drug design.

Terminalia chebula has unique phytoconstituents which are employed broadly in the development of medications against different diseases. It has been established that Terminalia chebula fruit could be used as therapeutic agent for cancer treatment. The aim of study was to evaluate the inhibitory effect of T. chebula fruit extract against DHFR enzyme activity and assessment the antioxidant and scavenging activity of T. chebula fruit extract, using DPPH and reducing activity tests Terminalia chebula fruits where extracted. The anti- DHFR enzyme activity was assessed in vitro for the four extracts of Terminalia chebula fruit and MTX. Phytochemical analysis of screening test, gas chromatography-mass spectrometry (GC-MS) analysis and high-performance liquid chromatography (HPLC) was done for the extract with highest biological activity. Antioxidant and radical scavenging activity of the extract with highest biological activity were evaluated via DPPH [1, 1-diphenyl-2-picrylhydrazyl (α, α-diphenyl-β-picrylhydrazyl] and reductive ability test. The percent of DHFR inhibiting activity for the cold methanolic extract was the highest and it was higher than that of MTX (96.0±1.4% vs. 89.0±1.1%, respectively), therefore, it was selected for the proceeding assay. Phytochemical analysis showed that the cold methanolic extract of T. chebula, showed a positive reaction for alkaloids, flavonoids, phenolic compounds, steroids and saponins. Besides, GC-MS analysis showed the presence of pyrogallol compound, while HPLC analysis recorded 3 major peaks with different retention times that were semi-identical to gallic acid, rutin and quercetin standard. The highest radical scavenging activity of T.chebula cold methanolic extract and ascorbic acid according to DPPH were (80.1±2.04% and 85.83±2.1%, respectively) at the maximum studied concentration (200μg/ml), where the activity of ascorbic acid was significantly higher (p≤0.05) than that of T.chebula. Meanwhile, the reductive ability of the cold extract was significantly higher (p ≤ 0.05) than that of vitamin E (0.72±0.15 and 0.41±0.08, respectively) at the maximum studied concentration (250μg/ml). These results suggesting the cold extract of Terminalia chebula has in vitro prominent anti-dihydrofolate reductase activity which is better than that of MTX.

 

References

- Srinivasan B, Tonddast‐Navaei S, Roy A, Zhou H, Skolnick J. Chemical space of Escherichia coli dihydrofolate reductase inhibitors: new approaches for discovering novel drugs for old bugs. Medicinal research reviews. 2019 Mar; 39(2):684-705. DOI: https://doi.org/10.1002/med.21538

- Raimondi MV, Randazzo O, La Franca M, Barone G, Vignoni E, Rossi D, Collina S. DHFR inhibitors: reading the past for discovering novel anticancer agents. Molecules. 2019 Jan; 24(6):1140. DOI: https://doi.org/10.3390/molecules24061140

- Babu BH. Chapter-8 Medicinal and Phytopharmacological Activities of Terminalia Species. Chief Editor. 2020:13

- Singh A, Deshpande N, Pramanik N, Jhunjhunwala S, Rangarajan A, Atreya HS. Optimized peptide-based inhibitors targeting the dihydrofolate reductase pathway in cancer. Scientific reports. 2018 Feb 16; 8(1):1-8. DOI: https://doi.org/10.1038/s41598-018-21435-5

- Gholamhossein A, Mohammadi A, Noroozi S, Sharifi-far F. Inhibitory effect of some methanol plant extracts on dihydrofolate reductase. Toxicological & Environmental Chemistry. 2011 Feb 1; 93(2):261-9. DOI: https://doi.org/10.1080/02772248.2010.522769

- Wang M, Yang J, Yuan M, Xue L, Li H, Tian C, Wang X, Liu J, Zhang Z. Synthesis and antiproliferative activity of a series of novel 6-substituted pyrido [3, 2-d] pyrimidines as potential nonclassical lipophilic antifolates targeting dihydrofolate reductase. European journal of medicinal chemistry. 2017 Mar 10; 128:88-97 DOI: https://doi.org/10.1016/j.ejmech.2017.01.033

- Kalogris C, Garulli C, Pietrella L, Gambini V, Pucciarelli S, Lucci C, Tilio M, Zabaleta ME, Bartolacci C, Andreani C, Giangrossi M. Sanguinarine suppresses basal-like breast cancer growth through dihydrofolate reductase inhibition. Biochemical pharmacology. 2014 Aug 1; 90(3):226-34. DOI: https://doi.org/10.1016/j.bcp.2014.05.014

- Albalawi MA, Bashir NA, Tawfik A. Anticancer and antifolate activities of extracts of six Saudi Arabian wild plants used in folk medicine. J. Life Sci. 2015; 9:334-40.

- Akhtar H, Husain SZ. A Descriptive Review on Traditional Herbal Drug-Terminalia Chebula. Journal of Advanced Research in Biochemistry and Pharmacology. 2019 Jul 1; 2(1):21-8.

- Zhao L, Duan Z, Wang Y, Wang M, Liu Y, Wang X, Li H. Protective effect of Terminalia chebula Retz. Extract against Aβ aggregation and Aβ-induced toxicity in Caenorhabditis elegans. Journal of Ethnopharmacology. 2021 Mar 25; 268:113640. DOI: https://doi.org/10.1016/j.jep.2020.113640

- Nigam M, Mishra AP, Adhikari‐Devkota A, Dirar AI, Hassan MM, Adhikari A, Belwal T, Devkota HP. Fruits of Terminalia chebula Retz.: A review on traditional uses, bioactive chemical constituents and pharmacological activities. Phytotherapy Research. 2020 Oct; 34(10):2518-33. DOI: https://doi.org/10.1002/ptr.6702

- Venkatesan A, Kathirvel A, Prakash S, Sujatha V. Antioxidant, antibacterial activities and identification of bioactive compounds from Terminalia chebula bark extracts. Free Radicals and Antioxidants. 2017;7(1):43-9. DOI: https://doi.org/10.5530/fra.2017.1.7

- Suganthy N, Muniasamy S, Archunan G. Safety assessment of methanolic extract of Terminalia chebula fruit, Terminalia arjuna bark and its bioactive constituent 7-methyl gallic acid: In vitro and in vivo studies. Regulatory Toxicology and Pharmacology. 2018 Feb 1; 92:347-57. DOI: https://doi.org/10.1016/j.yrtph.2017.12.019

- Choudhary RA, Manivannan E, Chandrashekar R, Ravi I, Sivasankari V, Arul AK. Phytochemical analysis of ethanolic extract of fruits of Terminalia chebula and its medicinal use in human. Phytochemical analysis. 2021; 2:43-54.

- Hayat J, Akodad M, Moumen A, Baghour M, Skalli A, Ezrari S, Belmalha S. Phytochemical screening, polyphenols, flavonoids and tannin content, antioxidant activities and FTIR characterization of Marrubium vulgare L. from 2 different localities of Northeast of Morocco. Heliyon. 2020 Nov 1;6(11): e05609. DOI: https://doi.org/10.1016/j.heliyon.2020.e05609

- Khalaf HA, Mahdi MF, and Abaas IS. Preliminary Phytochemical and GC-MS analysis of chemical constituents of Iraqi Plantago lanceoleta L. Al-Mustansiriyah Journal of Pharmaceutical Sciences (AJPS) (2018); 18.2: 114-121 DOI: https://doi.org/10.32947/ajps.v18i2.485

- AlSheikh HM, Sultan I, Kumar V, Rather IA, Al-Sheikh H, Tasleem Jan A, Haq QM. Plant-based phytochemicals as possible alternative to antibiotics in combating bacterial drug resistance. Antibiotics. 2020 Aug; 9(8):480. DOI: https://doi.org/10.3390/antibiotics9080480

- Pompimon W, Wattananon S, Udomputtimekakul P, Baison W, Sombutsiri P, Chuajedton A, Wingwon B. HPLC Determination of the Gallic Acid and Chebulinic Acid Contents of Phyllanthus emblica Linn., Terminalia bellirica Roxb., Terminalia chebula Retz. and Triphala Products from Chae Son district, Lampang, Thailand. American Journal of Food Science and Technology. 2020; 8(3):87-98.

- Ismaeel S, Waheed HJ, Kamel WM. Extraction and Detection of Some Flavonoids from Tamarix aphylla (F. Tamaricaceae) Grown in Iraq. Al Mustansiriyah Journal of Pharma- ceutical Sciences. 2020;20(4):156-62. DOI: https://doi.org/10.32947/ajps.v20i4.785

- Boligon AA, Jesus RD, Piana M, de Brum TF, da Cruz RC, Mossmann N, Athayde ML. Development and Validation of an HPLC-DAD Analysis for Flavonoids in the gel of Scutia buxifolia. Journal of Chromatographic Science. 2015 Oct 1; 53(9):1557-61. 75 DOI: https://doi.org/10.1093/chromsci/bmv056

- Dharmaratne M, Manoraj A, Thevanesam V, Ekanayake A, Kumar NS, Liyanapathirana V, Abeyratne E, Bandara BM. Terminalia bellirica fruit extracts: in-vitro antibacterial activity against selected multidrug-resistant bacteria, radical scavenging activity and cytotoxicity study on BHK-21 cells. BMC complementary and alternative medicine. 2018 Dec; 18(1):1-2. DOI: https://doi.org/10.1186/s12906-018-2382-7

- Saha S, Verma RJ. Antioxidant activity of polyphenolic extract of Terminalia chebula Retzius fruits. Journal of taibah university for science. 2016 Oct 1; 10(6):805-12. DOI: https://doi.org/10.1016/j.jtusci.2014.09.003

- Mandeville A, Cock IE. Terminalia chebula Retz. Fruit extracts inhibit bacterial triggers of some autoimmune diseases and potentiate the activity of tetracycline. Indian journal of microbiology. 2018 Dec; 58(4):496-506. DOI: https://doi.org/10.1007/s12088-018-0754-9

- Promila P, Madan VK. Therapeutic & phytochemical profiling of Terminalia chebula Retz. (harad): A review. J. Med. Plants Stud. 2018; 6:25-31.

- Manosroi A, Jantrawut P, Akihisa T, Manosroi W, Manosroi J. In vitro anti-aging activities of Terminalia chebula gall extract. Pharmaceutical Biology. 2010 Apr 1; 48(4):469-81. DOI: https://doi.org/10.3109/13880200903586286

- Surya Prakash DV, Meena V. Experimental and Modelling Equation of Chebulinic acid from the composition of medicinal herbs by using soxhlet extractor. International Journal of Innovative Research in Science, Engineering and Technology. 2015; 4(7):5217-20. DOI: https://doi.org/10.15680/IJIRSET.2015.0407025

- Sheng Z, Zhao J, Muhammad I, Zhang Y. Optimization of total phenolic content from Terminalia chebula Retz. Fruits using response surface methodology and evaluation of their antioxidant activities. PloS one. 2018 Aug 14;13(8): e0202368. DOI: https://doi.org/10.1371/journal.pone.0202368

- Baharuddin NS, Abdullah H, Wahab WN. Anti-Candida activity of Quercus infectoria gall extracts against Candida species. Journal of pharmacy & bioallied sciences. 2015 Jan;7(1):15. DOI: https://doi.org/10.4103/0975-7406.148742

- Zeeshan U, Barkat MQ, Mahmood HK. Phytochemical and antioxidant screening of Cassia angustifolia, Curcuma zedoaria, Embelia ribes, Piper nigrum, Rosa damascena, Terminalia belerica, Terminalia chebula, Zingiber officinale and their effect on stomach and liver. Matrix Sci. Pharma. 2018;2(2):15-20. DOI: https://doi.org/10.26480/msp.02.2018.15.20

- Swargiary A, Daimari M, Roy M, Haloi D, Ramchiary B. Evaluation of phytochemical properties and larvicidal activities of Cynodon dactylon, Clerodendrum viscosum, Spilanthes acmella and Terminalia chebula against Aedes aegypti. Asian Pacific Journal of Tropical Medicine. 2019 May 1;12(5):224 DOI: https://doi.org/10.4103/1995-7645.259243

- Singh G, Kumar P. Extraction, gas chromatography–mass spectrometry analysis and screening of fruits of Terminalia chebula Retz. For its antimicrobial potential. Pharmacognosy research. 2013 Jul; 5(3):162. DOI: https://doi.org/10.4103/0974-8490.112421

- Sabir SM, Abbas SR, Shahida S, Khan MF. In-Vitro antioxidant, anti-lipid peroxidative activities and In-Silico study of Terminalia chebula bioactive compounds. Clinical Phytoscience. 2020 Dec; 6(1):1-9. DOI: https://doi.org/10.1186/s40816-020-00233-5

- Naik GH, Priyadarsini KI, Naik DB, Gangabhagirathi R, Mohan H. Studies on the aqueous extract of Terminalia chebula as a potent antioxidant and a probable radioprotector. Phytomedicine. 2004 Sep 20; 11(6):530-8. DOI: https://doi.org/10.1016/j.phymed.2003.08.001

- Rani AA, Jeeva S, Punitha SM. Anti-Oxidant, Anti-Inflammatory, Antiproliferative and Apoptotic Properties of Terminalia Chebula (Fruit) Towards Raw 264.7 And Oral KB Cell Lines. International Journal of Applied and Pure Science and Agriculture. 2016; 2(5):90-100.

- Kathirvel A, Sujatha V. In vitro assessment of antioxidant and antibacterial properties of Terminalia chebula Retz. Leaves. Asian Pacific Journal of Tropical Biomedicine. 2012 Feb 1;2(2): S788 DOI: https://doi.org/10.1016/S2221-1691(12)60314-1

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Published

2023-01-15

How to Cite

Marwah Mohammed Salih Ali, Mayssaa Essam Abdalah, & Bahir Abdul-Razzaq Mshimesh. (2023). Phytochemical study and pharmacological activity of Terminalia chebula fruit extracts activity as Dihydrofolate Reductase enzyme inhibitors associated with antioxidant effect: In vitro study. Al Mustansiriyah Journal of Pharmaceutical Sciences, 22(4), 9–22. https://doi.org/10.32947/ajps.v22i4.948