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Medicinal Chemistry

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ISSN (Print): 1573-4064
ISSN (Online): 1875-6638

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Research Article

In vitro, In vivo and In silico Antihyperglycemic Activity of Some Semi-Synthetic Phytol Derivatives

Author(s): Harish C. Upadhyay, Akansha Mishra, Jyotsana Pandey, Pooja Sharma, Akhilesh K. Tamrakar, Arvind K. Srivastava, Feroz Khan and Santosh K. Srivastava*

Volume 18, Issue 1, 2022

Published on: 16 December, 2020

Page: [115 - 121] Pages: 7

DOI: 10.2174/1573406417666201216124018

Price: $65

Abstract

Background: Due to the prevalence of type-2 diabetes across the globe, there is an unmet need to explore new molecular targets for the development of cost-effective and safer antihyperglycemic agents.

Objective: Structural modification of phytol and evaluation of in vitro, in vivo and in silico antihyperglycemic activity of derivatives establishing the preliminary structure activity relationship (SAR).

Methods: The semi-synthetic derivatives of phytol were prepared following previously described methods. The antihyperglycemic potential was measured in vitro in terms of increase in 2- deoxyglucose (2-DG) uptake by L-6 rat skeletal muscle cells as well as in vivo in sucrose-loaded (SLM) and streptozotocin (STZ)-induced diabetic rat models. The blood glucose profile was measured at 30, 60, 90, 120, 180, 240, 300 and 1440 min post administration of sucrose in rats. The in silico docking was performed on peroxisome proliferator-activated receptor gamma (PPARγ) as antidiabetic target along with absorption, distribution, metabolism, excretion and toxicity (ADMET) studies.

Results: Nine semi-synthetic ester derivatives: acetyl (1), lauroyl (2), palmitoyl (3), pivaloyl (4), trans-crotonyl (5), benzoyl (6), m-anisoyl (7), 3,4,5-trimethoxy benzoyl (8) cinnamoyl (9) along with bromo derivative (10) of phytol were prepared. The derivatives 9, 8 and 2 caused 4.5, 3.2 and 2.7 times more in vitro uptake of 2-DG respectively than rosiglitazone (ROSI). The derivatives showed significant improvement in oral glucose tolerance both in SLM (29.6-21%) as well as STZ-induced diabetic (30.8-19.0%) rats. The in silico ADMET, docking studies showed non-toxicity and high binding affinity with PPARγ.

Conclusion: The potent antihyperglycemic activity with favorable pharmacokinetics supports phytol derivatives as a suitable antidiabetic lead.

Keywords: Phytol, diabetes, semi-synthesis, docking studies, PPARγ, ADMET.

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[1]
Zimmet, P.Z. Diabetes and its drivers: the largest epidemic in human history? Clin. Diabetes Endocrinol., 2017, 3, 1.
[http://dx.doi.org/10.1186/s40842-016-0039-3] [PMID: 28702255]
[2]
American Diabetes Association Economic costs of diabetes in the U.S. in 2017. Diabetes Care, 2018, 41(5), 917-928.
[http://dx.doi.org/10.2337/dci18-0007] [PMID: 29567642]
[3]
Krentz, A.J.; Ferner, R.E.; Bailey, C.J. Comparative tolerability profiles of oral antidiabetic agents. Drug Saf., 1994, 11(4), 223-241.
[http://dx.doi.org/10.2165/00002018-199411040-00002] [PMID: 7848543]
[4]
Kanaya, A.M.; Herrington, D.; Vittinghoff, E.; Ewing, S.K.; Liu, K.; Blaha, M.J.; Dave, S.S.; Qureshi, F.; Kandula, N.R. Understanding the high prevalence of diabetes in U.S. south Asians compared with four racial/ethnic groups: the MASALA and MESA studies. Diabetes Care, 2014, 37(6), 1621-1628.
[http://dx.doi.org/10.2337/dc13-2656] [PMID: 24705613]
[5]
Pramanik, S.; Rathwa, N.; Patel, R.; Ramachandran, A.V.; Begum, R. Treatment avenues for type 2 diabetes and current perspectives on adipokines. Curr. Diabetes Rev., 2018, 14(3), 201-221.
[http://dx.doi.org/10.2174/1573399813666170112142837] [PMID: 28081698]
[6]
Xiao, E.; Luo, L. Alternative therapies for diabetes: A comparison of western and traditional Chinese medicine (TCM) approaches. Curr. Diabetes Rev., 2018, 14(6), 487-496.
[http://dx.doi.org/10.2174/1573399813666170519103230] [PMID: 28523995]
[7]
Varela, M.T.; Fernandes, J.P.S. Natural Products: Key prototypes to drug discovery against neglected diseases caused by Trypanosomatids. Curr. Med. Chem., 2020, 27(13), 2133-2146.
[http://dx.doi.org/10.2174/0929867325666180501102450] [PMID: 29714138]
[8]
Harvey, A.L. Plant natural products in anti-diabetic drug discovery. Curr. Org. Chem., 2010, 14(16), 1670-1677.
[http://dx.doi.org/10.2174/138527210792927681]
[9]
Upadhyay, H.C. Medicinal chemistry of alternative therapeutics: Novelty and hopes with genus Ammannia. Curr. Top. Med. Chem., 2019, 19(10), 784-794.
[http://dx.doi.org/10.2174/1568026619666190412101047] [PMID: 30977452]
[10]
Thomford, N.E.; Senthebane, D.A.; Rowe, A.; Munro, D.; Seele, P.; Maroyi, A.; Dzobo, K. Natural products for drug discovery in the 21st century: Innovations for novel drug discovery. Int. J. Mol. Sci., 2018, 19(6), 1578.
[http://dx.doi.org/10.3390/ijms19061578] [PMID: 29799486]
[11]
Dwivedi, G.R.; Upadhyay, H.C.; Yadav, D.K.; Singh, V.; Srivastava, S.K.; Khan, F.; Darmwal, N.S.; Darokar, M.P. 4-Hydroxy-α-tetralone and its derivative as drug resistance reversal agents in multi drug resistant Escherichia coli. Chem. Biol. Drug Des., 2014, 83(4), 482-492.
[http://dx.doi.org/10.1111/cbdd.12263] [PMID: 24267788]
[12]
Islam, M.T.; Ali, E.S.; Uddin, S.J.; Shaw, S.; Islam, M.A.; Ahmed, M.I.; Chandra Shill, M.; Karmakar, U.K.; Yarla, N.S.; Khan, I.N.; Billah, M.M.; Pieczynska, M.D.; Zengin, G.; Malainer, C.; Nicoletti, F.; Gulei, D.; Berindan-Neagoe, I.; Apostolov, A.; Banach, M.; Yeung, A.W.K.; El-Demerdash, A.; Xiao, J.; Dey, P.; Yele, S.; Jóźwik, A.; Strzałkowska, N.; Marchewka, J.; Rengasamy, K.R.R.; Horbańczuk, J.; Kamal, M.A.; Mubarak, M.S.; Mishra, S.K.; Shilpi, J.A.; Atanasov, A.G. Phytol: A review of biomedical activities. Food Chem. Toxicol., 2018, 121, 82-94.
[http://dx.doi.org/10.1016/j.fct.2018.08.032] [PMID: 30130593]
[13]
Gloerich, J.; van den Brink, D.M.; Ruiter, J.P.N.; van Vlies, N.; Vaz, F.M.; Wanders, R.J.A.; Ferdinandusse, S. Metabolism of phytol to phytanic acid in the mouse, and the role of PPARalpha in its regulation. J. Lipid Res., 2007, 48(1), 77-85.
[http://dx.doi.org/10.1194/jlr.M600050-JLR200] [PMID: 17015885]
[14]
Heim, M.; Johnson, J.; Boess, F.; Bendik, I.; Weber, P.; Hunziker, W.; Fluhmann, B. Phytanic acid, a natural peroxisome proliferator-activated receptor (PPAR) agonist, regulates glucose metabolism in rat primary hepatocytes. FASEB J., 2002, 16(7), 718-720.
[http://dx.doi.org/10.1096/fj.01-0816fje] [PMID: 11923221]
[15]
McGinty, D.; Letizia, C.S.; Api, A.M. Fragrance material review on phytol. Food Chem. Toxicol., 2010, 48(Suppl. 3), S59-S63.
[http://dx.doi.org/10.1016/j.fct.2009.11.012] [PMID: 20141879]
[16]
Saludes, J.P.; Garson, M.J.; Franzblau, S.G.; Aguinaldo, A.M. Antitubercular constituents from the hexane fraction of Morinda citrifolia Linn. (Rubiaceae). Phytother. Res., 2002, 16(7), 683-685.
[http://dx.doi.org/10.1002/ptr.1003] [PMID: 12410555]
[17]
Alencar, M.V.O.B.; Islam, M.T.; Ali, E.S.; Santos, J.V.O.; Paz, M.F.C.J.; Sousa, J.M.C.; Dantas, S.M.M.M.; Mishra, S.K.; Cavalcante, A.A.C.M. Association of phytol with toxic and cytotoxic activities in an antitumoral perspective: A meta- analysis and systemic review. Anticancer. Agents Med. Chem., 2018, 18(13), 1828-1837.
[http://dx.doi.org/10.2174/1871520618666180821113830] [PMID: 30129418]
[18]
Costa, J.P.; Islam, M.T.; Santos, P.S.; Ferreira, P.B.; Oliveira, G.L.; Alencar, M.V.; Paz, M.F.; Ferreira, É.L.; Feitosa, C.M.; Citó, A.M.; Sousa, D.P.; Melo-Cavalcante, A.A. Evaluation of antioxidant activity of phytol using non- and pre-clinical models. Curr. Pharm. Biotechnol., 2016, 17(14), 1278-1284.
[http://dx.doi.org/10.2174/1389201017666161019155715] [PMID: 27774891]
[19]
Islam, M.T.; Ray, P.; Khalipha, A.B.R.; Hassan, S.M.H.; Khan, M.R.; Rouf, R. Molecular docking study of the phytol and its derivatives against COX-2 induced inflammation: a combined density functional study. Recent Res. Sci. Technol., 2020, 12(1), 1-5.
[http://dx.doi.org/10.25081/rrst.2020.12.6083]
[20]
Sanjeev, G.; Sidharthan, D.S.; Pranavkrishna, S.; Pranavadithya, S.; Abhinandan, R.; Akshaya, R.L.; Balagangadharan, K.; Siddabathuni, N.; Srinivasan, S.; Selvamurugan, N. An osteoinductive effect of phytol on mouse mesenchymal stem cells (C3H10T1/2) towards osteoblasts. Bioorg. Med. Chem. Lett., 2020, 30(11)127137
[http://dx.doi.org/10.1016/j.bmcl.2020.127137] [PMID: 32245598]
[21]
Upadhyay, H.C.; Dwivedi, G.R.; Roy, S.; Sharma, A.; Darokar, M.P.; Srivastava, S.K. Phytol derivatives as drug resistance reversal agents. ChemMedChem, 2014, 9(8), 1860-1868.
[http://dx.doi.org/10.1002/cmdc.201402027] [PMID: 24891085]
[22]
Saxena, A.; Upadhyay, H.C.; Cheema, H.S.; Srivastava, S.K.; Darokar, M.P.; Bawankule, D.U. Antimalarial activity of phytol derivatives: in vitro and in vivo study. Med. Chem. Res., 2018, 27(5), 1345-1354.
[http://dx.doi.org/10.1007/s00044-017-2132-2]
[23]
Elmazar, M.M.; El-Abhar, H.S.; Schaalan, M.F.; Farag, N.A. Phytol/Phytanic acid and insulin resistance: potential role of phytanic acid proven by docking simulation and modulation of biochemical alterations. PLoS One, 2013, 8(1)e45638
[http://dx.doi.org/10.1371/journal.pone.0045638] [PMID: 23300941]
[24]
Tamrakar, A.K.; Jaiswal, N.; Yadav, P.P.; Maurya, R.; Srivastava, A.K. Pongamol from Pongamia pinnata stimulates glucose uptake by increasing surface GLUT4 level in skeletal muscle cells. Mol. Cell. Endocrinol., 2011, 339(1-2), 98-104.
[http://dx.doi.org/10.1016/j.mce.2011.03.023] [PMID: 21497640]
[25]
Mishra, A.; Srivastava, R.; Srivastava, S.P.; Gautam, S.; Tamrakar, A.K.; Maurya, R.; Srivastava, A.K. Antidiabetic activity of heart wood of Pterocarpus marsupium Roxb. and analysis of phytoconstituents. Indian J. Exp. Biol., 2013, 51(5), 363-374.
[PMID: 23821824]
[26]
Mishra, A.; Srivastava, R.; Srivastava, A.K. Comparative antidiabetic profile of ayurvedic herbo-mineral formulation and its constituents on normal and streptozotocin-induced diabetic rats. Int. J. Pharm. Sci. Rev. Res., 2013, 22, 252-263.
[27]
Morris, G.M.; Huey, R.; Lindstrom, W.; Sanner, M.F.; Belew, R.K.; Goodsell, D.S.; Olson, A.J. AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility. J. Comput. Chem., 2009, 30(16), 2785-2791.
[http://dx.doi.org/10.1002/jcc.21256] [PMID: 19399780]
[28]
Tiwari, P.; Sharma, P.; Khan, F.; Sangwan, N.S.; Mishra, B.N.; Sangwan, R.S. Structure activity relationship studies of gymnemic acid analogues for antidiabetic activity targeting PPARγ. Curr Comput Aided Drug Des, 2015, 11(1), 57-71.
[http://dx.doi.org/10.2174/1573409911666150610093611] [PMID: 26058590]
[29]
Yadav, D.K.; Mudgal, V.; Agrawal, J.; Maurya, A.K.; Bawankule, D.U.; Chanotiya, C.S.; Khan, F.; Thul, S.T. Molecular docking and ADME studies of natural compounds of Agarwood oil for topical anti-inflammatory activity. Curr Comput Aided Drug Des, 2013, 9(3), 360-370.
[http://dx.doi.org/10.2174/1573409911309030012] [PMID: 23566359]
[30]
Celi, F.S.; Shuldiner, A.R. The role of peroxisome proliferator-activated receptor gamma in diabetes and obesity. Curr. Diab. Rep., 2002, 2(2), 179-185.
[http://dx.doi.org/10.1007/s11892-002-0078-2] [PMID: 12643137]
[31]
Hauner, H. The mode of action of thiazolidinediones. Diabetes Metab. Res. Rev., 2002, 18(2)(Suppl. 2), S10-S15.
[http://dx.doi.org/10.1002/dmrr.249] [PMID: 11921433]
[32]
Upadhyay, H.C.; Jaiswal, N.; Tamrakar, A.K.; Srivastava, A.K.; Gupta, N.; Srivastava, S.K. Antihyperglycemic agents from Ammannia multiflora. Nat. Prod. Commun., 2012, 7(7), 899-900.
[http://dx.doi.org/10.1177/1934578X1200700724] [PMID: 22908576]

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