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Letters in Drug Design & Discovery

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ISSN (Print): 1570-1808
ISSN (Online): 1875-628X

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Research Article

In Vitro and In Silico Studies of Glycyrrhetinic Acid Derivatives as Antitubercular Agents

Author(s): Sadhna Vishwakarma, Naveen K. Khare*, Aparna Shukla, Feroz Khan, Priyanka Trivedi, Vinita Chaturvedi and Santosh K. Srivastava*

Volume 20, Issue 4, 2023

Published on: 21 October, 2022

Page: [479 - 487] Pages: 9

DOI: 10.2174/1570180819666220929122614

Price: $65

Abstract

Background: Glycyrrhetinic acid (GA) is a biologically active triterpenoid acid, isolated from the root of the Glycyrrhiza plant species. In our earlier studies, the semisynthetic analogs of GA have been reported to possess improved anticancer activities against various cell lines, antimalarial, and antifilarial activities.

Objective: Synthesis of novel C-3 aryl ester derivatives and evaluation of antitubercular activity in order to study structure activity relationship (SAR).

Methods: GA was isolated and characterized from roots of Glycyrrhiza glabra and converted to its various C-3 aryl ester derivatives via the protection of C-30 carboxylic group. Antitubercular activity was determined against Mycobacterium tuberculosis H37Ra by Agar dilution assay. The in silico docking was performed for the most active analogue against three antitubercular targets, catalase peroxidase, dihydrofolate reductase and enoyl-ACP reductase.

Results: The derivatives, Methyl glycyrrhetinate (GA-1), 3-O-(4-methyl-phenyl)-ethanoyl methyl glycyrrhetinate (GA-1a), 3-O-(4-fluoro phenyl)-ethanoyl methyl glycyrrhetinate (GA-1c), 3-O-(4-methoxy trans cinnamyl)-ethanoyl methyl glycyrrhetinate (GA-1e) and 3-O-{(4-chlorophenyl)-ethanoyl methyl glycyrrhetinate (GA-1g) showed improved antitubercular activity (in the range 38.76 to 51.546 mM) over the parent molecule (MIC >106.157 mM). The derivative, 3-O-(4-aminobenzoyl)- methyl glycyrrhetinate (GA-1h) was found most active (MIC 20.695 mM), which was further supported by high binding affinity with the selected antitubercular target proteins in in silico docking studies.

Conclusion: Synthetic modifications on GA led to C-3 aryl ester derivatives with improved antitubercular activities. Further studies for the development of GA-1h as potential antitubercular lead is therefore warranted.

Keywords: Glycyrrhetinic acid, Triterpenoids, Semi-synthesis, Antitubercular, Docking, In Vitro, In Silico.

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[1]
Global tuberculosis report. World Health Organization 2021. Available from: https://www.who.int/publications/i/item/9789240037021 (Accessed October 14, 2021).
[2]
Klinton, J.S. Oga-Omenka, C.; Heitkamp, P. TB and COVID-Public and private health sectors adapt to a new reality. J. Clin. Tuberc. Other Mycobact. Dis., 2020, 21, 100199.
[http://dx.doi.org/10.1016/j.jctube.2020.100199] [PMID: 33163631]
[3]
Sotgiu, G.; Centis, R.; D’ambrosio, L.; Migliori, G.B. Tuberculosis treatment and drug regimens. Cold Spring Harb. Perspect. Med., 2015, 5(5), a017822.
[http://dx.doi.org/10.1101/cshperspect.a017822] [PMID: 25573773]
[4]
Singh, V.; Kabra, S.K. Advances in tuberculosis: Diagnostics. Indian J. Pediatr., 2019, 86(5), 439-440.
[http://dx.doi.org/10.1007/s12098-019-02942-3] [PMID: 30945232]
[5]
Prasad, R.; Gupta, N.; Banka, A. Multidrug-resistant tuberculosis/rifampicin-resistant tuberculosis: Principles of management. Lung India, 2018, 35(1), 78-81.
[http://dx.doi.org/10.4103/lungindia.lungindia_98_17] [PMID: 29319042]
[6]
Global tuberculosis report. World Health Organization, 2018. Available from: https://www.who.int/tb/publications/global_report/gtbr2018_main_text_28Feb (Accessed on: October 14, 2021).
[7]
Tian, X.R.; Feng, J.T.; Ma, Z.Q.; Xie, N.; Zhang, J.; Zhang, X.; Tang, H.F. Three new glycosides from the whole plant of Clematis lasiandra Maxim and their cytotoxicity. Phytochem. Lett., 2014, 10, 168-172.
[http://dx.doi.org/10.1016/j.phytol.2014.09.004]
[8]
Tucker, A.O.; Wink, M. Medicinal plants of the world: An illustrated scientific guide to important medicinal plants and their uses. Brittonia, 2004, 56(4), 381.
[http://dx.doi.org/10.1663/0007-196X(2004)056[0381:BR]2.0.CO;2]
[9]
Rout, S.P.; Choudary, K.A.; Kar, D.M.; Das, L.O.P.A.M.U.D.R.A.; Jain, A. Plants in traditional medicinal system-future source of new drugs. Int. J. Pharm. Pharm. Sci., 2009, 1(1), 1-23.
[10]
Upadhyay, H.C.; Singh, M.; Prakash, O.; Khan, F.; Srivastava, S.K.; Bawankule, D.U. QSAR, ADME and docking guided semi-synthesis and in vitro evaluation of 4-hydroxy-α-tetralone analogs for anti-inflammatory activity. SN Appl. Sci., 2020, 2(12), 2069.
[http://dx.doi.org/10.1007/s42452-020-03798-5]
[11]
Upadhyay, H.C. Coumarin-1,2,3-triazole hybrid molecules: An emerging scaffold for combating drug resistance. Curr. Top. Med. Chem., 2021, 21(16), 737-752.
[http://dx.doi.org/10.2174/1568026621666210303145759]
[12]
Jäger, S.; Trojan, H.; Kopp, T.; Laszczyk, M.; Scheffler, A. Pentacyclic triterpene distribution in various plants - rich sources for a new group of multi-potent plant extracts. Molecules, 2009, 14(6), 2016-2031.
[http://dx.doi.org/10.3390/molecules14062016] [PMID: 19513002]
[13]
Salvador, J.A.R.; Moreira, V.M.; Gonçalves, B.M.F.; Leal, A.S.; Jing, Y. Ursane-type pentacyclic triterpenoids as useful platforms to discover anticancer drugs. Nat. Prod. Rep., 2012, 29(12), 1463-1479.
[http://dx.doi.org/10.1039/c2np20060k] [PMID: 23047641]
[14]
Gao, D.; Tang, S. Duan; Tong, Oleanolic acid liposomes with polyethylene glycol modification: Promising antitumor drug delivery. Int. J. Nanomedicine, 2012, 7, 3517-3526.
[http://dx.doi.org/10.2147/IJN.S31725] [PMID: 22848175]
[15]
Srivastava, V.; Negi, A.S.; Kumar, J.K.; Gupta, M.M.; Khanuja, S.P.S. Plant-based anticancer molecules: A chemical and biological profile of some important leads. Bioorg. Med. Chem., 2005, 13(21), 5892-5908.
[http://dx.doi.org/10.1016/j.bmc.2005.05.066] [PMID: 16129603]
[16]
Gautam, R.; Jachak, S.M. Recent developments in anti-inflammatory natural products. Med. Res. Rev., 2009, 29(5), 767-820.
[http://dx.doi.org/10.1002/med.20156] [PMID: 19378317]
[17]
Zhu, Y.M.; Shen, J.K.; Wang, H.K.; Cosentino, L.M.; Lee, K.H. Synthesis and anti-HIV activity of oleanolic acid derivatives. Bioorg. Med. Chem. Lett., 2001, 11(24), 3115-3118.
[http://dx.doi.org/10.1016/S0960-894X(01)00647-3] [PMID: 11720855]
[18]
Kalani, K.; Chaturvedi, V.; Alam, S.; Khan, F.; Srivastava, S. Anti-tubercular agents from Glycyrrhiza glabra. Curr. Top. Med. Chem., 2015, 15(11), 1043-1049.
[http://dx.doi.org/10.2174/1568026615666150317223323] [PMID: 25786503]
[19]
Kalani, K.; Agarwal, J.; Alam, S.; Khan, F.; Pal, A.; Srivastava, S.K. In silico and in vivo anti-malarial studies of 18β glycyrrhetinic acid from Glycyrrhiza glabra. PLoS One, 2013, 8(9), e74761.
[http://dx.doi.org/10.1371/journal.pone.0074761] [PMID: 24086367]
[20]
Pastorino, G.; Cornara, L.; Soares, S.; Rodrigues, F.; Oliveira, M.B.P.P. Liquorice (Glycyrrhiza glabra): A phytochemical and pharmacological review. Phytother. Res., 2018, 32(12), 2323-2339.
[http://dx.doi.org/10.1002/ptr.6178] [PMID: 30117204]
[21]
Sheng, H.; Sun, H. Synthesis, biology and clinical significance of pentacyclic triterpenes: A multi-target approach to prevention and treatment of metabolic and vascular diseases. Nat. Prod. Rep., 2011, 28(3), 543-593.
[http://dx.doi.org/10.1039/c0np00059k] [PMID: 21290067]
[22]
Pollier, J.; Goossens, A. Oleanolic acid. Phytochemistry, 2012, 77, 10-15.
[http://dx.doi.org/10.1016/j.phytochem.2011.12.022] [PMID: 22377690]
[23]
Yadav, D.; Kalani, K.; Khan, F.; Srivastava, S. QSAR and docking based semi-synthesis and in vitro evaluation of 18 β-glycyrrhetinic acid derivatives against human lung cancer cell line A-549. Med. Chem., 2013, 9(8), 1073-1084.
[http://dx.doi.org/10.2174/1573406411309080009] [PMID: 23675978]
[24]
Kenneth McClatchy, J. Susceptibility testing of mycobacteria. Lab. Med., 1978, 9(3), 47-52.
[http://dx.doi.org/10.1093/labmed/9.3.47]
[25]
Bhukya, B.; Alam, S.; Chaturvedi, V.; Trivedi, P.; Kumar, S.; Khan, P.; Negi, A.S.; Srivastava, S.K. Brevifoliol and its analogs: A new class of anti-tubercular agents. Curr. Top. Med. Chem., 2020, 20, 1-11.
[http://dx.doi.org/10.2174/1568026620666200528155236] [PMID: 32484109]
[26]
Bhukya, B.; Shukla, A.; Chaturvedi, V.; Trivedi, P.; Kumar, S.; Khan, F.; Negi, A.S.; Srivastava, S.K. Design, synthesis, in vitro and in silico studies of 2, 3-diaryl benzofuran derivatives as antitubercular agents. Bioorg. Chem., 2020, 99, 103784.
[http://dx.doi.org/10.1016/j.bioorg.2020.103784] [PMID: 32361184]
[27]
Kuhn, M.; von Mering, C.; Campillos, M.; Jensen, L.J.; Bork, P. STITCH: Interaction networks of chemicals and proteins. Nucleic Acids Res., 2007, 36, D684-D688.
[http://dx.doi.org/10.1093/nar/gkm795] [PMID: 18084021]
[28]
Sanner, M.F. Python: A programming language for software integration and development. J. Mol. Graph. Model., 1999, 17(1), 57-61.
[PMID: 10660911]
[29]
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]
[30]
Cosconati, S.; Forli, S.; Perryman, A.L.; Harris, R.; Goodsell, D.S.; Olson, A.J. Virtual screening with AutoDock: Theory and practice. Expert Opin. Drug Discov., 2010, 5(6), 597-607.
[http://dx.doi.org/10.1517/17460441.2010.484460] [PMID: 21532931]
[31]
Upadhyay, H.C.; Thakur, J.P.; Saikia, D.; Srivastava, S.K. Anti-tubercular agents from Ammannia baccifera (Linn.). Med. Chem. Res., 2013, 22(1), 16-21.
[http://dx.doi.org/10.1007/s00044-012-9998-9]
[32]
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]
[33]
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]
[34]
Kalani, K.; Kushwaha, V.; Verma, R.; Murthy, P.K.; Srivastava, S.K. Glycyrrhetinic acid and its analogs: A new class of antifilarial agents. Bioorg. Med. Chem. Lett., 2013, 23(9), 2566-2570.
[http://dx.doi.org/10.1016/j.bmcl.2013.02.115] [PMID: 23541646]
[35]
Upadhyay, H.C.; Mishra, A.; Pandey, J.; Sharma, P.; Tamrakar, A.K.; Srivastava, A.K.; Khan, F.; Srivastava, S.K. In vitro, in vivo and in silico antihyperglycemic activity of some semi-synthetic phytol derivatives. Med. Chem., 2022, 18(1), 115-121.
[http://dx.doi.org/10.2174/1573406417666201216124018] [PMID: 33327922]
[36]
Shukla, A.; Tyagi, R.; Meena, S.; Datta, D.; Srivastava, S.K.; Khan, F. 2D and 3D QSAR modelling, molecular docking and in-vitro evaluation studies on 18β-glycyrrhetinic acid derivatives against triple negative breast cancer cell line. J. Biomol. Struct. Dyn., 2019, 38, 168-185.
[http://dx.doi.org/10.1080/07391102.2019.1570868]

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