Login Register Cart 0
Generic placeholder image

Medicinal Chemistry

Editor-in-Chief

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

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

Synthesis and Structural Activity Relationship Study of Ursolic Acid Derivatives as Antitubercular Agent

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

Volume 20, Issue 6, 2024

Published on: 07 November, 2023

Page: [630 - 645] Pages: 16

DOI: 10.2174/0115734064256660231027042758

Price: $65

Abstract

Objective: The chemical transformation of ursolic acid (UA) into novel C-3 aryl ester derivatives and in vitro and silico assessment of their antitubercular potential.

Background: UA is a natural pentacyclic triterpenoid with many pharmacological properties. Semisynthetic UA analogs have demonstrated enhanced anticancer, antimalarial, and antifilarial properties in our previous studies.

Methods: The C-30 carboxylic group of previously isolated UA was protected, and various C-3 aryl ester derivatives were semi-synthesized. The agar dilution method was used to evaluate the in vitro antitubercular efficacy of Mycobacterium tuberculosis (Mtb) H37Ra. In silico docking studies of the active derivative were carried out against Mtb targets, catalase peroxidase (PDB: 1SJ2), dihydrofolate reductase (PDB: 4M2X), enoyl-ACP reductase (PDB: 4TRO), and cytochrome bc1 oxidase (PDB: 7E1V).

Results: The derivative 3-O-(2-amino,3-methyl benzoic acid)-ethyl ursolate (UA-1H) was the most active among the eight derivatives (MIC1 2.5 μg/mL) against Mtb H37Ra. Also, UA-1H demonstrated significant binding affinity in the range of 10.8–11.4 kcal/mol against the antiTb target proteins, which was far better than the positive control Isoniazid, Ethambutol, and co-crystallized ligand (HEM). Moreover, the predicted hit UA-1H showed no inhibition of Cytochrome P450 2D6 (CYP2D6), suggesting its potential for favorable metabolism in Phase I clinical studies.

Conclusion: The ursolic acid derivative UA-1H possesses significant in vitro antitubercular potential with favorable in silico pharmacokinetics. Hence, further in vivo assessments are suggested for UA-1H for its possible development into a secure and efficient antitubercular drug.

« Previous Next »
Graphical Abstract

[1]
Sparg, S.G.; Light, M.E.; van Staden, J. Biological activities and distribution of plant saponins. J. Ethnopharmacol., 2004, 94(2-3), 219-243.
[http://dx.doi.org/10.1016/j.jep.2004.05.016] [PMID: 15325725]
[2]
Liu, J. Oleanolic acid and ursolic acid: Research perspectives. J. Ethnopharmacol., 2005, 100(1-2), 92-94.
[http://dx.doi.org/10.1016/j.jep.2005.05.024] [PMID: 15994040]
[3]
Kalani, K.; Yadav, D.K.; Khan, F.; Srivastava, S.K.; Suri, N. Pharmacophore, QSAR, and ADME based semisynthesis and In vitro evaluation of ursolic acid analogs for anticancer activity. J. Mol. Model., 2012, 18(7), 3389-3413.
[http://dx.doi.org/10.1007/s00894-011-1327-6] [PMID: 22271093]
[4]
Novotný, L.; Vachálková, A.; Biggs, D. Ursolic acid: An anti-tumorigenic and chemopreventive activity. Minireview. Neoplasma, 2001, 48(4), 241-246.
[PMID: 11712672]
[5]
Zhou, D.; Bao, Q.; Fu, S. Anticancer activity of ursolic acid on retinoblastoma cells determined by bioinformatics analysis and validation. Ann. Transl. Med., 2021, 9(20), 1548.
[http://dx.doi.org/10.21037/atm-21-4617] [PMID: 34790754]
[6]
Haridas, V.; Arntzen, C.J.; Gutterman, J.U. Avicins, a family of triterpenoid saponins from Acacia victoriae (Bentham), inhibit activation of nuclear factor-κB by inhibiting both its nuclear localization and ability to bind DNA. Proc. Natl. Acad. Sci. USA, 2001, 98(20), 11557-11562.
[http://dx.doi.org/10.1073/pnas.191363498] [PMID: 11572998]
[7]
Jung, H.J.; Nam, J.H.; Choi, J.; Lee, K.T.; Park, H.J. 19α-hydroxyursane-type triterpenoids: Antinociceptive anti-inflammatory principles of the roots of Rosa rugosa. Biol. Pharm. Bull., 2005, 28(1), 101-104.
[http://dx.doi.org/10.1248/bpb.28.101] [PMID: 15635171]
[8]
Nataraj, A.; Raghavendra, G.C.; Rajesh, R.; Vishwanath, B. Group IIA secretory PLA2 inhibition by ursolic acid: A potent anti-inflammatory molecule. Curr. Top. Med. Chem., 2007, 7(8), 801-809.
[http://dx.doi.org/10.2174/156802607780487696] [PMID: 17456043]
[9]
Ikeda, Y.; Murakami, A.; Ohigashi, H. Ursolic acid: An anti- and pro-inflammatory triterpenoid. Mol. Nutr. Food Res., 2008, 52(1), 26-42.
[http://dx.doi.org/10.1002/mnfr.200700389] [PMID: 18203131]
[10]
Ikeda, T.; Yokomizo, K.; Okawa, M.; Tsuchihashi, R.; Kinjo, J.; Nohara, T.; Uyeda, M. Anti-herpes virus type 1 activity of oleanane-type triterpenoids. Biol. Pharm. Bull., 2005, 28(9), 1779-1781.
[http://dx.doi.org/10.1248/bpb.28.1779] [PMID: 16141560]
[11]
Kalani, K.; Kushwaha, V.; Sharma, P.; Verma, R.; Srivastava, M.; Khan, F.; Murthy, P.K.; Srivastava, S.K. In vitro, in silico and In vivo studies of ursolic acid as an anti-filarial agent. PLoS One, 2014, 9(11), e111244.
[http://dx.doi.org/10.1371/journal.pone.0111244] [PMID: 25375886]
[12]
Ma, C.M.; Cai, S.Q.; Cui, J.R.; Wang, R.Q.; Tu, P.F.; Hattori, M.; Daneshtalab, M.; Daneshtalab, M. The cytotoxic activity of ursolic acid derivatives. Eur. J. Med. Chem., 2005, 40(6), 582-589.
[http://dx.doi.org/10.1016/j.ejmech.2005.01.001] [PMID: 15922841]
[13]
Feng, J.H.; Chen, W.; Zhao, Y.; Ju, X.L. Anti-tumor activity of oleanolic, ursolic and glycyrrhetinic acid. Open Nat. Prod. J., 2009, 2(1), 48-52.
[http://dx.doi.org/10.2174/1874848100902010048]
[14]
Maurya, A.; Khan, F.; Bawankule, D.U.; Yadav, D.K.; Srivastava, S.K. QSAR, docking and in vivo studies for immunomodulatory activity of isolated triterpenoids from Eucalyptus tereticornis and Gentiana kurroo. Eur. J. Pharm. Sci., 2012, 47(1), 152-161.
[http://dx.doi.org/10.1016/j.ejps.2012.05.009] [PMID: 22659375]
[15]
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]
[16]
Hussain, H.; Green, I.R.; Ali, I.; Khan, I.A.; Ali, Z.; Al-Sadi, A.M.; Ahmed, I. 2012-2016. Ursolic acid derivatives for pharmaceutical use: A patent review. Expert Opin. Ther. Pat., 2017, 27(9), 1061-1072.
[http://dx.doi.org/10.1080/13543776.2017.1344219] [PMID: 28637397]
[17]
Mancha-Ramirez, A.M.; Slaga, T.J. Ursolic acid and chronic disease: An overview of UA’s effects on prevention and treatment of obesity and cancer. Adv. Exp. Med. Biol., 2016, 75-96.
[http://dx.doi.org/10.1007/978-3-319-41334-1_4]
[18]
World Health Organization. Global tuberculosis report. 2022. Available from: http s://www.who.int/.../tb-reports/global-tuberculosis-report-2022
[19]
Gupta, S.; Dwivedi, G.R.; Darokar, M.P.; Srivastava, S.K. Antimycobacterial activity of fractions and isolated compounds from Vetiveria zizanioides. Med. Chem. Res., 2012, 21(7), 1283-1289.
[http://dx.doi.org/10.1007/s00044-011-9639-8]
[20]
Quan, D.; Nagalingam, G.; Payne, R.; Triccas, J.A. New tuberculosis drug leads from naturally occurring compounds. Int. J. Infect. Dis., 2017, 56, 212-220.
[http://dx.doi.org/10.1016/j.ijid.2016.12.024] [PMID: 28062229]
[21]
Zerin, T.; Lee, M.; Jang, W.S.; Nam, K.W.; Song, H.Y. Anti-inflammatory potential of ursolic acid in Mycobacterium tuberculosis-sensitized and Concanavalin A-stimulated cells. Mol. Med. Rep., 2016, 13(3), 2736-2744.
[http://dx.doi.org/10.3892/mmr.2016.4840] [PMID: 26847129]
[22]
do Nascimento, P.; Lemos, T.; Bizerra, A.; Arriaga, Â.; Ferreira, D.; Santiago, G.; Braz-Filho, R.; Costa, J. Antibacterial and antioxidant activities of ursolic acid and derivatives. Molecules, 2014, 19(1), 1317-1327.
[http://dx.doi.org/10.3390/molecules19011317] [PMID: 24451251]
[23]
Nguta, J.M.; Appiah-Opong, R.; Nyarko, A.K.; Yeboah-Manu, D.; Addo, P.G.A. Current perspectives in drug discovery against tuberculosis from natural products. Int. J. Mycobacteriol., 2015, 4(3), 165-183.
[http://dx.doi.org/10.1016/j.ijmyco.2015.05.004] [PMID: 27649863]
[24]
Salomon, C.E.; Schmidt, L.E. Natural products as leads for tuberculosis drug development. Curr. Top. Med. Chem., 2012, 12(7), 735-765.
[http://dx.doi.org/10.2174/156802612799984526] [PMID: 22283816]
[25]
Maurya, A.; Srivastava, S.K. Determination of ursolic acid and ursolic acid lactone in the leaves of Eucalyptus tereticornis by HPLC. J. Braz. Chem. Soc., 2012, 23(3), 468-472.
[http://dx.doi.org/10.1590/S0103-50532012000300013]
[26]
Seebacher, W.; Simic, N.; Weis, R.; Saf, R.; Kunert, O. Complete assignments of1H and13C NMR resonances of oleanolic acid, 18?-oleanolic acid, ursolic acid and their 11-oxo derivatives. Magn. Reson. Chem., 2003, 41(8), 636-638.
[http://dx.doi.org/10.1002/mrc.1214]
[27]
Kenneth McClatchy, J. Susceptibility testing of mycobacteria. Lab. Med., 1978, 9(3), 47-52.
[http://dx.doi.org/10.1093/labmed/9.3.47]
[28]
Bhukya, B.; Alam, S.; Chaturvedi, V.; Trivedi, P.; Kumar, S.; Khan, F.; Negi, A.S.; Srivastava, S.K. Brevifoliol and its analogs: A new class of anti-tubercular agents. Curr. Top. Med. Chem., 2021, 21(9), 767-776.
[http://dx.doi.org/10.2174/1568026620666200528155236] [PMID: 32484109]
[29]
Tembe, N.; Machaba, K.E.; Ndagi, U.; Kumalo, H.M.; Mhlongo, N.N. Ursolic acid as a potential inhibitor of Mycobacterium tuberculosis cytochrome bc1 oxidase-a molecular modelling perspective. J. Mol. Model., 2022, 28(2), 35.
[http://dx.doi.org/10.1007/s00894-021-04993-w] [PMID: 35022913]
[30]
Kapkoti, D.S.; Singh, S.; Alam, S.; Khan, F.; Luqman, S.; Bhakuni, R.S. In vitro antiproliferative activity of glabridin derivatives and their in silico target identification. Nat. Prod. Res., 2020, 34(12), 1735-1742.
[http://dx.doi.org/10.1080/14786419.2018.1530228] [PMID: 30580626]
[31]
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]
[32]
Alam, S.; Khan, F. 3D-QSAR studies on Maslinic acid analogs for Anticancer activity against Breast Cancer cell line MCF-7. Sci. Rep., 2017, 7(1), 6019.
[http://dx.doi.org/10.1038/s41598-017-06131-0] [PMID: 28729623]
[33]
Tyagi, R.; Verma, S.; Mishra, S.; Srivastava, M.; Alam, S.; Khan, F.; Srivastava, S.K. In vitro and In silico studies of glycyrrhetinic acid derivatives as anti-filarial agents. Curr. Top. Med. Chem., 2019, 19(14), 1191-1200.
[http://dx.doi.org/10.2174/1568026619666190618141450] [PMID: 31210109]
[34]
Alam, S.; Khan, F. QSAR, docking, ADMET, and system pharmacology studies on tormentic acid derivatives for anticancer activity. J. Biomol. Struct. Dyn., 2018, 36(9), 2373-2390.
[http://dx.doi.org/10.1080/07391102.2017.1355846] [PMID: 28705120]
[35]
Dassault Systèmes, B.I.O.V.I.A. Discovery Studio Modeling Environment, Release 2017; Dassault Systèmes: San Diego, 2016.
[36]
Almeida Da Silva, P.E.; Palomino, J.C. Molecular basis and mechanisms of drug resistance in Mycobacterium tuberculosis: Classical and new drugs. J. Antimicrob. Chemother., 2011, 66(7), 1417-1430.
[http://dx.doi.org/10.1093/jac/dkr173] [PMID: 21558086]
[37]
Schroeder, E.; de Souza, O.; Santos, D.; Blanchard, J.; Basso, L. Drugs that inhibit mycolic acid biosynthesis in Mycobacterium tuberculosis. Curr. Pharm. Biotechnol., 2002, 3(3), 197-225.
[http://dx.doi.org/10.2174/1389201023378328] [PMID: 12164478]
[38]
Jyoti, M.A.; Zerin, T.; Kim, T.H.; Hwang, T.S.; Jang, W.S.; Nam, K.W.; Song, H.Y. In vitro effect of ursolic acid on the inhibition of Mycobacterium tuberculosis and its cell wall mycolic acid. Pulm. Pharmacol. Ther., 2015, 33, 17-24.
[http://dx.doi.org/10.1016/j.pupt.2015.05.005] [PMID: 26021818]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy