The Introduction of Hydrazone, Hydrazide, or Azepane Moieties to the Triterpenoid Core Enhances an Activity Against M. tuberculosis

Author(s): Oxana B. Kazakova*, Natalya I. Medvedeva, Irina E. Smirnova, Tatyana V. Lopatina, Alexander V. Veselovsky

Journal Name: Medicinal Chemistry

Volume 17 , Issue 2 , 2021


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Graphical Abstract:


Abstract:

Background: Triterpenoids exhibit a wide spectrum of antimicrobial activity.

Objective: The objective of this study was to synthesize a series of nitrogen derivatives based on lupane, oleanane, and ursane triterpenoids with high antitubercular activity.

Methods: Isonicotinoylhydrazones were prepared via the reaction of 3-oxotriterpenic acids or betulonic aldehyde with isoniazid (INH) in yields of 54-72%. N-Acylation of betulonic or azepanobetulinic acids led to lupane C28 hydrazides and dihydrazides. The derivatives were evaluated for their in vitro antimycobacterial activities against Mycobacterium tuberculosis (MTB) H37RV and single-drug resistance (SDR)-TB in the National Institute of Allergy and Infectious Diseases, USA. Molecular docking was performed to evaluate the possible binding modes of investigated compounds in the active site of Diterpene synthase (Rv3378c).

Results: The obtained compounds are represented by C3 or C28 conjugates with hydrazine hydrate or INH. Some compounds demonstrated from high minimum inhibitory concentration (MIC ≤ 10 μg/mL) to excellent (MICs from 0.19 to 1.25 μg/mL) activity against MTB H37RV. Two lupane conjugates with INH were the leading compounds against MTB H37RV and some SDR-strains with MICs ranged from 0.19 to 1.70 μg/mL. Molecular docking of active compounds to diterpene synthase showed that these moieties accommodate the active site of the enzyme.

Conclusion: It was revealed that the conjugation of lupanes with INH at C3 is more effective than at C28 and the lupane skeleton is preferable among oleanane and ursane types. The replacement of native hexacarbocyclic A ring to seven-member azepane ring is favorably for inhibition of both MTB H37RV and SDR-strains. These data could possibly mean that the antitubercular activity against INH-resistant strains (INH-R) came from both triterpenoid and isoniazid parts of the hybrid molecules. Azepanobetulin showed the highest activity against both INH-R strains in comparison with other triterpenoids and INH. Thus, the introduction of hydrazone, hydrazide (dihydrazide), or azepane moieties into the triterpenoid core is a promising way for the development of new anti-tubercular agents.

Keywords: Triterpenoids, hydrazone, hydrazide, azepane, Mycobacterium tuberculosis, anti-tubercular agents.

[1]
Newman, D.J.; Cragg, G.M. Natural products as sources of new drugs from 1981 to 2014. J. Nat. Prod., 2016, 79(3), 629-661.
[http://dx.doi.org/10.1021/acs.jnatprod.5b01055 ] [PMID: 26852623]
[2]
Liu, W.K.; Ho, J.C.K.; Cheung, F.W.K.; Liu, B.P.L.; Ye, W.C.; Che, C.T. Apoptotic activity of betulinic acid derivatives on murine melanoma B16 cell line. Eur. J. Pharmacol., 2004, 498(1-3), 71-78.
[http://dx.doi.org/10.1016/j.ejphar.2004.07.103 ] [PMID: 15363977]
[3]
Barret, J.P.; Podmelle, F.; Lipový, B.; Rennekampff, H.O.; Schumann, H.; Schwieger-Briel, A.; Zahn, T.R.; Metelmann, H.R. BSH-12 and BSG-12 study groups. Accelerated re-epithelialization of partial-thickness skin wounds by a topical betulin gel: Results of a randomized phase III clinical trials program. Burns, 2017, 43(6), 1284-1294.
[http://dx.doi.org/10.1016/j.burns.2017.03.005 ] [PMID: 28400148]
[4]
Cunha, W.R.; de Matos, G.X.; Souza, M.G.; Tozatti, M.G.; Andrade e Silva, M.L.; Martins, C.H.; da Silva, R.; Da Silva Filho, A.A. Evaluation of the antibacterial activity of the methylene chloride extract of Miconia ligustroides, isolated triterpene acids, and ursolic acid derivatives. Pharm. Biol., 2010, 48(2), 166-169.
[http://dx.doi.org/10.3109/13880200903062648 ] [PMID: 20645834]
[5]
Catteau, G.L.; Zhu, L.; Bambeke, F.V.; Quetin-Leclercq, J. Natural and hemi-synthetic pentacyclic triterpenes as antimicrobials and resistance modifying agents against Staphylococcus aureus: a review. Phytochem. Rev., 2018, 17, 1129-1163.
[http://dx.doi.org/10.1007/s11101-018-9564-2]
[6]
Woldemichael, G.M.; Franzblau, S.G.; Zhang, F.; Wang, Y.; Timmermann, B.N. Inhibitory effect of sterols from Ruprechtia triflora and diterpenes from Calceolaria pinnifolia on the growth of Mycobacterium tuberculosis. Planta Med., 2003, 69(7), 628-631.
[http://dx.doi.org/10.1055/s-2003-41109 ] [PMID: 12898418]
[7]
Jesus, J.A.; Lago, J.H.G.; Laurenti, M.D.; Yamamoto, E.S.; Passero, L.F.D. Antimicrobial activity of oleanolic and ursolic acids: an update; Evid. Based Complement Alternat. Med., 2015. Article ID 620472, 14 pages.
[http://dx.doi.org/10.1155/2015/620472]
[8]
Cantrell, C.L.; Franzblau, S.G.; Fischer, N.H. Antimycobacterial plant terpenoids. Planta Med., 2001, 67(8), 685-694.
[http://dx.doi.org/10.1055/s-2001-18365 ] [PMID: 11731906]
[9]
Okunade, A.L.; Elvin-Lewis, M.P.F.; Lewis, W.H. Natural antimycobacterial metabolites: current status. Phytochemistry, 2004, 65(8), 1017-1032.
[http://dx.doi.org/10.1016/j.phytochem.2004.02.013 ] [PMID: 15110681]
[10]
Copp, B.R. Antimycobacterial natural products. Nat. Prod. Rep., 2003, 20(6), 535-557.
[http://dx.doi.org/10.1039/b212154a ] [PMID: 14700198]
[11]
Zhou, X.; Zhao, L.; Liu, X.; Li, X.; Jia, F.; Zhang, Y.; Wang, Y. Antimycobacterial and synergistic effects of 18β-glycyrrhetinic acid or glycyrrhetinic acid-30-piperazine in combination with isoniazid, rifampicin or streptomycin against Mycobacterium bovis. Phytother. Res., 2012, 26(2), 253-258.
[http://dx.doi.org/10.1002/ptr.3536 ] [PMID: 21656601]
[12]
Ge, F.; Zeng, F.; Liu, S.; Guo, N.; Ye, H.; Song, Y.; Fan, J.; Wu, X.; Wang, X.; Deng, X.; Jin, Q.; Yu, L. In vitro synergistic interactions of oleanolic acid in combination with isoniazid, rifampicin or ethambutol against Mycobacterium tuberculosis. J. Med. Microbiol., 2010, 59(Pt 5), 567-572.
[http://dx.doi.org/10.1099/jmm.0.014837-0 ] [PMID: 20075118]
[13]
Kalani, K.; Chaturvedi, V.; Alam, S.; Khan, F.; Srivastava, S.K. Anti-tubercular agents from Glycyrrhiza glabra. Curr. Top. Med. Chem., 2015, 15(11), 1043-1049.
[http://dx.doi.org/10.2174/1568026615666150317223323 ] [PMID: 25786503]
[14]
Suksamrarn, S.; Panseeta, P.; Kunchanawatta, S.; Distaporn, T.; Ruktasing, S. Suksamrarn. A. Ceanothane- and lupane-type triterpenes with antiplasmodial and antimycobacterial activities from Ziziphus cambodiana. Chem. Pharm. Bull. (Tokyo), 2006, 54, 535-537.
[http://dx.doi.org/10.1248/cpb.54.535 ] [PMID: 16595959]
[15]
Tanachatchairatana, T.; Bremner, J.B.; Chokchaisiri, R.; Suksamrarn, A. Antimycobacterial activity of cinnamate-based esters of the triterpenes betulinic, oleanolic and ursolic acids. Chem. Pharm. Bull. (Tokyo), 2008, 56(2), 194-198.
[http://dx.doi.org/10.1248/cpb.56.194 ] [PMID: 18239308]
[16]
Jiménez-Arellanes, A.; Meckes, M.; Torres, J.; Luna-Herrera, J. Antimycobacterial triterpenoids from Lantana hispida (Verbenaceae). J. Ethnopharmacol., 2007, 111(2), 202-205.
[http://dx.doi.org/10.1016/j.jep.2006.11.033 ] [PMID: 17236730]
[17]
Jiménez-Arellanes, A.; Luna-Herrera, J.; Cornejo-Garrido, J.; López-García, S.; Castro-Mussot, M.E.; Meckes-Fischer, M.; Mata-Espinosa, D.; Marquina, B.; Torres, J.; Hernández-Pando, R. Ursolic and oleanolic acids as antimicrobial and immunomodulatory compounds for tuberculosis treatment. BMC Complement. Altern. Med., 2013, 13, 258-269.
[http://dx.doi.org/10.1186/1472-6882-13-258 ] [PMID: 24098949]
[18]
Rogoza, L.N.; Salakhutdinov, N.F.; Tolstikov, G.A. Antituberculosis activity of natural and synthetic compounds. Chemistry for Sustainable Development, 2010, 4, 343-375.
[19]
Szakiel, A.; Ruszkowski, D.; Grudniak, A.; Kurek, A.; Wolska, K.I.; Doligalska, M.; Janiszowska, W. Antibacterial and antiparasitic activity of oleanolic acid and its glycosides isolated from marigold (Calendula officinalis). Planta Med., 2008, 74(14), 1709-1715.
[http://dx.doi.org/10.1055/s-0028-1088315 ] [PMID: 18951335]
[20]
Somova, L.O.; Nadar, A.; Rammanan, P.; Shode, F.O. Cardiovascular, antihyperlipidemic and antioxidant effects of oleanolic and ursolic acids in experimental hypertension. Phytomedicine, 2003, 10(2-3), 115-121.
[http://dx.doi.org/10.1078/094471103321659807 ] [PMID: 12725563]
[21]
Podder, B.; Jang, W.S.; Nam, K.W.; Lee, B.E.; Song, H.Y. Ursolic Acid Activates Intracellular Killing Effect of Macrophages During Mycobacterium tuberculosis Infection. J. Microbiol. Biotechnol., 2015, 25(5), 738-744.
[http://dx.doi.org/10.4014/jmb.1407.07020 ] [PMID: 25406534]
[22]
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]
[23]
Kataev, V.E.; Khaybullin, R.N.; Garifullin, B.F.; Sharipova, R.R. New targets for growth inhibition of Mycobacterium tuberculosis: why do natural terpenoids exhibit antitubercular activity? Russ. J. Bioorg Chem., 2018, 44, 438-452.
[http://dx.doi.org/10.1134/S1068162018040106]
[24]
Janin, Y.L. Antituberculosis drugs: ten years of research. Bioorg. Med. Chem., 2007, 15(7), 2479-2513.
[http://dx.doi.org/10.1016/j.bmc.2007.01.030 ] [PMID: 17291770]
[25]
Bedia, K.K.; Elçin, O.; Seda, U.; Fatma, K.; Nathaly, S.; Sevim, R.; Dimoglo, A. Synthesis and characterization of novel hydrazide-hydrazones and the study of their structure-antituberculosis activity. Eur. J. Med. Chem., 2006, 41(11), 1253-1261.
[http://dx.doi.org/10.1016/j.ejmech.2006.06.009 ] [PMID: 16919372]
[26]
Blair, L.M.; Sperry, J. Natural products containing a nitrogen-nitrogen bond. J. Nat. Prod., 2013, 76(4), 794-812.
[http://dx.doi.org/10.1021/np400124n ] [PMID: 23577871]
[27]
Kataev, V.E.; Strobykina, I.Yu.; Andreeva, O.V.; Garifullin, B.F.; Sharipova, R.R.; Mironov, V.F.; Chestnova, R.V. Synthesis and antituberculosis activity of derivatives of Stevia rebaudiana glycoside steviolbioside and diterpenoid isosteviol containing hydrazone, hydrazide, and pyridinoyl moieties. Russ. J. Bioorg Chem., 2011, 37, 483-491.
[http://dx.doi.org/10.1134/S1068162011030095 ] [PMID: 22096997]
[28]
Mahapatra, A.; Chauhan, N.; Patel, D.R.; Kalia, N.P.; Rajput, V.S.; Khan, I.A. Synthesis and antitubercular activity of oleanolic acid analogs. Pharm. Chem. J., 2014, 48, 39-43.
[http://dx.doi.org/10.1007/s11094-014-1042-6]
[29]
Medvedeva, N.I.; Kazakova, O.B.; Lopatina, T.V.; Smirnova, I.E.; Giniyatullina, G.V.; Baikova, I.P.; Kataev, V.E. Synthesis and antimycobacterial activity of triterpenic A-ring azepanes. Eur. J. Med. Chem., 2018, 143, 464-472.
[http://dx.doi.org/10.1016/j.ejmech.2017.11.035 ] [PMID: 29202408]
[30]
Kazakova, O.B.; Medvedeva, N.I.; Samoilova, I.A.; Baikova, I.P.; Tolstikov, G.A.; Kataev, V.E.; Mironov, V.F. Conjugates of several lupane, oleanane, and ursane triterpenoids with the antituberculosis drug isoniazid and pyridinecarboxaldehydes. Chem. Nat. Compd., 2011, 47, 752-758.
[http://dx.doi.org/10.1007/s10600-011-0050-y]
[31]
Merlani, M.I.; Amiranashvili, L.S.; Mulkidzhanyan, K.G.; Shelar, A.R.; Manvi, F.V. Synthesis and antituberculosis activity of certain steroidal derivatives of the 5α-series. Chem. Nat. Compd., 2008, 44, 618-620.
[http://dx.doi.org/10.1007/s10600-008-9126-8]
[32]
Flekhter, O.B.; Nigmatullina, L.R.; Baltina, L.A.; Karachurina, L.T.; Galin, F.Z.; Zarudii, F.S.; Tolstikov, G.A.; Boreko, E.I.; Pavlova, N.I.; Nikolaeva, S.N.; Savinova, O.V. Preparation of betulinic acids from betulin extract. Antiviral and antiulcer activity of some related terpenoids. Pharm. Chem. J., 2002, 36, 26-28.
[33]
Flekhter, O.B.; Boreko, E.I.; Nigmatullina, L.R.; Pavlova, N.I.; Nikolaeva, S.N.; Savinova, O.V.; Eremin, V.F.; Baltina, L.A.; Galin, F.Z.; Tolstikov, G.A. Synthesis and antiviral activity of hydrazides and substituted benzalhydrazides of betulinic acid and its derivatives. Russ. J. Bioorg Chem., 2003, 29(3), 296-302.
[PMID: 12845810]
[34]
Collins, L.; Franzblau, S.G. Microplate alamar blue assay versus BACTEC 460 system for high-throughput screening of compounds against Mycobacterium tuberculosis and Mycobacterium avium. Antimicrob. Agents Chemother., 1997, 41(5), 1004-1009.
[http://dx.doi.org/10.1128/AAC.41.5.1004 ] [PMID: 9145860]
[35]
Trott, O.; Olson, A.J. AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J. Comput. Chem., 2010, 31(2), 455-461.
[PMID: 19499576]
[36]
Salentin, S.; Schreiber, S.; Haupt, V.J.; Adasme, M.F.; Schroeder, M. PLIP: fully automated protein-ligand interaction profiler. Nucleic Acids Res., 2015, 43(W1)W443-7
[http://dx.doi.org/10.1093/nar/gkv315 ] [PMID: 25873628]
[37]
Kazakova, O.B.; Giniyatullina, G.V.; Tolstikov, G.A.; Medvedeva, N.I.; Utkina, T.M.; Kartashova, O.L. Synthesis, modification, and antimicrobial activity of the N-methylpiperazinyl amides of triterpenic acids. Russ. J. Bioorg Chem., 2010, 36, 383-389.
[http://dx.doi.org/10.1134/S1068162010030155]
[38]
Khusnutdinova, E.F.; Kazakova, O.B.; Lobov, A.N.; Kukovinets, O.S.; Suponitsky, K.Yu.; Meyers, C.B.; Prichard, M.N. Synthesis of A-ring quinolones, nine-membered oxolactams and spiroindoles by oxidative transformations of 2,3-indolotriterpenoids. Org. Biomol. Chem., 2019, 17(3), 585-597.
[http://dx.doi.org/10.1039/C8OB02624F ] [PMID: 30574983]


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Article Details

VOLUME: 17
ISSUE: 2
Year: 2021
Published on: 15 January, 2020
Page: [134 - 145]
Pages: 12
DOI: 10.2174/1573406416666200115161700
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