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

Discovery of Novel Tetramethylpyrazine Containing Chalcone Derivatives as Anti-Inflammatory Agents

Author(s): Syed Nasir Abbas Bukhari*, Mohamed Abdelwahab Abdelgawad, Muhammad Wahab Amjad, Muhammad Usman Munir and Fatima Akbar Sheikh

Volume 19, Issue 7, 2023

Published on: 27 January, 2023

Page: [669 - 685] Pages: 17

DOI: 10.2174/1573406419666230112110306

Price: $65

Abstract

Background: Chalcones are precursors of flavonoids and exhibit a broad spectrum of pharmacological activity.

Objective: As anti-inflammatory agents, two series of chalcone derivatives and chalcone-based oximes were synthesized and characterized. To integrate the tetramethylpyrazine moiety into these novel molecules, the multifunctional natural chemical ligustrazine was employed.

Methods: A variety of newly synthesized ligustrazine-based chalcones were utilized as precursors for the synthesis of new oximes and their inhibitory activity against COX-1, COX-2, and LOX-5 enzymes were compared.

Results: The conversion of ketones to their oxime derivatives increased the effectiveness of COX-1 and COX-2 inhibition. Due to the substituted ether groups, oxime derivative 5d had the lowest IC50 values of 0.027 ± 0.004 μM and 0.150 ± 0.027 μM for COX-1 and COX-2 isoenzymes, respectively. Notably, the oxime derivative's highest effectiveness is conferred by the presence of methoxymethoxy or hydroxy groups at the C-3 and C-4 positions on the phenyl ring. The 6b derivative with a long alkyl chain ether group was shown to be the most powerful 5-LOX inhibitor. All compounds were also assessed for their ability to inhibit nitric oxide generation and LPS-induced IL-6, IL-1β, and TNF-α production in RAW 264.7 macrophages. Finally, in order to determine the structural effects responsible for the binding mechanism of compounds, they were docked into the binding sites of COX-1, COX-2, and 5-LOX, which revealed an inhibitory mechanism of action and demonstrated the relevance of various types of interactions.

Conclusion: The findings showed that these novel compounds had a significant impact on antiinflammatory actions.

« Previous Next »
Graphical Abstract

[1]
Atanasov, A.G.; Zotchev, S.B.; Dirsch, V.M.; Supuran, C.T.; Banach, M.; Rollinger, J.M.; Barreca, D.; Weckwerth, W.; Bauer, R.; Bayer, E.A.; Majeed, M.; Bishayee, A.; Bochkov, V.; Bonn, G.K.; Braidy, N.; Bucar, F.; Cifuentes, A.; D’Onofrio, G.; Bodkin, M.; Diederich, M.; Dinkova-Kostova, A.T.; Efferth, T.; El Bairi, K.; Arkells, N.; Fan, T-P.; Fiebich, B.L.; Freissmuth, M.; Georgiev, M.I.; Gibbons, S.; Godfrey, K.M.; Gruber, C.W.; Heer, J.; Huber, L.A.; Ibanez, E.; Kijjoa, A.; Kiss, A.K.; Lu, A.; Macias, F.A.; Miller, M.J.S.; Mocan, A.; Müller, R.; Nicoletti, F.; Perry, G.; Pittalà, V.; Rastrelli, L.; Ristow, M.; Russo, G.L.; Silva, A.S.; Schuster, D.; Sheridan, H.; Skalicka-Woźniak, K.; Skaltsounis, L.; Sobarzo-Sánchez, E.; Bredt, D.S.; Stuppner, H.; Sureda, A.; Tzvetkov, N.T.; Vacca, R.A.; Aggarwal, B.B.; Battino, M.; Giampieri, F.; Wink, M.; Wolfender, J-L.; Xiao, J.; Yeung, A.W.K.; Lizard, G.; Popp, M.A.; Heinrich, M.; Berindan-Neagoe, I.; Stadler, M.; Daglia, M.; Verpoorte, R.; Supuran, C.T. Natural products in drug discovery: advances and opportunities. Nat. Rev. Drug Discov., 2021, 20(3), 200-216.
[http://dx.doi.org/10.1038/s41573-020-00114-z] [PMID: 33510482]
[2]
Bukhari, S.N.; Jasamai, M.; Jantan, I. Synthesis and biological evaluation of chalcone derivatives (mini review). Mini Rev. Med. Chem., 2012, 12(13), 1394-1403.
[PMID: 22876958]
[3]
Nasir Abbas Bukhari, S.; Jantan, I.; Jasamai, M. Anti-inflammatory trends of 1, 3-diphenyl-2-propen-1-one derivatives. Mini Rev. Med. Chem., 2013, 13(1), 87-94.
[http://dx.doi.org/10.2174/138955713804484767] [PMID: 22876943]
[4]
Zhang, X.; Rakesh, K.P.; Bukhari, S.N.A.; Balakrishna, M.; Manukumar, H.M.; Qin, H.L. Multi-targetable chalcone analogs to treat deadly Alzheimer’s disease: Current view and upcoming advice. Bioorg. Chem., 2018, 80, 86-93.
[http://dx.doi.org/10.1016/j.bioorg.2018.06.009] [PMID: 29890362]
[5]
Qin, H.L.; Leng, J.; Zhang, C.P.; Jantan, I.; Amjad, M.W.; Sher, M.; Naeem-ul-Hassan, M.; Hussain, M.A.; Bukhari, S.N.A. Synthesis of α,β-unsaturated carbonyl-based compounds, oxime and oxime ether analogs as potential anticancer agents for overcoming cancer multi-drug resistance by modulation of efflux pumps in tumor cells. J. Med. Chem., 2016, 59(7), 3549-3561.
[http://dx.doi.org/10.1021/acs.jmedchem.6b00276] [PMID: 27010345]
[6]
Bukhari, S.; Franzblau, S.; Jantan, I.; Jasamai, M. Current prospects of synthetic curcumin analogs and chalcone derivatives against Mycobacterium tuberculosis. Med. Chem., 2013, 9(7), 897-903.
[http://dx.doi.org/10.2174/1573406411309070002] [PMID: 23305394]
[7]
Ali, A.; Khalid, M.; Din, Z.U.; Asif, H.M.; Imran, M.; Tahir, M.N.; Ashfaq, M.; Rodrigues-Filho, E. Exploration of structural, electronic and third order nonlinear optical properties of crystalline chalcone systems: Monoarylidene and unsymmetrical diarylidene cycloalkanones. J. Mol. Struct., 2021, 1241, 130685.
[http://dx.doi.org/10.1016/j.molstruc.2021.130685]
[8]
Zhou, B.; Xing, C. Diverse molecular targets for chalcones with varied bioactivities. Med. Chem. (Los Angeles), 2015, 5(8), 388-404.
[http://dx.doi.org/10.4172/2161-0444.1000291] [PMID: 26798565]
[9]
Schwöbel, J.A.H.; Wondrousch, D.; Koleva, Y.K.; Madden, J.C.; Cronin, M.T.D.; Schüürmann, G. Prediction of michael-type acceptor reactivity toward glutathione. Chem. Res. Toxicol., 2010, 23(10), 1576-1585.
[http://dx.doi.org/10.1021/tx100172x] [PMID: 20882991]
[10]
Bukhari, S.N.A.; Jantan, I.; Masand, V.H.; Mahajan, D.T.; Sher, M.; Naeem-ul-Hassan, M.; Amjad, M.W. Synthesis of α, β-unsaturated carbonyl based compounds as acetylcholinesterase and butyrylcholinesterase inhibitors: Characterization, molecular modeling, QSAR studies and effect against amyloid β-induced cytotoxicity. Eur. J. Med. Chem., 2014, 83, 355-365.
[http://dx.doi.org/10.1016/j.ejmech.2014.06.034] [PMID: 24980117]
[11]
Qin, H.L.; Shang, Z.P.; Jantan, I.; Tan, O.U.; Hussain, M.A.; Sher, M.; Bukhari, S.N.A. Molecular docking studies and biological evaluation of chalcone based pyrazolines as tyrosinase inhibitors and potential anticancer agents. RSC Adv, 2015, 5(57), 46330-46338.
[http://dx.doi.org/10.1039/C5RA02995C]
[12]
Bukhari, S.N.A.; Lauro, G.; Jantan, I.; Bifulco, G.; Amjad, M.W. Pharmacological evaluation and docking studies of α,β-unsaturated carbonyl based synthetic compounds as inhibitors of secretory phospholipase A2, cyclooxygenases, lipoxygenase and proinflammatory cytokines. Bioorg. Med. Chem., 2014, 22(15), 4151-4161.
[http://dx.doi.org/10.1016/j.bmc.2014.05.052] [PMID: 24938495]
[13]
Fu, Y.S.; Lin, Y.Y.; Chou, S.C.; Tsai, T.H.; Kao, L.S.; Hsu, S.Y.; Cheng, F.C.; Shih, Y.H.; Cheng, H.; Fu, Y.Y.; Wang, J.Y. Tetramethylpyrazine inhibits activities of glioma cells and glutamate neuro-excitotoxicity: Potential therapeutic application for treatment of gliomas. Neuro-oncology., 2008, 10(2), 139-152.
[http://dx.doi.org/10.1215/15228517-2007-051] [PMID: 18314418]
[14]
Chen, L.; Lu, Y.; Wu, J.; Xu, B.; Zhang, L.; Gao, M.; Zheng, S.; Wang, A.; Zhang, C.; Zhang, W.; Lei, N. Ligustrazine inhibits B16F10 melanoma metastasis and suppresses angiogenesis induced by vascular endothelial growth factor. Biochem. Biophys. Res. Commun., 2009, 386(2), 374-379.
[http://dx.doi.org/10.1016/j.bbrc.2009.06.042] [PMID: 19523924]
[15]
Xiong, L.; Fang, Z.Y.; Tao, X.N.; Bai, M.; Feng, G. Effect and mechanism of ligustrazine on Th1/Th2 cytokines in a rat asthma model. Am. J. Chin. Med., 2007, 35(6), 1011-1020.
[http://dx.doi.org/10.1142/S0192415X07005478] [PMID: 18186587]
[16]
Wang, P.; She, G.; Yang, Y.; Li, Q.; Zhang, H.; Liu, J.; Cao, Y.; Xu, X.; Lei, H. Synthesis and biological evaluation of new ligustrazine derivatives as anti-tumor agents. Molecules, 2012, 17(5), 4972-4985.
[http://dx.doi.org/10.3390/molecules17054972] [PMID: 22547319]
[17]
Zha, G.F.; Qin, H.L.; Youssif, B.G.M.; Amjad, M.W.; Raja, M.A.G.; Abdelazeem, A.H.; Bukhari, S.N.A. Discovery of potential anticancer multi-targeted ligustrazine based cyclohexanone and oxime analogs overcoming the cancer multidrug resistance. Eur. J. Med. Chem., 2017, 135, 34-48.
[http://dx.doi.org/10.1016/j.ejmech.2017.04.025] [PMID: 28431353]
[18]
Bukhari, S.N.A.; Alotaibi, N.H.; Ahmad, W.; Alharbi, K.S.; Abdelgawad, M.A.; Al-Sanea, M.M.; Ahmad, M.M.; Amjad, M.W.; Raja, M.A.G.; Hussain, M.A. Evaluation of ligustrazine based synthetic compounds for mechanism based antiproliferative effects. Med. Chem., 2021, 17(9), 956-962.
[http://dx.doi.org/10.2174/1573406416666200905125038] [PMID: 32888274]
[19]
Alotaibi, N.H.; Alharbi, K.S.; Alzarea, A.I.; Alruwaili, N.K.; Alotaibi, M.R.; Alotaibi, N.M.; Alotaibi, B.S.; Bukhari, S.N.A. Pharmacological appraisal of ligustrazine based cyclohexanone analogs as inhibitors of inflammatory markers. Eur. J. Pharm. Sci., 2020, 147, 105299.
[http://dx.doi.org/10.1016/j.ejps.2020.105299] [PMID: 32165315]
[20]
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]
[21]
Binkowski, T.A.; Naghibzadeh, S.; Liang, J. CASTp: Computed atlas of surface topography of proteins. Nucleic Acids Res., 2003, 31(13), 3352-3355.
[http://dx.doi.org/10.1093/nar/gkg512] [PMID: 12824325]
[22]
Bukhari, S.N.A.; Tajuddin, Y.; Benedict, V.J.; Lam, K.W.; Jantan, I.; Jalil, J.; Jasamai, M. Synthesis and evaluation of chalcone derivatives as inhibitors of neutrophils’ chemotaxis, phagocytosis and production of reactive oxygen species. Chem. Biol. Drug Des., 2014, 83(2), 198-206.
[http://dx.doi.org/10.1111/cbdd.12226] [PMID: 24433224]
[23]
Wang, M.; Qin, H.L.; Leng, J. Ameeduzzafar; Amjad, M.W.; Raja, M.A.G.; Hussain, M.A.; Bukhari, S.N.A. Synthesis and biological evaluation of new tetramethylpyrazine-based chalcone derivatives as potential anti-Alzheimer agents. Chem. Biol. Drug Des., 2018, 92(5), 1859-1866.
[http://dx.doi.org/10.1111/cbdd.13355] [PMID: 29923315]
[24]
Wang, G.; Peng, F.; Cao, D.; Yang, Z.; Han, X.; Liu, J.; Wu, W.; He, L.; Ma, L.; Chen, J.; Sang, Y.; Xiang, M.; Peng, A.; Wei, Y.; Chen, L. Design, synthesis and biological evaluation of millepachine derivatives as a new class of tubulin polymerization inhibitors. Bioorg. Med. Chem., 2013, 21(21), 6844-6854.
[http://dx.doi.org/10.1016/j.bmc.2013.02.002] [PMID: 23993668]
[25]
Qin, H.L.; Leng, J.; Youssif, B.G.M.; Amjad, M.W.; Raja, M.A.G.; Hussain, M.A.; Hussain, Z.; Kazmi, S.N.; Bukhari, S.N.A. Synthesis and mechanistic studies of curcumin analog-based oximes as potential anticancer agents. Chem. Biol. Drug Des., 2017, 90(3), 443-449.
[http://dx.doi.org/10.1111/cbdd.12964] [PMID: 28186369]
[26]
Cheng, Y.W.; Chang, C.Y.; Lin, K.L.; Hu, C.M.; Lin, C.H.; Kang, J.J. Shikonin derivatives inhibited LPS-induced NOS in RAW 264.7 cells via downregulation of MAPK/NF-κB signaling. J. Ethnopharmacol., 2008, 120(2), 264-271.
[http://dx.doi.org/10.1016/j.jep.2008.09.002] [PMID: 18835347]
[27]
Tewari, D.; Sah, A.N.; Bawari, S.; Nabavi, S.F.; Dehpour, A.R.; Shirooie, S.; Braidy, N.; Fiebich, B.L.; Vacca, R.A.; Nabavi, S.M. Role of Nitric oxide in neurodegeneration: Function, regulation, and inhibition. Curr. Neuropharmacol., 2020, 19(2), 114-126.
[http://dx.doi.org/10.2174/1570159X18666200429001549] [PMID: 32348225]
[28]
Adebayo, S.A.; Ondua, M.; Shai, L.J.; Lebelo, S.L. Inhibition of nitric oxide production and free radical scavenging activities of four South African medicinal plants. J. Inflamm. Res., 2019, 12, 195-203.
[http://dx.doi.org/10.2147/JIR.S199377] [PMID: 31496781]
[29]
Micale, N.; Molonia, M.S.; Citarella, A.; Cimino, F.; Saija, A.; Cristani, M.; Speciale, A. Natural product-based hybrids as potential candidates for the treatment of cancer: focus on curcumin and resveratrol. Molecules, 2021, 26(15), 4665.
[http://dx.doi.org/10.3390/molecules26154665] [PMID: 34361819]
[30]
Sidhu, R.S.; Lee, J.Y.; Yuan, C.; Smith, W.L. Comparison of cyclooxygenase-1 crystal structures: cross-talk between monomers comprising cyclooxygenase-1 homodimers. Biochemistry, 2010, 49(33), 7069-7079.
[http://dx.doi.org/10.1021/bi1003298] [PMID: 20669977]
[31]
Dvorakova, M.; Langhansova, L.; Temml, V.; Pavicic, A.; Vanek, T.; Landa, P. Synthesis, inhibitory activity, and in silico modeling of selective COX-1 inhibitors with a quinazoline Core. ACS Med. Chem. Lett., 2021, 12(4), 610-616.
[http://dx.doi.org/10.1021/acsmedchemlett.1c00004] [PMID: 33854702]
[32]
Vitale, P.; Tacconelli, S.; Perrone, M.G.; Malerba, P.; Simone, L.; Scilimati, A.; Lavecchia, A.; Dovizio, M.; Marcantoni, E.; Bruno, A.; Patrignani, P. Synthesis, pharmacological characterization, and docking analysis of a novel family of diarylisoxazoles as highly selective cyclooxygenase-1 (COX-1) inhibitors. J. Med. Chem., 2013, 56(11), 4277-4299.
[http://dx.doi.org/10.1021/jm301905a] [PMID: 23651359]

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