Article Sidebar

Download
PDF

Main Article Content

Abstract

A new series of tryptanthrin analogues have been synthesized as potential antimalarial molecules. Synthesis of tryptanthrin aminoalkyl derivatives have been achieved via alkylation of oxime functionality of tryptanthrin derivatives by various alkyl amino pharmacophoric chains. A series of 21 tryptanthrin aminoalkyl analogues were synthesized with variation in both parent natural alkaloid and in aminoalkyl side chains. Synthesized compounds were fully characterized with 1H & 13C NMR, IR spectroscopy. Further all the members were screened for their antimalarial potential against Plasmoum falciparum in both sensitive (3D7) and in resistant (k1) strains. Most of the screened compounds were exhibited potent antimalarial activity in both strains. Compounds (5m, 3c and 5l) having nitro group at the 8 position in tryptanthrin framework were most promising compounds in series (IC50 = 10 nm) with IC50 value as low as 10 nm comparable to chloroquine. These compounds were also tested for their toxic effect and found to be highly safe with high value of SI index.

Keywords

Antimalarial Tryptanthrin Natural product Animo alkyl chains Oximes

Article Details

How to Cite
Deepak Tripathi, V. (2020). Natural Product Inspired Synthesis of Tryptanthrin Analogues as Potential Antimalarial Agents. Asian Journal of Organic & Medicinal Chemistry, 5(4), 348–354. https://doi.org/10.14233/ajomc.2020.AJOMC-P302
Download Citation
Endnote/Zotero/Mendeley (RIS)
BibTeX

References

  1. C.E. Schiaffo, M. Rottman, S. Wittlin and P.H. Dussault, 3-Alkoxy-1,2-Dioxolanes: Synthesis and Evaluation as Potential Antimalarial Agents, ACS Med. Chem. Lett., 2, 316 (2011); https://doi.org/10.1021/ml100308d
  2. V. Kumar, A. Mahajan and K. Chibale, Synthetic Medicinal Chemistry of Selected Antimalarial Natural Products, Bioorg. Med. Chem., 17, 2236 (2009); https://doi.org/10.1016/j.bmc.2008.10.072
  3. D. Gonzalez-Cabrera, F. Douelle, T.-S. Feng, A.T. Nchinda, Y. Younis, K.L. White, Q. Wu, E. Ryan, J.N. Burrows, D. Waterson, M.J. Witty, S. Wittlin, S.A. Charman and K. Chibale, Novel Orally Active Antimalarial Thiazoles, J. Med. Chem., 54, 7713 (2011); https://doi.org/10.1021/jm201108k
  4. S. Zhu, Q. Zhang, C. Gudise, L. Wei, E. Smith and Y. Zeng, Synthesis and Biological Evaluation of Febrifugine Analogues as Potential Anti-malarial Agents, Bioorg. Med. Chem., 17, 4496 (2009); https://doi.org/10.1016/j.bmc.2009.05.011
  5. E. Fernández-Álvaro, W.D. Hong, G.L. Nixon, P.M. O’Neill and F. Calderón, Antimalarial Chemotherapy: Natural Product Inspired Development of Preclinical and Clinical Candidates with Diverse Mechanisms of Action, J. Med. Chem., 59, 5587 (2016); https://doi.org/10.1021/acs.jmedchem.5b01485
  6. World Malaria Report, World Health Organization (2018).
  7. R.N. Price and F. Nosten, Single-Dose Radical Cure of Plasmodium vivax: A Step Closer, Lancet, 383, 1020 (2014); https://doi.org/10.1016/S0140-6736(13)62672-0
  8. K.K. Roy, Targeting the Active Sites of Malarial Proteases for Anti-malarial Drug Discovery: Approaches, Progress and Challenges, Int. J. Antimicrob. Agents, 50, 287 (2017); https://doi.org/10.1016/j.ijantimicag.2017.04.006
  9. R. Bobrovs, K. Jaudzems and A. Jirgensons, Exploiting Structural Dynamics to Design Open-Flap Inhibitors of Malarial Aspartic Proteases, J. Med. Chem., 62, 8931 (2019); https://doi.org/10.1021/acs.jmedchem.9b00184
  10. R. Banerjee, J. Liu, W. Beatty, L. Pelosof, M. Klemba and D.E. Goldberg, Four Plasmepsins are Active in the Plasmodium falciparum Food Vacuole, Including a Protease with an Active-site Histidine, Proc. Natl. Acad. Sci. USA, 99, 990 (2002); https://doi.org/10.1073/pnas.022630099
  11. A.-C. Uhlemann and D.A. Fidock, Loss of Malarial Susceptibility to Artemisinin in Thailand, Lancet, 379, 1928 (2012); https://doi.org/10.1016/S0140-6736(12)60488-7
  12. A. Sofowora, Medicinal Plants and Traditional Medicine in Africa, John Wiley & Sons: Chichester, UK, edn 1, pp 221-223 (1982).
  13. K. Cimanga, L. Pieters, M. Claeys, D. Berghe and A. Vlietinck, Biological Activities of Cryptolepine, An Alkaloid from Cryptolepis sanguinolenta, Planta Med., 57(S 2), A98 (1991); https://doi.org/10.1055/s-2006-960380
  14. D.J. Newman and G.M. Cragg, Natural Products as Sources of New Drugs over the Last 25 Years, J. Nat. Prod., 70, 461 (2007); https://doi.org/10.1021/np068054v
  15. K.H.J. Lee, Discovery and Development of Natural Product-Derived Chemotherapeutic Agents Based on a Medicinal Chemistry Approach, Nat. Prod. Prod., 73, 500 (2010); https://doi.org/10.1021/np900821e
  16. N.J. White, Qinghaosu (Artemisinin): The Price of Success, Science, 320, 330 (2008); https://doi.org/10.1126/science.1155165
  17. J. Achan, A.O. Talisuna, A. Erhart, A. Yeka, J.K. Tibenderana, F.N. Baliraine, P.J. Rosenthal and U. D’Alessandro, Quinine, An Old Anti-Malarial Drug in a Modern World: Role in the Treatment of Malaria, Malar. J., 10, 144 (2011); https://doi.org/10.1186/1475-2875-10-144
  18. A. Kumar, S. Katiyar, A. Agarwal and M.P.S. Chauhan, Perspective in Antimalarial Chemotherapy, Curr. Med. Chem., 10, 1137 (2003); https://doi.org/10.2174/0929867033457494
  19. H. Noedl, Y. Se, K. Schaecher, B.L. Smith, D. Socheat and M.M. Fukuda, Evidence of Artemisinin-Resistant Malaria in Western Cambodia, N. Engl. J. Med., 359, 2619 (2008); https://doi.org/10.1056/NEJMc0805011
  20. Y. Tang, Y. Dong and J.L. Vennerstrom, Synthetic Peroxides as Antimalarials, Med. Res. Rev., 24, 425 (2004); https://doi.org/10.1002/med.10066
  21. A.J. Lin, D.L. Klayman and W.K. Milhous, Antimalarial Activity of New Water-soluble Dihydroartemisinin Derivatives, J. Med. Chem., 30, 2147 (1987) https://doi.org/10.1021/jm00394a037
  22. V.W.-W. Yam, Molecular Design of Transition Metal Alkynyl Complexes as Building Blocks for Luminescent Metal-Based Materials: Structural and Photophysical Aspects, Acc. Chem. Res., 35, 555 (2002); https://doi.org/10.1021/ar0000758
  23. G.H. Posner, C.H. Oh, D. Wang, L. Gerena, W.K. Milhous, S.R. Meshnick and W. Asawamahasadka, Mechanism-Based Design, Synthesis and in vitro Antimalarial Testing of New 4-Methylated Trioxanes Structurally Related to Artemisinin: The Importance of a Carbon-Centered Radical for Antimalarial Activity, J. Med. Chem., 37, 1256 (1994); https://doi.org/10.1021/jm00035a003
  24. C.M. Martínez-Viturro and D. Domínguez, Synthesis of the Anti-tumoural Agent Batracylin and Related Isoindolo[1,2-b]quinazolin-12(10H)-ones, Tetrahedron Lett., 48, 1023 (2007); https://doi.org/10.1016/j.tetlet.2006.11.168
  25. K. Dzierzbicka, P. Trzonkowski, P.L. Sewerynek and A. Myœliwski, Synthesis and Cytotoxic Activity of Conjugates of Muramyl and Normuramyl Dipeptides with Batracylin Derivatives, J. Med. Chem., 46, 978 (2003); https://doi.org/10.1021/jm021067v
  26. S.-T. Yu, T.-M. Chen, S.-Y. Tseng and Y.-H. Chen, Tryptanthrin Inhibits MDR1 and Reverses Doxorubicin Resistance in Breast Cancer Cells, Biochem. Biophys. Res. Commun., 358, 79 (2007); https://doi.org/10.1016/j.bbrc.2007.04.107
  27. J. Scovill, E. Blank, M. Konnick, E. Nenortas and T. Shapiro, Anti-trypanosomal Activities of Tryptanthrins, Antimicrob. Agents Chemother., 46, 882 (2002); https://doi.org/10.1128/AAC.46.3.882-883.2002
  28. A.K. Bhattacharjee, D.J. Skanchy, B.T. Jennings, H. Hudson, J.J. Brendle and K.A. Werbovetz, Analysis of Stereoelectronic Properties, Mechanism of Action and Pharmacophore of Synthetic Indolo[2,1-b]-quinazoline-6,12-dione Derivatives in Relation to Antileishmanial Activity using Quantum Chemical, Cyclic Voltammetry and 3D-QSAR Catalyst Procedures, Bioorg. Med. Chem., 10, 1979 (2002); https://doi.org/10.1016/S0968-0896(02)00013-5
  29. H. Danz, S. Stoyanova, O.A.R. Thomet, H.-U. Simon, G. Dannhardt, H. Ulbrich and M. Hamburger, Inhibitory Activity of Tryptanthrin on Prostaglandin and Leukotriene Synthesis, Planta Med., 68, 875 (2002); https://doi.org/10.1055/s-2002-34922
  30. W.R. Bowman, M.R.J. Elsegood, T. Stein and G.W. Weaver, Radical Reactions with 3H-quinazolin-4-ones: Synthesis of Deoxyvasicinone, Mackinazolinone, Luotonin A, Rutaecarpine and Tryptanthrin, Org. Biomol. Chem., 5, 103 (2007); https://doi.org/10.1039/B614075K
  31. A. Kumar, V.D. Tripathi and P. Kumar, b-Cyclodextrin catalyzed Synthesis of Tryptanthrin in Water, Green Chem., 13, 51 (2011); https://doi.org/10.1039/C0GC00523A