Antiplasmodial Bis-Indole Alkaloids from the Bark of Flindersia pimenteliana

Abstract

Three new (1–3) and 2 known (4–5) bis-indole alkaloids were identified from the bark of Flindersia pimenteliana (Rutaceae). The structures of 1–3 were elucidated on the basis of their (+)-HRESESIMS and 2D NMR spectroscopic data. Antiplasmodial activity for 1–3 against chloroquine sensitive (3D7) and chloroquine-resistant (Dd2) Plasmodium falciparum is also reported, with IC₅₀ values ranging from 0.96 to 2.41 µg/mL. These results expand our knowledge of the structure-activity relationships of potently antiplasmodial isoborreverine-type alkaloids, the bioactivity of which have recently attracted significant attention in the literature.

Key words

Flindersia pimenteliana - Rutaceae, antiplasmodial - bis-indole - alkaloids

• References

• 1 Keeling PJ, Rayner JC. The origins of malaria: there are more things in heaven and earth …. Parasitology 2015; 142: 16-25
• 2 WHO. World Malaria Report 2018. Available at: https://www.who.int/malaria/publications/world-malaria-report-2018/en/ Accessed July 30, 2019
• 3 Schlitzer M. Malaria chemotherapeutics part I: history of antimalarial drug development, currently used therapeutics, and drugs in clinical development. ChemMedChem 2007; 2: 944-986
• 4 Eastman RT, Fidock DA. Artemisinin-based combination therapies: a vital tool in efforts to eliminate malaria. Nat Rev Microbiol 2009; 7: 864-874
• 5 Ashley EA, Dhorda M, Fairhurst RM, Amaratunga C, Lim P, Suon S, Sreng S, Anderson JM, Mao S, Sam B. Spread of artemisinin resistance in Plasmodium falciparum malaria. N Engl J Med 2014; 371: 411-423
• 6 Payne D. Spread of chloroquine resistance in Plasmodium falciparum . Parasitol Today 1987; 3: 241-246
• 7 Trape J-F. The public health impact of chloroquine resistance in Africa. Am J Trop Med Hyg 2001; 64: 12-17
• 8 Lubell Y, Dondorp A, Guérin PJ, Drake T, Meek S, Ashley E, Day NPJ, White NJ, White LJ. Artemisinin resistance–modelling the potential human and economic costs. Malar J 2014; 13: 452
• 9 Wells TNC. Natural products as starting points for future anti-malarial therapies: going back to our roots?. Malar J 2011; 10: S3
• 10 Fernandez LS, Jobling MF, Andrews KT, Avery VM. Antimalarial activity of natural product extracts from Papua New Guinean and Australian plants against Plasmodium falciparum . Phytother Res 2008; 22: 1409-1412
• 11 Fernandez LS, Buchanan MS, Carroll AR, Feng YJ, Quinn RJ, Avery VM. Flinderoles a−c: antimalarial bis-indole alkaloids from Flindersia species. Org Lett 2008; 11: 329-332
• 12 Fernandez LS, Sykes ML, Andrews KT, Avery VM. Antiparasitic activity of alkaloids from plant species of Papua New Guinea and Australia. Int J Antimicrob Agents 2010; 36: 275-279
• 13 Dethe DH, Erande RD, Ranjan A. Biomimetic total syntheses of borreverine and flinderole alkaloids. J Org Chem 2013; 78: 10106-10120
• 14 Dethe DH, Erande RD, Ranjan A. Biomimetic total syntheses of flinderoles B and C. J Am Chem Soc 2011; 133: 2864-2867
• 15 Zeldin RM, Toste FD. Synthesis of flinderoles B and C by a gold-catalyzed allene hydroarylation. Chem Sci 2011; 2: 1706-1709
• 16 Vallakati R, May JA. Biomimetic synthesis of the antimalarial flindersial alkaloids. J Am Chem Soc 2012; 134: 6936-6939
• 17 Tejeda JEC, Landschoot BK, Kerr MA. Radical cyclizations for the synthesis of pyrroloindoles: progress toward the flinderoles. Org Lett 2016; 18: 2142-2145
• 18 Kaur R, Garg Y, Pandey SK. A short total synthesis of the antimalarial flindersial alkaloids. ChemistrySelect 2016; 1: 4286-4288
• 19 Vallakati R, Lundy BJ, Jansone-Popova S, May JA. Biomimetic synthesis and studies toward enantioselective synthesis of flindersial alkaloids. Chirality 2015; 27: 14-17
• 20 Makarov AS, Merkushev AA, Uchuskin MG, Trushkov IV. Oxidative furan-to-indole rearrangement. Synthesis of 2-(2-acylvinyl) indoles and flinderole c analogues. Org Lett 2016; 18: 2192-2195
• 21 Dethe DH, Erande RD, Dherange BD. Remarkable switch of regioselectivity in diels–alder reaction: divergent total synthesis of borreverine, caulindoles, and flinderoles. Org Lett 2014; 16: 2764-2767
• 22 Dethe DH, Erande RD, Ranjan A. Flinderole analogues and process for synthesis thereof. Patent WO2012107934A1, 2012
• 23 Robertson LP, Duffy S, Wang Y, Wang D, Avery VM, Carroll AR. Pimentelamines a–c, indole alkaloids isolated from the leaves of the Australian tree Flindersia pimenteliana . J Nat Prod 2017; 80: 3211-3217
• 24 Robertson LP, Hall CR, Forster PI, Carroll AR. Alkaloid diversity in the leaves of Australian Flindersia (Rutaceae) species driven by adaptation to aridity. Phytochemistry 2018; 152: 71-81
• 25 Hartley TG. Flindersia . In: Wilson A. ed. Flora of Australia Volume 26, Meliaceae, Rutaceae, Zygophyllaceae. Melbourne: ABRS/CSIRO Australia; 2013: 62-72
• 26 Nunes DS, Luzia K, Taveira JJ, Francisco AMR. Indole alkaloids from Aspodosperma pruinosum . Phytochemistry 1992; 31: 2507-2511
• 27 Tillequin F, Koch M. Trois nouveaux alcaloïdes bis-indoliques de Flindersia fournieri . Phytochemistry 1979; 18: 1559-1561
• 28 Duffy S, Avery VM. Development and optimization of a novel 384-well anti-malarial imaging assay validated for high-throughput screening. Am J Trop Med Hyg 2012; 86: 84-92