Abstract
Malaria represents a significant health issue, and novel effective drugs are needed to address parasite resistance that has emerged to the current drug arsenal. The most popular antimalarial drugs are focused on the 7-chloro-4-aminoquinoline [e.g., chloroquine (CQ), amodiaquine (AQ), isoquine (IQ), and tebuquine (TBQ)], artemisinin, and atovaquone systems. Recently, endochin has been used as a platform to design a variety of novel potent and safe antimalarial agents named endochin-like quinolones (ELQs). Also, antimalarial quinolones have been constructed from other quinolones drugs such as ICI-56780 and floxacrine. Trifluoromethyl substitution has provided a significant increase in the antimalarial response of many of the designed ELQs against Plasmodium-resistant strains and for in vivo models. In particular, attachment of a substituted trifluoromethoxy (or trifluoromethyl in some cases) biaryl side chain at 2-, 3-, 4-, or 6-position of the quinolone core has shown to be crucially important to generate selective and potent novel ELQs. Furthermore, 6-chloro and 7-methoxy moieties on the quinolone core have been identified as essential pharmacophores when the trifluoromethoxy biaryl side chain is placed at 2- or 3-position of the quinolone core. Methyl or ethyl ester attached at 3-position is essential when the trifluoromethoxy aryl side chain is attached at 6- or 7-position of the quinolone core. Some promising ELQs are currently under clinical trials, representing an excellent platform for the design of new potent, selective, effective, and safe antimalarial drugs against emergent resistance malarial models.
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References
Miller LH, Baruch DL, Marsk K, Doumbo OK (2002) Nature 415:673–679
Fidock DA, Rosenthal PJ, Croft SL, Brunn R, Nwaka S (2004) Nat Rev Drug Discov 3:509
World Malaria Report (2017). (http://www.who.int/malaria/publications/world-malaria-report-2017/en/). Accessed 29 Nov 2017
http://www.who.int/malaria/media/world-malaria-day-2018/en/. Accessed Apr 2018
O’Neill PM, Bray PG, Hawley SR, Ward SA, Park BK (1998) Pharmacol Ther 77:29
Foley M, Tilley L (1998) Pharmacol Ther 79:55
Singh-Sidhu AB, Verdier-Pinard D, Fidock DA (2002) Science 298:210–213
Cui L, Mharakurwa S, Ndiaye D, Rathod PK, Rosenthal PJ (2015) Am J Trop Med Hyg 93:57–68
Wells TNC, Alonso PL, Gutteridge WE (2009) Nat Rev Drug Discov 8:879–891
Ridley RG (2002) Nature 415:686–693
Werbel LM, Cook PD, Elslager EF, Hung JH, Johnson JL, Kesten SJ, McNamara DJ, Ortwinw DF, Worth DF (1986) J Med Chem 29:924
O’Neill PM, Mukhtar A, Stocks PA, Randle LE, Hindley S, Ward SA, Storr RC, Bickley JF, O’Neil IA, Maggs JL, Hughes RH, Winstanley PA, Bray PG, Park BK (2003) J Med Chem 46:4933–4945
O’Neill PM, Shone AE, Stanford D, Nixon G, Asadollahy E, Park BK, Maggs JL, Roberts P, Stocks PA, Biagini G, Bray PG, Davies J, Berry N, Hall C, Rimmer K, Winstanley PA, Hindley S, Bambal RB, Davis CB, Bates M, Gresham SL, Brigandi RA, Gomez-de-las-Heras FM, Gargallo OV, Parapini OS, Vivas L, Lander H, Taramelli D, Ward SA (2009) J Med Chem 52:1828–1844
Kesten SJ, Johnson J, Werbel LM (1987) J Med Chem 30:907
O’Neill PM, Willock DJ, Hawley SR, Bray PG, Storr RC, Ward SA, Park BK (1997) J Med Chem 40:437–448
O’Neill PM, Harrison AC, Storr RC, Hawley SR, Ward SA, Park BK (1994) J Med Chem 37:1362–1370
Raynes KJ, Stocks PA, O’Neill PM, Park BK, Ward SA (1999) J Med Chem 42:2747–2751
Miroshnikova OV, Hudson TH, Gerena L, Kyle DE, Lin AJ (2007) J Med Chem 50:889–896
Casagrande M, Basilico N, Parapini S, Romeo S, Taramelli D, Sparatore A (2008) Bioorg Med Chem 16:6813–6823
Romero AH, Acosta ME, Gamboa N, Charris J, Salazar J, López SE (2015) Bioorg Med Chem 23:4755–4762
Valverde EA, Romero AH, Acosta ME, Gamboa N, Henriques G, Rodrigues JR, López SE (2018) Eur J Med Chem 148:498–506
Cumming JN, Ploypradith P, Posner GH (1997) Adv Pharmacol 37:253–297
White NJ, Olliaro P (1998) Med Trop (Mars) 58:54–56
Li Y, Zhu YM, Jiang JH, Pan JP, Wu GS, Wu JM, Shi YL, Yang JD, Wu BA (2000) J Med Chem 43:1635–1640
Vennerstrom JL, Arbe-Barnes S, Brun R, Charman SA, Chiu FCK, Chollet J, Dong Y, Dorn A, Hunziker D, Matile H, McIntosh K, Padmanilayam M, Santo Tomas J, Scheurer C, Scorneaux B, Tang Y, Urwyler H, Wittlin S, Charman WN (2004) Nature 430:900–904
Shandilya A, Chacko S, Jayaram B, Ghosh I (2013) Sci Rep 3:2513. https://doi.org/10.1038/srep02513
Ni Loo CS, Kei Lam NS, Yu D, Su X, Lu F (2017) Pharmacol Res 117:192–217
Nixon GL, Moss DM, Shone AE, Lalloo DG, Fisher N, O’Neill PM, Ward SA, Biagini GA (2013) J Antimicrob Chemother 68:977–985
Edstein MD, Kotecka BM, Anderson KL, Pombo DJ, Kyle DE, Rieckmann KH, Good MF (2005) Antimicrob Agents Chemother 49(10):4421–4422
El Hage S, Ane M, Stigliani J-L, Marjorie M, Vial H, Baziard-Mouysset G, Payard M (2009) Eur J Med Chem 44:4778–4782
Douglas NM, Anstey NM, Angus BJ, Nosten F, Price RN (2010) Lancet Infect Dis 10:405–416
Plowe CV (2014) Nature 505:30–31
Noedl H, Se Y, Schaecher K, Smith BL, Socheat D, Fukuda MM (2008) N Engl J Med 359:2619–2620
Greenwood B (2010) Malar J 9:S2
Nosten F, White NJ (2007) Am J Trop Med Hyg 77:181–192
McKeage K, Scott L (2003) Drugs 63:597–623
Butcher GA, Sinden RE (2003) Am J Trop Med Hyg 68(1):111–114
Touze JE, Fourcade L, Pradines B, Hovette P, Paule P, Heno P (2002) Med Trop (Mars) 62(3):219–224
Camus D, Dutoit E, Masson V, Inglebert P, Delhaes L (2002) Med Trop (Mars) 62(3):225–228
Sehdev PS (2002) Pediatr Infect Dis J 21(8):787–789
Kyle DE, Gerena L, Pitzer K, Gettyacamin M (2005) Antimalarial activity of 4(1H)-quinolones. Presented at the 54th Annual Meeting of the American Society of Tropical Medicine and Hygiene. Washington, DC
Winter RW, Kelly JX, Smilkstein MJ, Dodean R, Hinrichs D, Riscoe MK (2008) Exp Parasitol 118:487–497
Ryley JF, Peters W (1970) Ann Trop Med Parasitol 64:209–222
Raether W, Fink E (1979) Ann Trop Med Parasitol 73:505–526
Schmidt LH (1979) Antimicrob Agents Chemother 16:475–485
Kesten SJ, Degnan MJ, Hung J, McNamara DJ, Ortwine DF, Uhlendorf SE, Werbel LM (1992) J Med Chem 35:3429–3447
Berman J, Brown L, Miller R, Andersen SL, McGreevy P, Schuster BG, Ellis W, Ager A, Rossan R (1994) Antimicrob Agents Chemother 38:1753–1756
Salzer W, Timmler H, Andersag H (1948) Chem Ber 81:12–19
Stephen JML, Tonkin IM, Walker J (1947) J Chem Soc. pp 1034–1039. https://doi.org/10.1039/JR9470001034
Coatey GR, Cooper WC (1948) J Parasitol 34:275–289
Winter R, Kelly JX, Smilkstein MJ, Hinrichs D, Koop DR, Riscoe MK (2011) Exp Parasitol 127:545–551
Puri SK, Dutta GP (1990) Trans R Soc Trop Med Hyg 84:759–760
Fry M, Pudney M (1992) Biochem Pharmacol 43:1545
Suswam E, Kyle D, Lang-Unnasch N (2001) Exp Parasitol 98:180–187
Cross RM, Monastyrskyi A, Mutka TS, Burrows JN, Kyle DE, Manetsch R (2010) J Med Chem 53:7076–7094
Yeates CL, Batchelor JF, Capon EC, Cheesman NJ, Fry M, Hudson AT, Pudney M, Trimming H, Woolven J, Bueno JM, Chicharro J, Fernández E, Fiandor JM, Gargallo-Viola D, Gómez de las Heras F, Herreros E, León ML (2008) J Med Chem 51:2845–2852
Gamo FJ, Sanz LM, Mendoza A, Llergo JL, Lopez EM, Gómez de las Heras FM, Pompliano DL, Vaidya AB, García-Bustos JF (2005) Am J Trop Med Hyg 73(Suppl. 6):272
Gamo FJ, Sanz LM, Lafuente MJ, Mendoza A, de Cozar C, Rodríguez A, Llergo JL, Lopez EM, Gómez de las Heras F, García-Bustos JF (2007) Am J Trop Med Hyg 77(Suppl. 5):49–50
Cross RM, Maignan JR, Mutka TS, Luong L, Sargent J, Kyle DE, Manetsch R (2011) J Med Chem 54:4399–4426
Cross RM, Namelikonda NK, Mutka TS, Luong L, Kyle DE, Manetsch R (2011) J Med Chem 54:8321–8327
Zhang Y, Clark JA, Connelly MC, Zhu F, Min J, Guiguemde WA, Pradhan A, Iyer L, Furimsky A, Gow J, Parman T, El Mazouni F, Phillips MA, Kyle DE, Mirsalis J, Guy RK (2012) J Med Chem 55:4205–4219
Painter HJ, Morrisey JM, Mather MW, Vaidya AB (2007) Nature 446:88–91
Gardner MJ, Hall N, Fung E, White O, Berriman M, Hyman RW, Carlton JM, Pain A, Nelson KE, Bowman S, Paulsen IT, James K, Eisen JA, Rutherford K, Salzberg SL, Craig A, Kyes S, Chan M-S, Nene V, Shallom SJ, Suh B, Peterson J, Angiuoli S, Pertea M, Allen J, Selengut J, Haft D, Mather MW, Vaidya AB, Martin DMA, Fairlamb AH, Fraunholz MJ, Roos DS, Ralph SA, McFadden GI, Cummings LM, Subramanian GM, Mungall C, Venter JC, Carucci DJ, Hoffman SL, Newbold C, Davis RW, Fraser CM, Barrell B (2002) Nature 419:498–511
Vaidya AB, Mather MW (2005) Curr Top Microbiol Immunol 295:233–250
Ke H, Morrisey JM, Ganesan SM, Painter HJ, Mather MW, Vaidya AB (2011) Eukaryot Cell 10:1053–1061
Pidathala C, Amewu R, Pacorel B, Nixon GL, Gibbons P, Hong WD, Leung SC, Berry NG, Sharma R, Stocks PA, Srivastava A, Shone AE, Charoensutthivarakul S, Taylor L, Berger O, Mbekeani A, Hill A, Fisher NE, Warman AJ, Biagini GA, Ward SA, O’Neill PM (2012) J Med Chem 55:1831–1843
Leung SC, Gibbons P, Amewu R, Nixon GL, Pidathala C, Hong WD, Pacorel B, Berry NG, Sharma R, Stocks PA, Srivastava A, Shone AE, Charoensutthivarakul S, Taylor L, Berger O, Mbekeani A, Hill A, Fisher NE, Warman AJ, Biagini GA, Ward SA, O’Neill PM (2012) J Med Chem 55:1844–1857
Biagini GA, Fisher N, Shone AE, Mubaraki MA, Srivastava A, Hill A, Antoine T, Warman AJ, Davies J, Pidathala C, Amewu RK, Leung SC, Sharma R, Gibbons P, Hong DW, Pacorel B, Lawrenson AS, Charoensutthivarakul S, Taylor L, Berger O, Mbekeani A, Stocks PA, Nixon GL, Chadwick J, Hemingway J, Delves MJ, Sinden RE, Zeeman AM, Kocken CHM, Berry NG, O’Neill PM, Ward SA (2012) PNAS 109:8298–8303
Cowley R, Leung S, Fisher N, Al-Helal M, Berry NG, Lawrenson AS, Sharma R, Shone AE, Ward SA, Biagini GA, O’Neill PM (2012) Med Chem Commun 3:39–44
Rodrigues T, da Cruz FP, Lafuente-Monasterio MJ, Goncalves D, Ressurreicao AS, Sito AR, Bronze MR, Gut J, Schneider G, Mota MM, Rosenthal PJ, Prudencio M, Gamo FJ, Lopes F, Moreira R (2013) J Med Chem 56:4811–4815
Nilsen A, Miley GP, Forquer IP, Mather MW, Katneni K, Li Y, Pou S, Pershing AM, Stickles AM, Ryan E, Kelly JX, Stone Doggett J, White KL, Hinrichs DJ, Winter RW, Charman SA, Zakharov LN, Bathurst I, Burrows JN, Vaidya AB, Riscoe MK (2014) J Med Chem 57:3818–3834
Cross RM, Flanigan DL, Monastyrskyi A, LaCrue AN, Saenz FE, Maignan JR, Mutka TS, White KL, Shackleford DM, Bathurst I, Fronczek FR, Wojtas L, Guida WC, Charman SA, Burrows JN, Kyle DE, Manetsch R (2014) J Med Chem 57:8860–8879
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The author thanks the Facultad de Farmacia, Universidad Central de Venezuela for bibliographic material and financial support.
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Romero, A.H. Role of Trifluoromethyl Substitution in Design of Antimalarial Quinolones: a Comprehensive Review. Top Curr Chem (Z) 377, 9 (2019). https://doi.org/10.1007/s41061-019-0234-7
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DOI: https://doi.org/10.1007/s41061-019-0234-7