Molecular Targets for Malarial Chemotherapy: A Review

Author(s): Dharmendra K. Yadav*, Surendra Kumar, Mahesh K. Teli, Ravikant Yadav, Sandeep Chaudhary

Journal Name: Current Topics in Medicinal Chemistry

Volume 19 , Issue 10 , 2019

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Graphical Abstract:


The malaria parasite resistance to the existing drugs is a serious problem to the currently used antimalarials and, thus, highlights the urgent need to develop new and effective anti-malarial molecules. This could be achieved either by the identification of the new drugs for the validated targets or by further refining/improving the existing antimalarials; or by combining previously effective agents with new/existing drugs to have a synergistic effect that counters parasite resistance; or by identifying novel targets for the malarial chemotherapy. In this review article, a comprehensive collection of some of the novel molecular targets has been enlisted for the antimalarial drugs. The targets which could be deliberated for developing new anti-malarial drugs could be: membrane biosynthesis, mitochondrial system, apicoplasts, parasite transporters, shikimate pathway, hematin crystals, parasite proteases, glycolysis, isoprenoid synthesis, cell cycle control/cycline dependent kinase, redox system, nucleic acid metabolism, methionine cycle and the polyamines, folate metabolism, the helicases, erythrocyte G-protein, and farnesyl transferases. Modern genomic tools approaches such as structural biology and combinatorial chemistry, novel targets could be identified followed by drug development for drug resistant strains providing wide ranges of novel targets in the development of new therapy. The new approaches and targets mentioned in the manuscript provide a basis for the development of new unique strategies for antimalarial therapy with limited off-target effects in the near future.

Keywords: Drug targets, Anti-malaria, Plasmodium falciparum drug development, Cyclin-ependent, Kinases, Parasite proteases, Helicases.

Vial, H.J.; Calas, M. Inhibitors of phospholipid metabolism.Antimalarial Chemotherapy: Mechanisms of Action, Resistance, and New Directions in Drug Discovery; Rosenthal, P.J., Ed.; Humana Press: Totowa, NJ, 2001, pp. 347-365.
Shetty, P. The numbers game. Nature, 2012, 484(7395), S14-S15.
[] [PMID: 22534525]
Centers for disease control and prevention. The history of malaria, An ancient disease. (Accessed Oct. 6, 2011 at
World Health Organization. (Accessed on Oct. 6, 2011 at.
W.H.O.. Guidelines for the treatment of malaria, 3rd ed; World Health Organization, 2006.
Zhang, Y-K.; Plattner, J.J.; Easom, E.E.; Jacobs, R.T.; Guo, D.; Freund, Y.R.; Berry, P.; Ciaravino, V.; Erve, J.C.L.; Rosenthal, P.J.; Campo, B.; Gamo, F-J.; Sanz, L.M.; Cao, J. Benzoxaborole antimalarial agents. Part 5. lead optimization of novel amide pyrazinyloxy benzoxaboroles and identification of a preclinical candidate. J. Med. Chem., 2017, 60(13), 5889-5908.
[] [PMID: 28635296]
Gething, P.W.; Patil, A.P.; Smith, D.L.; Guerra, C.A.; Elyazar, I.; Johnston, G.L.; Tatem, A.J.; Hay, S.I. Malar. J., 2011, 10, 1475-2875.
Battle, K.E.; Gething, P.W.; Elyazar, I.R.F.; Moyes, C.L.; Sinka, M.E.; Howes, R.E.; Guerra, C.A.; Price, R.N.; Baird, J.K.; Hay, S.I. Advances in Parasitology; Hay, S.I.; Baird, J.K.; Eds., Part BAcademic Press, Elsevier, 2011.
Wu, T.; Nagle, A.S.; Chatterjee, A.K. Road towards new antimalarials - Overview of the strategies and their chemical progress. Curr. Med. Chem., 2011, 18(6), 853-871.
[] [PMID: 21182479]
Chatterjee, A.K.; Yeung, B.K. Back to the future: Lessons learned in modern target-based and whole-cell lead optimization of antimalarials. Curr. Top. Med. Chem., 2012, 12(5), 473-483.
[] [PMID: 22242845]
Crabb, B.S.; Beeson, J.G.; Amino, R.; Ménard, R.; Waters, A.; Winzeler, E.A.; Wahlgren, M.; Fidock, D.A.; Nwaka, S. Perspectives: The missing pieces. Nature, 2012, 484(7395), S22-S23.
[] [PMID: 22534528]
Dechy-Cabaret, O.; Benoit-Vical, F. Effects of antimalarial molecules on the gametocyte stage of Plasmodium falciparum: the debate. J. Med. Chem., 2012, 55(23), 10328-10344.
[] [PMID: 23075290]
DeWeerdt, S. Vaccines: The take-home lesson. Nature, 2012, 484(7395), S24-S25.
[] [PMID: 22534529]
Eisenstein, M. Drug development: Holding out for reinforcements. Nature, 2012, 484(7395), S16-S18.
[] [PMID: 22534526]
Gravitz, L. Vector control: The last bite. Nature, 2012, 484(7395), S26-S27.
[] [PMID: 22534530]
Grayson, M. Malaria. Nature, 2012, 484(7395), S13-S13.
[] [PMID: 22534524]
Zhang, V.M.; Chavchich, M.; Waters, N.C. Targeting protein kinases in the malaria parasite: update of an antimalarial drug target. Curr. Top. Med. Chem., 2012, 12(5), 456-472.
[] [PMID: 22242850]
Maxmen, A. Public health: Death at the doorstep. Nature, 2012, 484, S19-S21. [Title and DOI missing
Wells, T.N. Treatment and prevention of malaria. In:Antimalarial drug chemistry, action and use; Staines, Henry.M.; Krishna, Sanjeev., Eds.; Springer, 2012, pp. 227-247. [Book Title and editors missing]
Zhang, Y-K.; Ge, M.; Plattner, J.J. Recent Progress in the synthesis of antimalarial agents. Org. Prep. Proced. Int., 2012, 44, 340-374. [Title missing]
Thota, S.; Yerra, R. Drug discovery and development of antimalarial agents: Recent advances. Curr. Protein Pept. Sci., 2016, 17, 275-279. [Title and author names missing]
[] [PMID: 26796302]
Wells, T.N.; Hooft van Huijsduijnen, R.; Van Voorhis, W.C. Malaria medicines: A glass half full? Nat. Rev. Drug Discov., 2015, 14(6), 424-442.
[] [PMID: 26000721]
Bushell, E; Gomes, AR; Sanderson, T; Anar, B; Girling, G; Herd, C Functional profiling of a plasmodium genome reveals an abundance of essential genes. Cell, 2017. 170(2), 260e8-272e8. []
Hovlid, M.L.; Winzeler, E.A. Phenotypic screens in antimalarial drug discovery. Trends Parasitol., 2016, 32(9), 697-707.
[] [PMID: 27247245]
Cowell, A.N.; Istvan, E.S.; Lukens, A.K.; Gomez-Lorenzo, M.G.; Vanaerschot, M.; Sakata-Kato, T.; Flannery, E.L.; Magistrado, P.; Owen, E.; Abraham, M.; LaMonte, G.; Painter, H.J.; Williams, R.M.; Franco, V.; Linares, M.; Arriaga, I.; Bopp, S.; Corey, V.C.; Gnädig, N.F.; Coburn-Flynn, O.; Reimer, C.; Gupta, P.; Murithi, J.M.; Moura, P.A.; Fuchs, O.; Sasaki, E.; Kim, S.W.; Teng, C.H.; Wang, L.T.; Akidil, A.; Adjalley, S.; Willis, P.A.; Siegel, D.; Tanaseichuk, O.; Zhong, Y.; Zhou, Y.; Llinás, M.; Ottilie, S.; Gamo, F.J.; Lee, M.C.S.; Goldberg, D.E.; Fidock, D.A.; Wirth, D.F.; Winzeler, E.A. Mapping the malaria parasite druggable genome by using in vitro evolution and chemogenomics. Science, 2018, 359(6372), 191-199.
[] [PMID: 29326268]
Wells, T.N.; Willis, P.; Burrows, J.N.; Hooft van Huijsduijnen, R. Open data in drug discovery and development: Lessons from malaria. Nat. Rev. Drug Discov., 2016, 15(10), 661-662.
[] [PMID: 27516171]
McCarthy, J.S.; Marquart, L.; Sekuloski, S.; Trenholme, K.; Elliott, S.; Griffin, P.; Rockett, R.; O’Rourke, P.; Sloots, T.; Angulo-Barturen, I.; Ferrer, S.; Jiménez-Díaz, M.B.; Martínez, M.S.; Hooft van Huijsduijnen, R.; Duparc, S.; Leroy, D.; Wells, T.N.; Baker, M.; Möhrle, J.J. Linking murine and human Plasmodium falciparum challenge models in a translational path for antimalarial drug development. Antimicrob. Agents Chemother., 2016, 60(6), 3669-3675.
[] [PMID: 27044554]
Hien, T.T.; White, N.J.; Thuy-Nhien, N.T.; Hoa, N.T.; Thuan, P.D.; Tarning, J. Estimation of the in vivo MIC of cipargamin in uncomplicated Plasmodium falciparum malaria. Antimicrob. Agents Chemother., 2017, 61(2), e01940-e16. [DOI:]
Alam, A.; Goyal, M.; Iqbal, M.S.; Pal, C.; Dey, S.; Bindu, S.; Maity, P.; Bandyopadhyay, U. Novel antimalarial drug targets: hope for new antimalarial drugs. Expert Rev. Clin. Pharmacol., 2009, 2(5), 469-489.
[] [PMID: 22112223]
Rosenthal, P.J. Antimalarial drug discovery: Old and new approaches. J. Exp. Biol., 2003, 206(Pt 21), 3735-3744.
[] [PMID: 14506208]
Phillips, M.A.; Rathod, P.K. Plasmodium dihydroorotate dehydrogenase: A promising target for novel anti-malarial chemotherapy. Infect. Disord. Drug Targets, 2010, 10(3), 226-239.
[] [PMID: 20334617]
Rosenthal, P.J. Proteases of malaria parasites: New targets for chemotherapy. Emerg. Infect. Dis., 1998, 4(1), 49-57.
[] [PMID: 9452398]
Murata, C.E.; Goldberg, D.E. Plasmodium falciparum falcilysin: An unprocessed food vacuole enzyme. Mol. Biochem. Parasitol., 2003, 129(1), 123-126.
[] [PMID: 12798513]
Ancelin, M.L.; Calas, M.; Vidal-Sailhan, V.; Herbuté, S.; Ringwald, P.; Vial, H.J. Potent inhibitors of Plasmodium phospholipid metabolism with a broad spectrum of in vitro antimalarial activities. Antimicrob. Agents Chemother., 2003, 47(8), 2590-2597.
[] [PMID: 12878524]
Vial, H. Recent developments and rationale towards new strategies for malarial chemotherapy. Parasite, 1996, 3(1), 3-23.
[] [PMID: 8731759]
Roggero, R.; Zufferey, R.; Minca, M.; Richier, E.; Calas, M.; Vial, H.; Ben Mamoun, C. Unraveling the mode of action of the antimalarial choline analog G25 in Plasmodium falciparum and Saccharomyces cerevisiae. Antimicrob. Agents Chemother., 2004, 48(8), 2816-2824.
[] [PMID: 15273086]
Painter, H.J.; Morrisey, J.M.; Mather, M.W.; Vaidya, A.B. Specific role of mitochondrial electron transport in blood-stage Plasmodium falciparum. Nature, 2007, 446(7131), 88-91. [Title and DOI missing]
Ellis, J.E. Coenzyme Q homologs in parasitic protozoa as targets for chemotherapeutic attack. Parasitol. Today (Regul. Ed.),1994, 10(8), 296-301. [] [PMID: 15275423]
Srivastava, I.K.; Rottenberg, H.; Vaidya, A.B. Atovaquone, a broad spectrum antiparasitic drug, collapses mitochondrial membrane potential in a malarial parasite. J. Biol. Chem., 1997, 272(7), 3961-3966.
[] [PMID: 9020100]
Hogh, B.; Clarke, P.D.; Camus, D.; Nothdurft, H.D.; Overbosch, D.; Gunther, M.; Joubert, I.; Kain, K.; Shaw, D.; Roskell, N. Atovaquone-proguanil versus chloroquine- proguanil for malaria prophylaxis in non-immune travellers: A randomized, double-blind study. Malarone International Study Team. Lancet, 2000, 356, 1888-1894. [Title missing]
Radloff, P.D.; Philipps, J.; Nkeyi, M.; Hutchinson, D.; Kremsner, P.G. Atovaquone and proguanil for Plasmodium falciparum malaria. Lancet, 1996, 347(9014), 1511-1514.
[] [PMID: 8684102]
Phillips, M.A.; Rathod, P.K. Plasmodium dihydroorotate dehydrogenase: A promising target for novel anti-malarial chemotherapy. Infect. Disord. Drug Targets, 2010, 10(3), 226-239.
[] [PMID: 20334617]
Nair, S.C.; Striepen, B. What do human parasites do with a chloroplast anyway? PLoS Biol., 2011, 9(8), e1001137.
[] [PMID: 21912515]
Goodman, C.D.; McFadden, G.I. Targeting apicoplasts in malaria parasites. Expert Opin. Ther. Targets, 2013, 17(2), 167-177.
[] [PMID: 23231425]
Kita, K.; Miyadera, H.; Saruta, F.; Miyoshi, H. Parasite mitochondria as a target for chemotherapy. J. Health Sci., 2001, 47, 219-239.
McFadden, G.I.; Roos, D.S. Apicomplexan plastids as drug targets. Trends Microbiol., 1999, 7(8), 328-333.
[] [PMID: 10431206]
Surolia, N. Fatty acid synthesis in Plasmodium: a novel target for anti-malarial drug development: pathogen genomics. S. Afr. J. Sci., 2004, 100(9-10), 459-464.
Waller, R.F.; Keeling, P.J.; Donald, R.G.; Striepen, B.; Handman, E.; Lang-Unnasch, N.; Cowman, A.F.; Besra, G.S.; Roos, D.S.; McFadden, G.I. Nuclear-encoded proteins target to the plastid in Toxoplasma gondii and Plasmodium falciparum. Proc. Natl. Acad. Sci. USA, 1998, 95(21), 12352-12357.
[] [PMID: 9770490]
Surolia, N.; Surolia, A. Triclosan offers protection against blood stages of malaria by inhibiting enoyl-ACP reductase of Plasmodium falciparum. Nat. Med., 2001, 7(2), 167-173.
[] [PMID: 11175846]
Martin, R.E.; Henry, R.I.; Abbey, J.L.; Clements, J.D.; Kirk, K. The ‘permeome’ of the malaria parasite: an overview of the membrane transport proteins of Plasmodium falciparum. Genome Biol., 2005, 6(3), R26.
[] [PMID: 15774027]
Staines, H.M.; Dee, B.C.; O’Brien, M.; Lang, H.J.; Englert, H.; Horner, H.A.; Ellory, J.C.; Kirk, K. Furosemide analogues as potent inhibitors of the new permeability pathways of Plasmodium falciparum-infected human erythrocytes. Mol. Biochem. Parasitol., 2004, 133(2), 315-318.
[] [PMID: 14698443]
Joet, T.; Eckstein-Ludwig, U.; Morin, C.; Krishna, S. Validation of the hexose transporter of Plasmodium falciparum as a novel drug target. Proc. Natl. Acad. Sci. USA, 2003, 100(13), 7476-7479.
[] [PMID: 12792024]
Ehrenkranz, J.R.; Lewis, N.G.; Kahn, C.R.; Roth, J. Phlorizin: A review. Diabetes Metab. Res. Rev., 2005, 21(1), 31-38.
[] [PMID: 15624123]
Rosenthal, P.J.; Press, H.; Chiodini, P.L. Mechanisms of action, resistance and new directions in drug discovery. J. Antimicrob. Chemother., 2003, 51, 1053-1053.
Barton, V.; Fisher, N.; Biagini, G.A.; Ward, S.A.; O’Neill, P.M. Inhibiting Plasmodium cytochrome bc1: A complex issue. Curr. Opin. Chem. Biol., 2010, 14(4), 440-446.
[] [PMID: 20570550]
Rodrigues, T.; Moreira, R.; Lopes, F. New hope in the fight against malaria? Future Med. Chem., 2011, 3(1), 1-3.
[] [PMID: 21428820]
Upston, J.M.; Gero, A.M. Parasite-induced permeation of nucleosides in Plasmodium falciparum malaria. Biochim. Biophys. Acta, 1995, 1236(2), 249-258.
[] [PMID: 7794964]
Slavic, K.; Krishna, S.; Derbyshire, E.T.; Staines, H.M. Plasmodial sugar transporters as anti-malarial drug targets and comparisons with other protozoa. Malar. J., 2011, 10, 165.
[] [PMID: 21676209]
Roberts, F.; Roberts, C.W.; Johnson, J.J.; Kyle, D.E.; Krell, T.; Coggins, J.R.G.H. Coombs., W.K. Milhous, S. Tzipori, D.J. Ferguson, D. Chakrabarti, R. McLeod. Nature, 1998, 393, 801-805.
[] [PMID: 9655396]
Abell, C. Comprehensive Natural Products Chemistry; Sankawa, U., Ed.; Elsevier: Amsterdam, 1998, Vol. 1, pp. 573-607.
McConkey, G.A. Targeting the shikimate pathway in the malaria parasite Plasmodium falciparum. Antimicrob. Agents Chemother., 1999, 43(1), 175-177.
[] [PMID: 9869588]
Roberts, C.W.; Roberts, F.; Lyons, R.E.; Kirisits, M.J.; Mui, E.J.; Finnerty, J.; Johnson, J.J.; Ferguson, D.J.; Coggins, J.R.; Krell, T.; Coombs, G.H.; Milhous, W.K.; Kyle, D.E.; Tzipori, S.; Barnwell, J.; Dame, J.B.; Carlton, J.; McLeod, R. The shikimate pathway and its branches in apicomplexan parasites. J. Infect. Dis., 2002, 185(Suppl. 1), S25-S36.
[] [PMID: 11865437]
McConkey, G.A.; Pinney, J.W.; Westhead, D.R.; Plueckhahn, K.; Fitzpatrick, T.B.; Macheroux, P.; Kappes, B. Annotating the Plasmodium genome and the enigma of the shikimate pathway. Trends Parasitol., 2004, 20(2), 60-65.
[] [PMID: 14747018]
Fitzpatrick, T.; Ricken, S.; Lanzer, M.; Amrhein, N.; Macheroux, P.; Kappes, B. Subcellular localization and characterization of chorismate synthase in the apicomplexan Plasmodium falciparum. Mol. Microbiol., 2001, 40(1), 65-75.
[] [PMID: 11298276]
McRobert, L.; McConkey, G.A. RNA interference (RNAi) inhibits growth of Plasmodium falciparum. Mol. Biochem. Parasitol., 2002, 119(2), 273-278.
[] [PMID: 11814579]
McRobert, L.; Jiang, S.; Stead, A.; McConkey, G.A. Plasmodium falciparum: Interaction of shikimate analogues with antimalarial drugs. Exp. Parasitol., 2005, 111(3), 178-181.
[] [PMID: 16140296]
Robert, A.; Coppel, Y.; Meunier, B. Alkylation of heme by the antimalarial drug artemisinin. Chem. Commun. (Camb.), 2002, 5, 414-415. [Title missing]
[] [PMID: 12120518]
Egan, T.J.; Combrinck, J.M.; Egan, J.; Hearne, G.R.; Marques, H.M.; Ntenteni, S.; Sewell, B.T.; Smith, P.J.; Taylor, D.; van Schalkwyk, D.A.; Walden, J.C. Fate of haem iron in the malaria parasite Plasmodium falciparum. Biochem. J., 2002, 365(Pt 2), 343-347.
[] [PMID: 12033986]
Egan, T.J. Haemozoin (malaria pigment): A unique crystalline drug target. Targets, 2003, 2(3), 115-124. [Incomplete title]
Biamonte, M.A.; Wanner, J.; Le Roch, K.G. Recent advances in malaria drug discovery. Bioorg. Med. Chem. Lett., 2013, 23(10), 2829-2843.
[] [PMID: 23587422]
Blackman, M.J. Proteases involved in erythrocyte invasion by the malaria parasite: Function and potential as chemotherapeutic targets. Curr. Drug Targets, 2000, 1(1), 59-83.
[] [PMID: 11475536]
Banerjee, R.; Liu, J.; Beatty, W.; Pelosof, L.; Klemba, M.; Goldberg, D.E. Four plasmepsins are active in the Plasmodium falciparum food vacuole, including a protease with an active-site histidine. Proc. Natl. Acad. Sci. USA, 2002, 99(2), 990-995.
[] [PMID: 11782538]
Rosenthal, P.J. Cysteine proteases of malaria parasites. Int. J. Parasitol., 2004, 34(13-14), 1489-1499.
[] [PMID: 15582526]
Sijwali, P.S.; Koo, J.; Singh, N.P.J. Gene disruptions demonstrate independent roles for the four falcipain cysteine proteases of Plasmodium falciparum. Mol. Biochem. Parasitol., 2006, 150, 96-106. [Incomplete title]
[] [PMID: 16890302]
Eggleson, K.K.; Duffin, K.L.; Goldberg, D.E. Identification and characterization of falcilysin, a metallopeptidase involved in hemoglobin catabolism within the malaria parasite Plasmodium falciparum. J. Biol. Chem., 1999, 274(45), 32411-32417.
[] [PMID: 10542284]
Klemba, M.; Gluzman, I.; Goldberg, D.E. A Plasmodium falciparum dipeptidyl aminopeptidase I participates in vacuolar hemoglobin degradation. J. Biol. Chem., 2004, 279(41), 43000-43007.
[] [PMID: 15304495]
Le Bonniec, S.; Deregnaucourt, C.; Redeker, V.; Banerjee, R.; Grellier, P.; Goldberg, D.E.; Schrével, J. Plasmepsin II, an acidic hemoglobinase from the Plasmodium falciparum food vacuole, is active at neutral pH on the host erythrocyte membrane skeleton. J. Biol. Chem., 1999, 274(20), 14218-14223.
[] [PMID: 10318841]
Rosenthal, P.J. Antimalarial drug discovery: Old and new approaches. J. Exp. Biol., 2003, 206(Pt 21), 3735-3744.
[] [PMID: 14506208]
Rosenthal, P.J. Antimalarial chemotherapy. In:Mechanisms of action, resistance, and new directions in drug discovery; Humana Press: Totawa, NJ, 2001, pp. 325-345.
Ersmark, K.; Samuelsson, B.; Hallberg, A. Plasmepsins as potential targets for new antimalarial therapy. Med. Res. Rev., 2006, 26(5), 626-666.
[] [PMID: 16838300]
Pandey, K. Macromolecular inhibitors of malarial cysteine proteases: An invited review. J. Biomed. Sci. Eng., 2013, 6, 885-895.
Bailly, E.; Jambou, R.; Savel, J.; Jaureguiberry, G. Plasmodium falciparum: differential sensitivity in vitro to E-64 (cysteine protease inhibitor) and Pepstatin A (aspartyl protease inhibitor). J. Protozool., 1992, 39(5), 593-599.
[] [PMID: 1522541]
Singh, P.J. Rosenthal. Antimicrob. Agents Chemother., 2001, 45, 949-951.
[] [PMID: 11181388]
Pandey, K.C.; Wang, S.X.; Sijwali, P.S.; Lau, A.L.; McKerrow, J.H.; Rosenthal, P.J. The Plasmodium falciparum cysteine protease falcipain-2 captures its substrate, hemoglobin, via a unique motif. Proc. Natl. Acad. Sci. USA, 2005, 102(26), 9138-9143.
[] [PMID: 15964982]
Moneriz, C.; Mestres, J.; Bautista, J.M.; Diez, A.; Puyet, A. Multi-targeted activity of maslinic acid as an antimalarial natural compound. FEBS J., 2011, 278(16), 2951-2961.
[] [PMID: 21689375]
Rosenthal, P.J.; Olson, J.E.; Lee, G.K.; Palmer, J.T.; Klaus, J.L.; Rasnick, D. Antimalarial effects of vinyl sulfone cysteine proteinase inhibitors. Antimicrob. Agents Chemother., 1996, 40(7), 1600-1603.
[] [PMID: 8807047]
Lee, B.J.; Singh, A.; Chiang, P.; Kemp, S.J.; Goldman, E.A.; Weinhouse, M.I.; Vlasuk, G.P.; Rosenthal, P.J. Antimalarial activities of novel synthetic cysteine protease inhibitors. Antimicrob. Agents Chemother., 2003, 47(12), 3810-3814.
[] [PMID: 14638488]
Coombs, G.H.; Goldberg, D.E.; Klemba, M.; Berry, C.; Kay, J.; Mottram, J.C. Aspartic proteases of Plasmodium falciparum and other parasitic protozoa as drug targets. Trends Parasitol., 2001, 17(11), 532-537.
[] [PMID: 11872398]
Bradshaw, R.A.; Brickey, W.W.; Walker, K.W. N-terminal processing: the methionine aminopeptidase and N alpha-acetyl transferase families. Trends Biochem. Sci., 1998, 23(7), 263-267.
[] [PMID: 9697417]
Chen, X.; Chong, C.R.; Shi, L.; Yoshimoto, T.; Sullivan, D.J., Jr; Liu, J.O. Inhibitors of Plasmodium falciparum methionine aminopeptidase 1b possess antimalarial activity. Proc. Natl. Acad. Sci. USA, 2006, 103(39), 14548-14553.
[] [PMID: 16983082]
Philippe, G.; Christiane, D.; Isabelle, F. Advances in antimalarial drug evaluation and new targets for antimalarials In: Malaria Parasites; IntechOpen: London, United Kingdom, 2011, pp. 320-350. [Book title, DOI and Publisher info missing] [DOI: 10.5772/34075]
Ben Mamoun, C.; Prigge, S.T.; Vial, H. Targeting the lipid metabolic pathways for the treatment of malaria. Drug Dev. Res., 2010, 71(1), 44-55.
[PMID: 20559451]
Joet, T.; Eckstein-Ludwig, U.; Morin, C.; Krishna, S. Validation of the hexose transporter of Plasmodium falciparum as a novel drug target. Proc. Natl. Acad. Sci. USA, 2003, 100(13), 7476-7479.
[] [PMID: 12792024]
Cameron, A.; Read, J.; Tranter, R.; Winter, V.J.; Sessions, R.B.; Brady, R.L.; Vivas, L.; Easton, A.; Kendrick, H.; Croft, S.L.; Barros, D.; Lavandera, J.L.; Martin, J.J.; Risco, F.; García-Ochoa, S.; Gamo, F.J.; Sanz, L.; Leon, L.; Ruiz, J.R.; Gabarró, R.; Mallo, A.; Gómez de las Heras, F. Identification and activity of a series of azole-based compounds with lactate dehydrogenase-directed anti-malarial activity. J. Biol. Chem., 2004, 279, 31429-31439.
Choi, S.R.; Beeler, A.B.; Pradhan, A.; Watkins, E.B.; Rimoldi, J.M.; Tekwani, B.; Avery, M.A. Generation of oxamic acid libraries: antimalarials and inhibitors of Plasmodium falciparum lactate dehydrogenase. J. Comb. Chem., 2007, 9(2), 292-300.
[] [PMID: 17316052]
Chan, M.; Tan, D.S.; Sim, T.S. Plasmodium falciparum pyruvate kinase as a novel target for antimalarial drug-screening. Travel Med. Infect. Dis., 2007, 5(2), 125-131.
[] [PMID: 17298920]
Jomaa, H.; Wiesner, J.; Sanderbrand, S.; Altincicek, B.; Weidemeyer, C.; Hintz, M.; Türbachova, I.; Eberl, M.; Zeidler, J.; Lichtenthaler, H.K.; Soldati, D.; Beck, E. Inhibitors of the nonmevalonate pathway of isoprenoid biosynthesis as antimalarial drugs. Science, 1999, 285(5433), 1573-1576.
[] [PMID: 10477522]
Phillips, M.A.; Rathod, P.K. Plasmodium dihydroorotate dehydrogenase: A promising target for novel anti-malarial chemotherapy. Infect. Disord. Drug Targets, 2010, 10(3), 226-239.
[] [PMID: 20334617]
Kuntz, L.; Tritsch, D.; Grosdemange-Billiard, C.; Hemmerlin, A.; Willem, A.; Bach, T.J.; Rohmer, M. Isoprenoid biosynthesis as a target for antibacterial and antiparasitic drugs: phosphonohydroxamic acids as inhibitors of deoxyxylulose phosphate reducto-isomerase. Biochem. J., 2005, 386(Pt 1), 127-135.
[] [PMID: 15473867]
Goodman, C.D.; McFadden, G.I. Targeting apicoplasts in malaria parasites. Expert Opin. Ther. Targets, 2013, 17(2), 167-177.
[] [PMID: 23231425]
Kita, K.; Miyadera, H.; Saruta, F.; Miyoshi, H. Parasite mitochondria as a target for chemotherapy. J. Health Sci., 2001, 47, 219-239.
Lell, B.; Ruangweerayut, R.; Wiesner, J.; Missinou, M.A.; Schindler, A.; Baranek, T.; Hintz, M.; Hutchinson, D.; Jomaa, H.; Kremsner, P.G. Fosmidomycin, a novel chemotherapeutic agent for malaria. Antimicrob. Agents Chemother., 2003, 47(2), 735-738.
[] [PMID: 12543685]
Wiesner, J.; Ortmann, R.; Jomaa, H.; Schlitzer, M. Double ester prodrugs of FR900098 display enhanced in-vitro antimalarial activity Arch. Pharm. Chem. Life Sci., 2007, 340, 667-669. [Title and DOI missing]
Doerig, C.; Endicott, J.; Chakrabarti, D. Cyclin-dependent kinase homologues of Plasmodium falciparum. Int. J. Parasitol., 2002, 32(13), 1575-1585.
[] [PMID: 12435442]
Doerig, C.; Billker, O.; Haystead, T.; Sharma, P.; Tobin, A.B.; Waters, N.C. Protein kinases of malaria parasites: an update. Trends Parasitol., 2008, 24(12), 570-577.
[] [PMID: 18845480]
Geyer, J.A.; Prigge, S.T.; Waters, N.C. Targeting malaria with specific CDK inhibitors. Biochim. Biophys. Acta, 2005, 1754(1-2), 160-170.
[] [PMID: 16185941]
Christian, G.; Stranger, R.; Petrie, S.; Yates, B.F.; Cummins, C.C. Breaking chemistry’s strongest bond: can three-coordinate [MN(R)Ar3] complexes cleave carbon monoxide? Chemistry, 2007, 13(15), 4264-4272.
[] [PMID: 17385762]
Morgan, D.O. Cyclin-dependent kinases: engines, clocks, and microprocessors. Annu. Rev. Cell Dev. Biol., 1997, 13, 261-291.
[] [PMID: 9442875]
Aminake, M.N.; Arndt, H.D.; Pradel, G. The proteasome of malaria parasites: A multi-stage drug target for chemotherapeutic intervention? Int. J. Parasitol. Drugs Drug Resist., 2012, 2, 1-10.
[] [PMID: 24533266]
Knockaert, M.; Greengard, P.; Meijer, L. Pharmacological inhibitors of cyclin-dependent kinases. Trends Pharmacol. Sci., 2002, 23(9), 417-425.
[] [PMID: 12237154]
Zhang, V.M.; Chavchich, M.; Waters, N.C. Targeting protein kinases in the malaria parasite: update of an antimalarial drug target. Curr. Top. Med. Chem., 2012, 12(5), 456-472.
[] [PMID: 22242850]
Hardcastle, I.R.; Golding, B.T.; Griffin, R.J. Designing inhibitors of cyclin-dependent kinases. Annu. Rev. Pharmacol. Toxicol., 2002, 42, 325-348.
[] [PMID: 11807175]
Xiao, Z.; Waters, N.C.; Woodard, C.L.; Li, Z.; Li, P.K. Design and synthesis of Pfmrk inhibitors as potential antimalarial agents. Bioorg. Med. Chem. Lett., 2001, 11(21), 2875-2878.
[] [PMID: 11597420]
Knockaert, M.; Greengard, P.; Meijer, L. Pharmacological inhibitors of cyclin-dependent kinases. Trends Pharmacol. Sci., 2002, 23(9), 417-425.
[] [PMID: 12237154]
Kim, H.; Certa, U.; Döbeli, H.; Jakob, P.; Hol, W.G. Crystal structure of fructose-1,6-bisphosphate aldolase from the human malaria parasite Plasmodium falciparum. Biochemistry, 1998, 37(13), 4388-4396.
[] [PMID: 9521758]
Krauth-Siegel, R.L.; Coombs, G.H. Enzymes of parasite thiol metabolism as drug targets. Parasitol. Today (Regul. Ed.),1999, 15(10), 404-409. [] [PMID: 10481152]
Lüersen, K.; Walter, R.D.; Müller, S. Plasmodium falciparum-infected red blood cells depend on a functional glutathione de novo synthesis attributable to an enhanced loss of glutathione. Biochem. J., 2000, 346(Pt 2), 545-552.
[] [PMID: 10677377]
Werner, C.; Stubbs, M.T.; Krauth-Siegel, R.L.; Klebe, G. The crystal structure of Plasmodium falciparum glutamate dehydrogenase, a putative target for novel antimalarial drugs. J. Mol. Biol., 2005, 349(3), 597-607.
[] [PMID: 15878595]
Keough, D.T.; Ng, A.L.; Winzor, D.J.; Emmerson, B.T.; de Jersey, J. Purification and characterization of Plasmodium falciparum hypoxanthine-guanine-xanthine phosphoribosyltransferase and comparison with the human enzyme. Mol. Biochem. Parasitol., 1999, 98(1), 29-41.
[] [PMID: 10029307]
Flannery, E.L.; Chatterjee, A.K.; Winzeler, E.A. Antimalarial drug discovery-Approaches and progress towards new medicines. Nat. Rev. Microbiol., 2013, 11(12), 849-862.
[] [PMID: 24217412]
Kicsca, G.A.; Long, L.; Hçrig, H.; Fairchild, G.; Tyler, P.C.; Furneaux, R.H.; Schramm, V.L.; Kaufman, H.L. Immucillin H, a powerful transition-state analog inhibitor of purine nucleoside phosphorylase, selectively inhibits human T lymphocytes. Proc. Natl. Acad. Sci. USA, 2001, 98, 4593-4598.
Biagini, G.A.; O’Neill, P.M.; Nzila, A.; Ward, S.A.; Bray, P.G. Antimalarial chemotherapy: Young guns or back to the future? Trends Parasitol., 2003, 19(11), 479-487.
[] [PMID: 14580958]
Heikkila, T.; Ramsey, C.; Davies, M.; Galtier, C.; Stead, A.M.W.; Johnson, A.P.; Fishwick, C.W.G.; Boa, A.N.; McConkey, G.A. Design and synthesis of potent inhibitors of the malaria parasite dihydroorotate dehydrogenase. J. Med. Chem., 2007, 50(2), 186-191. [Title and DOI missing]
Walker, J.; Barrett, J. Parasite sulphur amino acid metabolism. Int. J. Parasitol., 1997, 27(8), 883-897.
[] [PMID: 9292304]
Heby, O.; Roberts, S.C.; Ullman, B. Polyamine biosynthetic enzymes as drug targets in parasitic protozoa. Biochem. Soc. Trans., 2003, 31(2), 415-419.
[] [PMID: 12653650]
Ikeguchi, Y.; Bewley, M.C.; Pegg, A.E. Aminopropyltransferases: Function, structure and genetics. J. Biochem., 2006, 139(1), 1-9.
[] [PMID: 16428313]
Haider, N.; Eschbach, M.L. Dias, Sde.S.; Gilberger, T.W.; Walter, R.D.; Lüersen, K. The spermidine synthase of the malaria parasite Plasmodium falciparum: molecular and biochemical characterisation of the polyamine synthesis enzyme. Mol. Biochem. Parasitol., 2005, 142(2), 224-236.
[] [PMID: 15913804]
Dufe, V.T.; Qiu, W.; Müller, I.B.; Hui, R.; Walter, R.D.; Al-Karadaghi, S. Crystal structure of Plasmodium falciparum spermidine synthase in complex with the substrate decarboxylated S-adenosylmethionine and the potent inhibitors 4MCHA and AdoDATO. J. Mol. Biol., 2007, 373(1), 167-177.
[] [PMID: 17822713]
Joet, T.; Eckstein-Ludwig, U.; Morin, C.; Krishna, S. Validation of the hexose transporter of Plasmodium falciparum as a novel drug target. Proc. Natl. Acad. Sci. USA, 2003, 100(13), 7476-7479.
[] [PMID: 12792024]
Brady, R.L.; Cameron, A. Structure-based approaches to the development of novel anti-malarials. Curr. Drug Targets, 2004, 5(2), 137-149.
[] [PMID: 15011947]
Wunderlich, J.; Rohrbach, P.; Dalton, J.P. The malaria digestive vacuole. Front. Biosci. (Schol. Ed.), 2012, 4, 1424-1448.
[PMID: 22652884]
Sardarian, A.; Douglas, K.T.; Read, M.; Sims, P.F.G.; Hyde, J.E.; Chitnumsub, P.; Sirawaraporn, R.; Sirawaraporn, W. Pyrimethamine analogs as strong inhibitors of double and quadruple mutants of dihydrofolate reductase in human malaria parasites. Org. Biomol. Chem., 2003, 1, 960-964.
[] [PMID: 12929634]
Nzila, T. The past, present and future of antifolates in the treatment of Plasmodium falciparum infection. J. Antimicrob. Chemother., 2006, 57, 1043-1054.
Rieckmann, K.H.; Brewer, G.J.; Powell, R.D. Effects of diaphenylsulphone (dapsone) against Plasmodium vivax of South West Pacific origin. Trans. R. Soc. Trop. Med. Hyg., 1968, 62(5), 649-653.
[] [PMID: 4387731]
Yeo, A.E.; Rieckmann, K.H. The activity of PS-15 in combination with sulfamethoxazole. Trop. Med. Parasitol., 1994, 45(2), 136-137.
[PMID: 7939165]
Naik, P.K.; Srivastava, M.; Bajaj, P.; Jain, S.; Dubey, A.; Ranjan, P.; Kumar, R.; Singh, H. The binding modes and binding affinities of artemisinin derivatives with Plasmodium falciparum Ca2+-ATPase (PfATP6). J. Mol. Model., 2011, 17(2), 333-357.
[] [PMID: 20461426]
Yuthavong, Y.; Yuvaniyama, J.; Chitnumsub, P.; Vanichtanankul, J.; Chusacultanachai, S.; Tarnchompoo, B.; Vilaivan, T.; Kamchonwongpaisan, S. Malarial (Plasmodium falciparum) dihydrofolate reductase-thymidylate synthase: Structural basis for antifolate resistance and development of effective inhibitors. Parasitology, 2005, 130(Pt 3), 249-259.
[] [PMID: 15796007]
Salmon, B.L.; Oksman, A.; Goldberg, D.E. Malaria parasite exit from the host erythrocyte: a two-step process requiring extraerythrocytic proteolysis. Proc. Natl. Acad. Sci. USA, 2001, 98(1), 271-276.
[] [PMID: 11114161]
Singh, A.; Rosenthal, P.J. Comparison of efficacies of cysteine protease inhibitors against five strains of Plasmodium falciparum. Antimicrob. Agents Chemother., 2001, 45, 949-951. [Title missing]
[] [PMID: 11181388]
Mbengue, A.; Bhattacharjee, S.; Pandharkar, T.; Liu, H.; Estiu, G.; Stahelin, R.V.; Rizk, S.S.; Njimoh, D.L.; Ryan, Y.; Chotivanich, K.; Nguon, C.; Ghorbal, M.; Lopez-Rubio, J.J.; Pfrender, M.; Emrich, S.; Mohandas, N.; Dondorp, A.M.; Wiest, O.; Haldar, K. A molecular mechanism of artemisinin resistance in Plasmodium falciparum malaria. Nature, 2015, 520(7549), 683-687.
[] [PMID: 25874676]
Tuteja, R. Helicases - feasible antimalarial drug target for Plasmodium falciparum. FEBS J., 2007, 274(18), 4699-4704.
[] [PMID: 17824956]
Ohkanda, J.; Knowles, D.B.; Blaskovich, M.A.; Sebti, S.M.; Hamilton, A.D. Inhibitors of protein farnesyltransferase as novel anticancer agents. Curr. Top. Med. Chem., 2002, 2(3), 303-323.
[] [PMID: 11944822]
Okhanda, J.; Lockman, J.W.; Yokoyama, K.; Gelb, M.H.; Croft, S.L.; Kendrick, H.; Harrell, M.I.; Feagin, J.E.; Blaskovich, M.A.; Sebti, S.M.; Hamilton, A.D. Peptidomimetic inhibitors of protein farnesyltransferase show potent antimalarial activity. Bioorg. Med. Chem. Lett., 2001, 11, 761-764. [Title missing]
[] [PMID: 11277514]
Mitsch, A.; Bohm, M.; Wißner, P.; Sattler, I.; Schlitzer, M. Non-Thiol farnesyltransferase inhibitors: utilization of an aryl binding site by 5-arylacryloylaminobenzophenones. Bioorg. Med. Chem., 2002, 10, 2657-2662.
[] [PMID: 12057654]
Haldar, K.; Hiller, N.L.; van Ooij, C.; Bhattacharjee, S. Plasmodium parasite proteins and the infected erythrocyte. Trends Parasitol., 2005, 21(9), 402-403.
[] [PMID: 16043411]
Mehlin, C. Structure-based drug discovery for Plasmodium falciparum. Comb. Chem. High Throughput Screen., 2005, 8(1), 5-14.
[] [PMID: 15720193]
Meng, X.Y.; Zhang, H.X.; Mezei, M.; Cui, M. Molecular docking: A powerful approach for structure-based drug discovery. Curr Comput Aided Drug Des., 2011, 7(2), 146-157.
[] [PMID: 21534921]
Ferreira, L.G.; Dos Santos, R.N.; Oliva, G.; Andricopulo, A.D. Molecular docking and structure-based drug design strategies. Molecules, 2015, 20(7), 13384-13421.
[] [PMID: 26205061]
Lionta, E.; Spyrou, G.; Vassilatis, D.K.; Cournia, Z. Structure-based virtual screening for drug discovery: principles, applications and recent advances. Curr. Top. Med. Chem., 2014, 14(16), 1923-1938.
[] [PMID: 25262799]

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Year: 2019
Published on: 18 July, 2019
Page: [861 - 873]
Pages: 13
DOI: 10.2174/1568026619666190603080000
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