Skip to content
2000
Volume 26, Issue 9
  • ISSN: 1389-4501
  • E-ISSN: 1873-5592

Abstract

Malaria control is severely hindered by a lack of effective treatment options and the rise of drug-resistant strains of the parasite. Despite the absence of a reliable vaccine, the therapeutic application of antimalarial drugs remains the primary strategy for controlling and preventing malaria. However, most existing antimalarial drugs target the blood stage of the parasite's lifecycle and may not effectively eliminate liver-stage parasites, limiting their efficacy in complete parasite clearance. The urgent need for novel antimalarial drugs with innovative mechanisms of action is critical to preventing a major public health crisis. Developing new antimalarial drugs involves both optimizing existing compounds and designing novel molecules that target unique biological pathways in . This review explores promising drug targets, including heme detoxification, food vacuole function, mitochondria, protein kinases, apicoplast pathways, nucleic acid biosynthesis, fatty acid metabolism, the electron transport chain (ETC), and P-Type ATPases. Lead candidates targeting these mechanisms are discussed, highlighting their potential as next-generation antimalarial agents. Additionally, we provide updates on clinically validated targets and the progress of antimalarial drug candidates in different stages of clinical development. Emerging therapeutic strategies focusing on malarial transporters, protein interaction networks, and substrate repertoires offer new avenues for drug discovery. A deeper understanding of these pathways can enhance drug efficacy, mitigate resistance, and support the development of long-lasting antimalarial therapies. This review aims to provide insights into the current landscape of antimalarial drug development and future directions for combating malaria.

Loading

Article metrics loading...

/content/journals/cdt/10.2174/0113894501380738250414111540
2025-04-18
2025-10-06
Loading full text...

Full text loading...

References

  1. YuS. WangJ. LuoX. Transmission-blocking strategies against malaria parasites during their mosquito stages.Front. Cell. Infect. Microbiol.20221282065010.3389/fcimb.2022.820650 35252033
    [Google Scholar]
  2. RougeronV. BoundengaL. ArnathauC. A population genetic perspective on the origin, spread and adaptation of the human malaria agents Plasmodium falciparum and Plasmodium vivax.FEMS Microbiol. Rev.202246110.1093/femsre/fuab047
    [Google Scholar]
  3. ShibeshiM.A. KifleZ.D. AtnafieS.A. Antimalarial drug resistance and novel targets for antimalarial drug discovery.Infect. Drug Resist.2020134047406010.2147/IDR.S279433 33204122
    [Google Scholar]
  4. KhanJ. KaushikM. SinghS. Molecular Mechanisms of action and resistance of antimalarial drugs. MandalS. PaulD. Bacterial adaptation to co-resistance.SingaporeSpringer201926729610.1007/978‑981‑13‑8503‑2_14
    [Google Scholar]
  5. De BellisE. DonnarummaD. ZarrellaA. Drug-drug interactions between HIV antivirals and concomitant drugs in HIV patients: What we know and what we need to know.Pharmaceutics20241713110.3390/pharmaceutics17010031 39861680
    [Google Scholar]
  6. AggarwalS. PengW.K. SrivastavaS. Multi-omics advancements towards Plasmodium vivax malaria diagnosis.Diagnostics20211112222210.3390/diagnostics11122222 34943459
    [Google Scholar]
  7. BourgardC. AlbrechtL. KayanoA.C.A.V. SunnerhagenP. CostaF.T.M. Plasmodium vivax biology: Insights provided by genomics, transcriptomics and proteomics.Front. Cell. Infect. Microbiol.201883410.3389/fcimb.2018.00034 29473024
    [Google Scholar]
  8. BeleteT.M. Recent progress in the development of new antimalarial drugs with novel targets.Drug Des. Devel. Ther.2020143875388910.2147/DDDT.S265602 33061294
    [Google Scholar]
  9. BasoreK. ChengY. KushwahaA.K. NguyenS.T. DesaiS.A. How do antimalarial drugs reach their intracellular targets?Front. Pharmacol.201569110.3389/fphar.2015.00091 25999857
    [Google Scholar]
  10. MeshnickS.R. Artemisinin antimalarials: Mechanisms of action and resistance.Méd. Trop.1998583Suppl.131710.1016/S0020‑7519(02)00194‑7 10212891
    [Google Scholar]
  11. RudrapalM. ChetiaD. Endoperoxide antimalarials: Development, structural diversity and pharmacodynamic aspects with reference to 1,2,4-trioxane-based structural scaffold.Drug Des. Devel. Ther.2016103575359010.2147/DDDT.S118116 27843298
    [Google Scholar]
  12. MenardD. DondorpA. Antimalarial drug resistance: A threat to malaria elimination.Cold Spring Harb. Perspect. Med.201777a02561910.1101/cshperspect.a025619 28289248
    [Google Scholar]
  13. BairdJ.K. Chloroquine resistance in Plasmodium vivax.Antimicrob. Agents Chemother.200448114075408310.1128/AAC.48.11.4075‑4083.2004 15504824
    [Google Scholar]
  14. WhiteN.J. Antimalarial drug resistance.J. Clin. Invest.200411381084109210.1172/JCI21682 15085184
    [Google Scholar]
  15. NzilaA. Antifolates: Pyrimethamine, Proguanil, Sulphadoxine and Dapsone.Treatment and Prevention of Malaria Milestones in Drug Therapy. StainsH. KrishnaS. BaselSpringer201111312510.1007/978‑3‑0346‑0480‑2_6
    [Google Scholar]
  16. BurchardG.D. WinklerE. Concurrent chloroquine and Fansidar resistance of Plasmodium falciparum: An imported case from Gabon.Trop. Geogr. Med.1988401686910.1186/1475‑2875‑9‑357 3289215
    [Google Scholar]
  17. SchlagenhaufP. AdamcovaM. RegepL. SchaererM.T. RheinH.G. The position of mefloquine as a 21st century malaria chemoprophylaxis.Malar. J.20109135710.1186/1475‑2875‑9‑357 21143906
    [Google Scholar]
  18. CisseB. CairnsM. FayeE. Randomized trial of piperaquine with sulfadoxine-pyrimethamine or dihydroartemisinin for malaria intermittent preventive treatment in children.PLoS One200949e716410.1371/journal.pone.0007164 19784374
    [Google Scholar]
  19. BoonyalaiN. VeselyB.A. ThamnurakC. Piperaquine resistant Cambodian Plasmodium falciparum clinical isolates: In vitro genotypic and phenotypic characterization.Malar. J.202019126910.1186/s12936‑020‑03339‑w 32711538
    [Google Scholar]
  20. EzzetF. van VugtM. NostenF. LooareesuwanS. WhiteN.J. Pharmacokinetics and pharmacodynamics of lumefantrine (benflumetol) in acute falciparum malaria.Antimicrob. Agents Chemother.200044369770410.1128/AAC.44.3.697‑704.2000 10681341
    [Google Scholar]
  21. OgutuB. YekaA. KusemererwaS. Ganaplacide (KAF156) plus lumefantrine solid dispersion formulation combination for uncomplicated Plasmodium falciparum malaria: An open-label, multicentre, parallel-group, randomised, controlled, phase 2 trial.Lancet Infect. Dis.20232391051106110.1016/S1473‑3099(23)00209‑8 37327809
    [Google Scholar]
  22. PryceJ. TaylorM. FoxT. HineP. Pyronaridine-artesunate for treating uncomplicated Plasmodium falciparum malaria.Cochrane Libr.202220226CD00640410.1002/14651858.CD006404.pub4 35726133
    [Google Scholar]
  23. PradinesB. Antimalarial drug resistance: Clinical perspectives.Antimicrobial Drug Resistance. MayersD. SobelJ. QuelletteeM. KayeK. MarchaimD. ChamSpringer20171245127510.1007/978‑3‑319‑47266‑9_27
    [Google Scholar]
  24. MamedeL. FallF. SchoumacherM. Recent metabolomic developments for antimalarial drug discovery.Parasitol. Res.2022121123351338010.1007/s00436‑022‑07673‑7 36194273
    [Google Scholar]
  25. ComerE. BeaudoinJ.A. KatoN. Diversity-oriented synthesis-facilitated medicinal chemistry: Toward the development of novel antimalarial agents.J. Med. Chem.201457208496850210.1021/jm500994n 25211597
    [Google Scholar]
  26. de VilliersK.A. EganT.J. Heme detoxification in the malaria parasite: A target for antimalarial drug development.Acc. Chem. Res.202154112649265910.1021/acs.accounts.1c00154 33982570
    [Google Scholar]
  27. WaniW.A. JameelE. BaigU. MumtazuddinS. HunL.T. Ferroquine and its derivatives: New generation of antimalarial agents.Eur. J. Med. Chem.201510153455110.1016/j.ejmech.2015.07.009 26188909
    [Google Scholar]
  28. GuptaM. KumarS. KumarR. Inhibition of heme detoxification pathway in malaria parasite by 3-hydroxy-11-keto-β-boswellic acid isolated from Boswellia serrata.Biomed. Pharmacother.202114411230210.1016/j.biopha.2021.112302 34678731
    [Google Scholar]
  29. MishraR. da Cunha XavierJ. KumarN. Exploring quinoline derivatives: Their antimalarial efficacy and structural features.Med. Chem.20252129612110.2174/0115734064318361240827072124 40007183
    [Google Scholar]
  30. ZhangV.M. ChavchichM. WatersN.C. Targeting protein kinases in the malaria parasite: Update of an antimalarial drug target.Curr. Top. Med. Chem.201212545647210.2174/156802612799362922 22242850
    [Google Scholar]
  31. ChapmanT.M. OsborneS.A. WallaceC. Optimization of an imidazopyridazine series of inhibitors of Plasmodium falciparum calcium-dependent protein kinase 1 (PfCDPK1).J. Med. Chem.20145783570358710.1021/jm500342d 24689770
    [Google Scholar]
  32. IrfanI. UddinA. JainR. Biological evaluation of novel side chain containing CQTrICh-analogs as antimalarials and their development as PfCDPK1 kinase inhibitors.Heliyon2024103e2507710.1016/j.heliyon.2024.e25077 38327451
    [Google Scholar]
  33. OjoK.K. EastmanR.T. VidadalaR. A specific inhibitor of PfCDPK4 blocks malaria transmission: Chemical-genetic validation.J. Infect. Dis.2014209227528410.1093/infdis/jit522 24123773
    [Google Scholar]
  34. ArendseL.B. WyllieS. ChibaleK. GilbertI.H. Plasmodium kinases as potential drug targets for malaria: Challenges and opportunities.ACS Infect. Dis.20217351853410.1021/acsinfecdis.0c00724 33590753
    [Google Scholar]
  35. MinnowY.V. SchrammV.L. Purine and pyrimidine pathways as antimalarial targets.In: Malaria - Recent Advances and New Perspectives. IntechOpen202210646810.5772/intechopen.106468
    [Google Scholar]
  36. EnninfulK.S. KwofieS.K. Tetteh-TsifoanyaM. Targeting the Plasmodium falciparum’s Thymidylate Monophosphate Kinase for the Identification of novel antimalarial natural compounds.Front. Cell. Infect. Microbiol.20221286852910.3389/fcimb.2022.868529 35694550
    [Google Scholar]
  37. GalalK.A. TruongA. KwarcinskiF. Identification of novel 2,4,5-trisubstituted pyrimidines as potent dual inhibitors of Plasmodial Pf GSK3/Pf PK6 with activity against blood stage parasites in vitro.J. Med. Chem.20226519131721319710.1021/acs.jmedchem.2c00996 36166733
    [Google Scholar]
  38. GoodmanC.D. McFaddenG.I. Targeting apicoplasts in malaria parasites.Expert Opin. Ther. Targets201317216717710.1517/14728222.2013.739158 23231425
    [Google Scholar]
  39. SadhukhanG.C. MukherjeeA. Antimalarial drug design by targeting apicoplasts: New perspectives.J. Pharmacopuncture201619171510.3831/KPI.2016.19.001 27280044
    [Google Scholar]
  40. MuhseenZ.T. HameedA.R. Al-BhadlyO. AhmadS. LiG. Natural products for treatment of Plasmodium falciparum malaria: An integrated computational approach.Comput. Biol. Med.202113410441510.1016/j.compbiomed.2021.104415 33910128
    [Google Scholar]
  41. BioscaA. RamírezM. Gomez-GomezA. Characterization of domiphen bromide as a new fast-acting antiplasmodial agent inhibiting the apicoplastidic methyl erythritol phosphate pathway.Pharmaceutics2022147132010.3390/pharmaceutics14071320 35890216
    [Google Scholar]
  42. GhavamiM. MerinoE.F. YaoZ.K. Biological studies and target engagement of the 2- C -Methyl- d -Erythritol 4-Phosphate Cytidylyltransferase (IspD)-targeting antimalarial Agent (1 R, 3 S)- MMV008138 and analogs.ACS Infect. Dis.20184454955910.1021/acsinfecdis.7b00159 29072835
    [Google Scholar]
  43. GisselbergJ.E. HerreraZ. OrchardL.M. LlinásM. YehE. Specific inhibition of the bifunctional farnesyl/geranylgeranyl diphosphate synthase in malaria parasites via a new small-molecule binding site.Cell Chem. Biol.2018252185193.e510.1016/j.chembiol.2017.11.010 29276048
    [Google Scholar]
  44. ChahineZ. AbelS. HollinT. A potent kalihinol analogue disrupts apicoplast function and vesicular trafficking in P. falciparum Malaria.bioRxiv3804534110.1101/2023.11.21.568162
    [Google Scholar]
  45. MarshallV.M. CoppelR.L. Characterisation of the gene encoding adenylosuccinate lyase of Plasmodium falciparum1Note: Nucleotide sequence data reported in this paper available in the GenBank™ data base under the accession number U84403.1.Mol. Biochem. Parasitol.1997881-223724110.1016/S0166‑6851(97)00054‑6 9274883
    [Google Scholar]
  46. BhatJ.Y. ShastriB.G. BalaramH. Kinetic and biochemical characterization of Plasmodium falciparum GMP synthetase.Biochem. J.2008409126327310.1042/BJ20070996 17868038
    [Google Scholar]
  47. MadridD.C. TingL.M. WallerK.L. SchrammV.L. KimK. Plasmodium falciparum purine nucleoside phosphorylase is critical for viability of malaria parasites.J. Biol. Chem.200828351358993590710.1074/jbc.M807218200 18957439
    [Google Scholar]
  48. MinnowY.V.T. HarijanR.K. SchrammV.L. A resistant mutant of Plasmodium falciparum purine nucleoside phosphorylase uses wild-type neighbors to maintain parasite survival.J. Biol. Chem.202129610034210.1016/j.jbc.2021.100342 33524395
    [Google Scholar]
  49. Hortua TrianaM.A. Cajiao HerreraD. ZimmermannB.H. FoxB.A. BzikD.J. Pyrimidine pathway-dependent and-independent functions of the Toxoplasma gondii mitochondrial dihydroorotate dehydrogenase.Infect. Immun.201684102974298110.1128/IAI.00187‑16 27481247
    [Google Scholar]
  50. BlascoB. LeroyD. FidockD.A. Antimalarial drug resistance: Linking Plasmodium falciparum parasite biology to the clinic.Nat. Med.201723891792810.1038/nm.4381 28777791
    [Google Scholar]
  51. KumarS. BhardwajT.R. PrasadD.N. SinghR.K. Drug targets for resistant malaria: Historic to future perspectives.Biomed. Pharmacother.201810482710.1016/j.biopha.2018.05.009 29758416
    [Google Scholar]
  52. IwaloyeO. ElekofehintiO. OlawaleF. Plasmodium falciparum dihydroorotate dehydrogenase, fragment-based drug design, 2D-QSAR, DFT calculation, lead optimization, induced fit docking.Preprints2021202112029610.20944/preprints202112.0296.v1
    [Google Scholar]
  53. ChughlayM.F. El GaaloulM. DoniniC. Chemoprotective antimalarial activity of P218 against Plasmodium falciparum: A randomized, placebo-controlled volunteer infection study.Am. J. Trop. Med. Hyg.202110441348135810.4269/ajtmh.20‑1165 33556040
    [Google Scholar]
  54. TäubelJ. LorchU. FerberG. Concentration-QT modelling of the novel DHFR inhibitor P218 in healthy male volunteers.Br. J. Clin. Pharmacol.202288112813710.1111/bcp.14933 34075612
    [Google Scholar]
  55. LaMonteG.M. RocamoraF. MarapanaD.S. Pan-active imidazolopiperazine antimalarials target the Plasmodium falciparum intracellular secretory pathway.Nat. Commun.2020111178010.1038/s41467‑020‑15440‑4 32286267
    [Google Scholar]
  56. YipsirimeteeA. ChiewpooP. TripuraR. Assessment in vitro of the antimalarial and transmission-blocking activities of Cipargamin and Ganaplacide in Artemisinin-resistant Plasmodium falciparum.Antimicrob. Agents Chemother.2022663e01481e2110.1128/aac.01481‑21 34978886
    [Google Scholar]
  57. SilvaM. CalçadaC. OsórioN. The Plasmodium falciparum protein PfMRP1 functions as an influx ABC transporter.Preprints202210.21203/rs.3.rs‑1210682/v1
    [Google Scholar]
  58. AnhC.X. ChavchichM. BirrellG.W. Pharmacokinetics and ex vivo antimalarial activity of artesunate-amodiaquine plus methylene blue in healthy volunteers.Antimicrob. Agents Chemother.2020643e01441e1910.1128/AAC.01441‑19 31907186
    [Google Scholar]
  59. van SchalkwykD.A. RiscoeM.K. PouS. Novel endochin-like quinolones exhibit potent in vitro activity against Plasmodium knowlesi but do not synergize with Proguanil.Antimicrob. Agents Chemother.2020645e02549e1910.1128/AAC.02549‑19 32094134
    [Google Scholar]
  60. RoquesM. BindschedlerA. BeyelerR. HeusslerV.T. Same, same but different: Exploring Plasmodium cell division during liver stage development.PLoS Pathog.2023193e101121010.1371/journal.ppat.1011210 36996035
    [Google Scholar]
  61. NofianiR. PhilmusB. NinditaY. MahmudT. 3-Ketoacyl-ACP synthase (KAS) III homologues and their roles in natural product biosynthesis.MedChemComm20191091517153010.1039/C9MD00162J 31673313
    [Google Scholar]
  62. TibonN.S. NgC.H. CheongS.L. Current progress in antimalarial pharmacotherapy and multi-target drug discovery.Eur. J. Med. Chem.202018811198310.1016/j.ejmech.2019.111983 31911292
    [Google Scholar]
  63. KuoM.R. MorbidoniH.R. AllandD. Targeting tuberculosis and malaria through inhibition of Enoyl reductase: Compound activity and structural data.J. Biol. Chem.200327823208512085910.1074/jbc.M211968200 12606558
    [Google Scholar]
  64. SharmaS.K. KapoorM. RamyaT.N.C. Identification, characterization, and inhibition of Plasmodium falciparum β-hydroxyacyl-acyl carrier protein dehydratase (FabZ).J. Biol. Chem.200327846456614567110.1074/jbc.M304283200 12930838
    [Google Scholar]
  65. PainterH.J. MorriseyJ.M. VaidyaA.B. Mitochondrial electron transport inhibition and viability of intraerythrocytic Plasmodium falciparum.Antimicrob. Agents Chemother.201054125281528710.1128/AAC.00937‑10 20855748
    [Google Scholar]
  66. NixonG.L. PidathalaC. ShoneA.E. Targeting the mitochondrial electron transport chain of Plasmodium falciparum: New strategies towards the development of improved antimalarials for the elimination era.Future Med. Chem.20135131573159110.4155/fmc.13.121 24024949
    [Google Scholar]
  67. LunevS BatistaFA BoschSS 201610.5772/65659
  68. NugrahaA.B. TuvshintulgaB. GuswantoA. Screening the medicines for malaria venture pathogen box against piroplasm parasites.Int. J. Parasitol. Drugs Drug Resist.201910849010.1016/j.ijpddr.2019.06.004 31254719
    [Google Scholar]
  69. DuffyS. SykesM.L. JonesA.J. Screening the medicines for malaria venture pathogen box across multiple pathogens reclassifies starting points for open-source drug discovery.Antimicrob. Agents Chemother.2017619e00379e1710.1128/AAC.00379‑17 28674055
    [Google Scholar]
  70. WalunjS.B. DiasM.M. KaurC. High-throughput screening to identify inhibitors of Plasmodium falciparum importin α.Cells2022117120110.3390/cells11071201 35406765
    [Google Scholar]
  71. EversF. Cabrera-OreficeA. ElurbeD.M. Composition and stage dynamics of mitochondrial complexes in Plasmodium falciparum.Nat. Commun.2021121382010.1038/s41467‑021‑23919‑x 34155201
    [Google Scholar]
  72. GoodmanC.D. BuchananH.D. McFaddenG.I. Is the mitochondrion a good malaria drug target?Trends Parasitol.201733318519310.1016/j.pt.2016.10.002 27789127
    [Google Scholar]
  73. BuchananH.D. GoodmanC.D. McFaddenG.I. Roles of the apicoplast across the life cycles of rodent and human malaria parasites.J. Eukaryot. Microbiol.2022696e1294710.1111/jeu.12947 36070203
    [Google Scholar]
  74. MaL. FeiH. Antimalarial drug artesunate is effective against chemoresistant anaplastic thyroid carcinoma via targeting mitochondrial metabolism.J. Bioenerg. Biomembr.202052212313010.1007/s10863‑020‑09824‑w 32036542
    [Google Scholar]
  75. PhillipsM.A. RathodP.K. Plasmodium dihydroorotate dehydrogenase: A promising target for novel anti-malarial chemotherapy.Infect. Disord. Drug Targets201010322623910.2174/187152610791163336 20334617
    [Google Scholar]
  76. WernerC. StubbsM.T. Krauth-SiegelR.L. KlebeG. The crystal structure of Plasmodium falciparum glutamate dehydrogenase, a putative target for novel antimalarial drugs.J. Mol. Biol.2005349359760710.1016/j.jmb.2005.03.077 15878595
    [Google Scholar]
  77. BiaginiG.A. FisherN. ShoneA.E. Generation of quinolone antimalarials targeting the Plasmodium falciparum mitochondrial respiratory chain for the treatment and prophylaxis of malaria.Proc. Natl. Acad. Sci. USA2012109218298830310.1073/pnas.1205651109 22566611
    [Google Scholar]
  78. YangY. YuY. LiX. Target elucidation by cocrystal structures of NADH-ubiquinone oxidoreductase of Plasmodium falciparum (Pf NDH2) with small molecule to eliminate drug-resistant malaria.J. Med. Chem.20176051994200510.1021/acs.jmedchem.6b01733 28195463
    [Google Scholar]
  79. EsserL. ZhouF. ZeherA. Structure of complex III with bound antimalarial agent CK-2-68 provides insights into selective inhibition of Plasmodium cytochrome bc1 complexes.J. Biol. Chem.2023299710486010.1016/j.jbc.2023.104860 37236355
    [Google Scholar]
  80. PadmanabanG. NagarajV.A. RangarajanP.N. Drugs and drug targets against malaria.Curr. Sci.2007921115451555
    [Google Scholar]
  81. BirthD. KaoW.C. HunteC. Structural analysis of atovaquone-inhibited cytochrome bc1 complex reveals the molecular basis of antimalarial drug action.Nat. Commun.201451402910.1038/ncomms5029 24893593
    [Google Scholar]
  82. BascoL.K. RamiliarisoaO. Le BrasJ. In vitro activity of atovaquone against the African isolates and clones of Plasmodium falciparum.Am. J. Trop. Med. Hyg.199553438839110.4269/ajtmh.1995.53.388 7485692
    [Google Scholar]
  83. VerdaguerI.B. CrispimM. ZafraC.A. Exploring ubiquinone biosynthesis inhibition as a strategy for improving atovaquone efficacy in malaria.Antimicrob. Agents Chemother.2021654e01516e0152010.1128/AAC.01516‑20 33495230
    [Google Scholar]
  84. BuenoJ.M. HerrerosE. Angulo-BarturenI. Exploration of 4(1H)-pyridones as a novel family of potent antimalarial inhibitors of the plasmodial cytochrome bc1.Future Med. Chem.20124182311232310.4155/fmc.12.177 23234553
    [Google Scholar]
  85. CapperM.J. O’NeillP.M. FisherN. Antimalarial 4(1H)-pyridones bind to the Q i site of cytochrome bc1.Proc. Natl. Acad. Sci. USA2015112375576010.1073/pnas.1416611112 25564664
    [Google Scholar]
  86. SchlitzerM. Antimalarial drugs - What is in use and what is in the pipeline.Arch. Pharm.2008341314916310.1002/ardp.200700184 18297679
    [Google Scholar]
  87. KühlbrandtW. Biology, structure and mechanism of P-type ATPases.Nat. Rev. Mol. Cell Biol.20045428229510.1038/nrm1354 15071553
    [Google Scholar]
  88. ApellH.J. How do P-Type ATPases transport ions?Bioelectrochemistry2004631-214915610.1016/j.bioelechem.2003.09.021 15110265
    [Google Scholar]
  89. SpillmanN.J. AllenR.J.W. McNamaraC.W. Na(+) regulation in the malaria parasite Plasmodium falciparum involves the cation ATPase PfATP4 and is a target of the spiroindolone antimalarials.Cell Host Microbe201313222723710.1016/j.chom.2012.12.006 23414762
    [Google Scholar]
  90. BouwmanS.A.M. Zoleko-ManegoR. RennerK.C. SchmittE.K. Mombo-NgomaG. GrobuschM.P. The early preclinical and clinical development of cipargamin (KAE609), a novel antimalarial compound.Travel Med. Infect. Dis.20203610176510.1016/j.tmaid.2020.101765 32561392
    [Google Scholar]
  91. HameedP.S. SolapureS. PatilV. Triaminopyrimidine is a fast-killing and long-acting antimalarial clinical candidate.Nat. Commun.201561671510.1038/ncomms7715 25823686
    [Google Scholar]
  92. BarberB.E. FernandezM. PatelH.B. Safety, pharmacokinetics, and antimalarial activity of the novel triaminopyrimidine ZY-19489: A first-in-human, randomised, placebo-controlled, double-blind, single ascending dose study, pilot food-effect study, and volunteer infection study.Lancet Infect. Dis.202222687989010.1016/S1473‑3099(21)00679‑4 35247321
    [Google Scholar]
  93. GaurA.H. McCarthyJ.S. PanettaJ.C. Safety, tolerability, pharmacokinetics, and antimalarial efficacy of a novel Plasmodium falciparum ATP4 inhibitor SJ733: A first-in-human and induced blood-stage malaria phase 1a/b trial.Lancet Infect. Dis.202020896497510.1016/S1473‑3099(19)30611‑5 32275867
    [Google Scholar]
  94. GaurA.H. PanettaJ.C. SmithA.M. Combining SJ733, an oral ATP4 inhibitor of Plasmodium falciparum, with the pharmacokinetic enhancer cobicistat: An innovative approach in antimalarial drug development.EBioMedicine20228010406510.1016/j.ebiom.2022.104065 35598441
    [Google Scholar]
  95. WhiteN.J. PukrittayakameeS. PhyoA.P. Spiroindolone KAE609 for falciparum and vivax malaria.N. Engl. J. Med.2014371540341010.1056/NEJMoa1315860 25075833
    [Google Scholar]
  96. AsihP.B.S. SiregarJ.E. DewayantiF.K. Treatment with specific and pan-plasma membrane calcium ATPase (PMCA) inhibitors reduces malaria parasite growth in vitro and in vivo.Malar. J.202221120610.1186/s12936‑022‑04228‑0 35768835
    [Google Scholar]
  97. de Lera RuizM. FavuzzaP. GuoZ. The invention of WM382, a highly potent PMIX/X dual inhibitor toward the treatment of malaria.ACS Med. Chem. Lett.202213111745175410.1021/acsmedchemlett.2c00355 36385924
    [Google Scholar]
  98. HodderA.N. ChristensenJ. ScallyS. Basis for drug selectivity of plasmepsin IX and X inhibition in Plasmodium falciparum and vivax.Structure2022307947961.e610.1016/j.str.2022.03.018 35460613
    [Google Scholar]
  99. FavuzzaP. de Lera RuizM. ThompsonJ.K. Dual plasmepsin-targeting antimalarial agents disrupt multiple stages of the malaria parasite life cycle.Cell Host Microbe2020274642658.e1210.1016/j.chom.2020.02.005 32109369
    [Google Scholar]
  100. KumiR.O. AgoniC. IbrahimM.A.A. SolimanM.E.S. Dual enzymatic inhibitory mechanism of WM382 on plasmepsin IX and X: Atomistic perspectives from dynamic analysis.Inform. Med. Unlocked20222910087410.1016/j.imu.2022.100874
    [Google Scholar]
  101. Le BihanA. de KanterR. Angulo-BarturenI. Characterization of novel antimalarial compound ACT-451840: Preclinical assessment of activity and dose-efficacy modeling.PLoS Med.20161310e100213810.1371/journal.pmed.1002138 27701420
    [Google Scholar]
  102. RottmannM. JonatB. GumppC. Preclinical antimalarial combination study of M5717, a Plasmodium falciparum elongation factor 2 inhibitor, and pyronaridine, a hemozoin formation inhibitor.Antimicrob. Agents Chemother.2020644e02181e1910.1128/AAC.02181‑19 32041711
    [Google Scholar]
  103. MurithiJ.M. PascalC. BathJ. The antimalarial MMV688533 provides potential for single-dose cures with a high barrier to Plasmodium falciparum parasite resistance.Sci. Transl. Med.202113603eabg601310.1126/scitranslmed.abg6013 34290058
    [Google Scholar]
  104. Abd-RahmanA.N. ZaloumisS. McCarthyJ.S. SimpsonJ.A. CommonsR.J. Scoping review of antimalarial drug candidates in phase I and II drug development.Antimicrob. Agents Chemother.2022662e01659e2110.1128/aac.01659‑21 34843390
    [Google Scholar]
  105. BalevicS.J. RajaS.M. RandellR. Adverse reactions in a phase 1 trial of the anti-malarial DM1157: An example of pharmacokinetic modeling and simulation guiding clinical trial decisions.Infect. Dis. Ther.202211284185210.1007/s40121‑022‑00605‑z 35184256
    [Google Scholar]
  106. TaftB.R. YokokawaF. KirraneT. Discovery and preclinical pharmacology of INE963, a potent and fast-acting blood-stage antimalarial with a high barrier to resistance and potential for single-dose cures in uncomplicated malaria.J. Med. Chem.20226553798381310.1021/acs.jmedchem.1c01995 35229610
    [Google Scholar]
  107. OsoroC.B. OchodoE. KwambaiT.K. Policy uptake and implementation of the RTS,S/AS01 malaria vaccine in sub-Saharan African countries: Status 2 years following the WHO recommendation.BMJ Glob. Health202494e01471910.1136/bmjgh‑2023‑014719 38688566
    [Google Scholar]
  108. MugishaE.K. Advances and challenges for the malaria vaccine: A review.IDOSR J Biochem Biotechnol Allied Fields202493252910.59298/IDOSR/JBBAF/24/93.2529000
    [Google Scholar]
  109. ChutiyamiM BelloUM SalihuD Global malaria vaccine research and community perception in Africa: A systematic review.Eur J Public Health202434ckae144.1080 (Suppl. 3)10.1093/eurpub/ckae144.1080
    [Google Scholar]
  110. LehaneA.M. KirkK. Efflux of a range of antimalarial drugs and ‘chloroquine resistance reversers’ from the digestive vacuole in malaria parasites with mutant PfCRT.Mol. Microbiol.20107741039105110.1111/j.1365‑2958.2010.07272.x20598081
    [Google Scholar]
/content/journals/cdt/10.2174/0113894501380738250414111540
Loading
/content/journals/cdt/10.2174/0113894501380738250414111540
Loading

Data & Media loading...

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error
Please enter a valid_number test