Skip to content
2000
Volume 32, Issue 37
  • ISSN: 0929-8673
  • E-ISSN: 1875-533X

Abstract

Introduction

Prevention of the formation of β-haematin is the target of several existing antimalarials drugs, most notably chloroquine. This target is therefore attractive for the development of new molecules with antimalarial potential.

Methods

In this study, we have used a combination of molecular dynamics and density functional tight-binding to examine the possible interaction mechanisms between five amodiaquine analogues and four conformations of haematin. Reactivity and stability of these complexes were investigated using bond length (Fe-N and Fe-O), energies (HOMO-LUMO) and molecular dynamics.

Results

Results revealed a good interaction between haem and the compounds, stable geometries of complexes.

Conclusion

The findings from this study are valuable because they can aid the design and understanding of new therapeutic molecules that could be used to treat drug-resistant malaria, a global threat of today.

© 2025 Bentham Science Publishers
Loading

Article metrics loading...

/content/journals/cmc/10.2174/0109298673346612250320080402
2025-04-15
2025-11-01

  • From This Site

    /content/journals/cmc/10.2174/0109298673346612250320080402
    dcterms_title,dcterms_subject,pub_keyword
    -contentType:Contributor -contentType:Concept -contentType:Institution
    10
    5
Loading full text...

Full text loading...

References

  1. FoleyM. TilleyL. Quinoline antimalarials: Mechanisms of action and resistance and prospects for new agents.Pharmacol. Ther.1998791558710.1016/S0163‑7258(98)00012‑6 9719345
     [Google Scholar]
  2. BosakA. OpsenicaD.M. ŠinkoG. ZlatarM. KovarikZ. Structural aspects of 4-aminoquinolines as reversible inhibitors of human acetylcholinesterase and butyrylcholinesterase.Chem. Biol. Interact.201930810110910.1016/j.cbi.2019.05.024 31100281
     [Google Scholar]
  3. Al-AhmaryK.M. AleneziM.S. HabeebM.M. Synthesis, spectroscopic and DFT theoretical studies on the hydrogen bonded charge transfer complex of 4-aminoquinoline with chloranilic acid.J. Mol. Liq.201622016618210.1016/j.molliq.2016.04.074
     [Google Scholar]
  4. O’NeillP.M. BartonV.E. WardS.A. ChadwickJ. 4-aminoquinolines: Chloroquine, Amodiaquine and next-generation analogues.Treatment and Prevention of Malaria: Antimalarial Drug Chemistry, Action and Use. StainesH.M. KrishnaS. BaselSpringer2012194410.1007/978‑3‑0346‑0480‑2_2
     [Google Scholar]
  5. ReddyP.L. KhanS.I. PonnanP. TripathiM. RawatD.S. Design, synthesis and evaluation of 4-aminoquinoline-purine hybrids as potential antiplasmodial agents.Eur. J. Med. Chem.201712667568610.1016/j.ejmech.2016.11.057 27936446
     [Google Scholar]
  6. OuabaneM. ZakiK. SekkateC. SbaiA. BouachrineM. LakhlifiT. In silico study of 4-aminoquinoline derivatives as antimalarial agents.RHAZES Green Appl Chem.20241924425810.48419/IMIST.PRSM/RHAZES‑V19.48522
     [Google Scholar]
  7. RajabalianS. ForoumadiA. ShafieeA. EmamiS. Functionalized N(2-oxyiminoethyl) piperazinyl quinolones as new cytotoxic agents.J. Pharm. Pharm. Sci.2007102153158 17706174
     [Google Scholar]
  8. SuaifanG.A.R.Y. MohammedA.A.M. AlkhawajaB.A. Fluoroquinolones biological activities against laboratory microbes and cancer cell lines.Molecules2022275165810.3390/molecules27051658 35268759
     [Google Scholar]
  9. ShindikarA.V. ViswanathanC.L. Novel fluoroquinolones: Design, synthesis, and in vivo activity in mice against Mycobacterium tuberculosis H37Rv.Bioorg. Med. Chem. Lett.20051571803180610.1016/j.bmcl.2005.02.037 15780610
     [Google Scholar]
  10. GuoR.H. ZhangQ. MaY.B. HuangX.Y. LuoJ. WangL.J. GengC.A. ZhangX.M. ZhouJ. JiangZ.Y. ChenJ.J. Synthesis and biological assay of 4-aryl-6-chloro-quinoline derivatives as novel non-nucleoside anti-HBV agents.Bioorg. Med. Chem.20111941400140810.1016/j.bmc.2011.01.006 21292495
     [Google Scholar]
  11. YousufM. MukherjeeD. PalA. DeyS. MandalS. PalC. AdhikariS. Synthesis and biological evaluation of ferrocenylquinoline as a potential antileishmanial agent.ChemMedChem201510354655410.1002/cmdc.201402537 25619822
     [Google Scholar]
  12. GuglielmoS. BertinariaM. RolandoB. CrosettiM. FrutteroR. YardleyV. CroftS.L. GascoA. A new series of amodiaquine analogues modified in the basic side chain with in vitro antileishmanial and antiplasmodial activity.Eur. J. Med. Chem.200944125071507910.1016/j.ejmech.2009.09.012 19811859
     [Google Scholar]
  13. ChenY.L. ZhaoY.L. LuC.M. TzengC.C. WangJ.P. Synthesis, cytotoxicity, and anti-inflammatory evaluation of 2-(furan-2-yl)-4-(phenoxy)quinoline derivatives. Part 4.Bioorg. Med. Chem.200614134373437810.1016/j.bmc.2006.02.039 16524734
     [Google Scholar]
  14. RavindarL. HasbullahS.A. RakeshK.P. HassanN.I. Recent developments in antimalarial activities of 4-aminoquinoline derivatives.Eur. J. Med. Chem.202325611545810.1016/j.ejmech.2023.115458 37163950
     [Google Scholar]
  15. ChenY.F. LawalB. HuangL.J. KuoS.C. SumitraM.R. MokgautsiN. LinH.Y. HuangH.S. In vitro and in silico biological studies of 4-phenyl-2-quinolone (4-PQ) derivatives as anticancer agents.Molecules202328255510.3390/molecules28020555 36677621
     [Google Scholar]
  16. MathadaB.S. The versatile quinoline and its derivatives as anti-cancer agents: An overview.Polycycl. Aromat. Compd.20234354333434510.1080/10406638.2022.2089177
     [Google Scholar]
  17. SaxenaA. MajeeS. RayD. SahaB. Inhibition of cancer cells by quinoline-based compounds: A review with mechanistic insights.Bioorg. Med. Chem.202410311768110.1016/j.bmc.2024.117681 38492541
     [Google Scholar]
  18. KrstulovićL. LeventićM. RastijaV. StarčevićK. JiroušM. JanićI. KarnašM. LasićK. BajićM. Glavaš-ObrovacL. Novel 7-chloro-4-aminoquinoline-benzimidazole hybrids as inhibitors of cancer cells growth: Synthesis, antiproliferative activity, in silico ADME predictions, and docking.Molecules202328254010.3390/molecules28020540 36677600
     [Google Scholar]
  19. Manwal A MekoungP. MalloumA. GovindarajanM. MballaR.N. PatouossaI. Abouem A ZintchemA. NanseuC.P.N. MbouombouoI.N. Spectroscopic properties (FT-IR, NMR and UV) and DFT studies of amodiaquine.Heliyon2023912e2218710.1016/j.heliyon.2023.e22187 38076079
     [Google Scholar]
  20. AguiarA.C.C. SantosR.M. FigueiredoF.J.B. CortopassiW.A. PimentelA.S. FrançaT.C.C. MeneghettiM.R. KrettliA.U. Antimalarial activity and mechanisms of action of two novel 4-aminoquinolines against chloroquine-resistant parasites.PLoS One201275e3725910.1371/journal.pone.0037259 22649514
     [Google Scholar]
  21. World malaria report 20232023Available from: https://reliefweb.int/report/world/world-malaria-report-2023-enarruzh
  22. GoldbergD.E. SlaterA.F. CeramiA. HendersonG.B. Hemoglobin degradation in the malaria parasite Plasmodium falciparum: An ordered process in a unique organelle.Proc. Natl. Acad. Sci. USA19908782931293510.1073/pnas.87.8.2931 2183218
     [Google Scholar]
  23. HempelmannE. Hemozoin Biocrystallization in Plasmodium falciparum and the antimalarial activity of crystallization inhibitors.Parasitol. Res.2007100467167610.1007/s00436‑006‑0313‑x 17111179
     [Google Scholar]
  24. AmodL. MohunlalR. TeixeiraN. EganT.J. WichtK.J. Identifying inhibitors of β-haematin formation with activity against chloroquine-resistant Plasmodium falciparum malaria parasites via virtual screening approaches.Sci. Rep.2023131264810.1038/s41598‑023‑29273‑w 36788274
     [Google Scholar]
  25. SigalaP.A. GoldbergD.E. The peculiarities and paradoxes of Plasmodium heme metabolism.Annu. Rev. Microbiol.201468125927810.1146/annurev‑micro‑091313‑103537 25002093
     [Google Scholar]
  26. KumarS. GuhaM. ChoubeyV. MaityP. BandyopadhyayU. Antimalarial drugs inhibiting hemozoin (β-hematin) formation: A mechanistic update.Life Sci.200780981382810.1016/j.lfs.2006.11.008 17157328
     [Google Scholar]
  27. WiserM.F. The digestive vacuole of the malaria parasite: A specialized Lysosome.Pathogens202413318210.3390/pathogens13030182 38535526
     [Google Scholar]
  28. SugishimaM. HagiwaraY. ZhangX. YoshidaT. MigitaC.T. FukuyamaK. Crystal structure of dimeric heme oxygenase-2 from Synechocystis sp. PCC 6803 in complex with heme.Biochemistry200544114257426610.1021/bi0480483 15766254
     [Google Scholar]
  29. PaoliM. LiddingtonR. TameJ. WilkinsonA. DodsonG. Crystal structure of T state haemoglobin with oxygen bound at all four haems.J. Mol. Biol.1996256477579210.1006/jmbi.1996.0124 8642597
     [Google Scholar]
  30. BannwarthC. EhlertS. GrimmeS. GFN2-xTB—An accurate and broadly parametrized self-consistent tight-binding quantum chemical method with multipole electrostatics and density-dependent dispersion contributions.J. Chem. Theory Comput.20191531652167110.1021/acs.jctc.8b01176 30741547
     [Google Scholar]
  31. GrimmeS. BannwarthC. ShushkovP. A robust and accurate tight-binding quantum chemical method for structures, vibrational frequencies, and noncovalent interactions of large molecular systems parametrized for all spd-block elements (Z = 1–86).J. Chem. Theory Comput.20171351989200910.1021/acs.jctc.7b00118 28418654
     [Google Scholar]
  32. R. Dennington, T.A. Keith, J.M. Millam, GaussView 6.0. 16, Semichem Inc.: Shawnee Mission, KS, USA(2016)
     [Google Scholar]
  33. Biovia Discovery Studio2023Available from: https://www.3ds.com/products/biovia/discovery-studio
  34. LuT. ChenF. Multiwfn: A multifunctional wavefunction analyzer.J. Comput. Chem.201233558059210.1002/jcc.22885 22162017
     [Google Scholar]
  35. HumphreyW. DalkeA. SchultenK. VMD: Visual molecular dynamics.J. Mol. Graph.199614133-38, 27-28.10.1016/0263‑7855(96)00018‑5 8744570
     [Google Scholar]
  36. MacettiG. LoconteL. RizzatoS. GattiC. Lo PrestiL. Intermolecular recognition of the antimalarial drug Chloroquine: A quantum theory of atoms in molecules–density functional theory investigation of the hydrated dihydrogen phosphate salt from the 103 K X-ray structure.Cryst. Growth Des.201616106043605410.1021/acs.cgd.6b01069
     [Google Scholar]
  37. TercelM. LeeH.H. MehtaS.Y. Youte TendoungJ.J. BaiS.Y. LiyanageH.D.S. PruijnF.B. Influence of a basic side chain on the properties of hypoxia-selective nitro analogues of the Duocarmycins: Demonstration of substantial anticancer activity in combination with irradiation or chemotherapy.J. Med. Chem.201760135834585610.1021/acs.jmedchem.7b00563 28644035
     [Google Scholar]
  38. NishiyamaT. HataeN. YoshimuraT. TakakiS. AbeT. IshikuraM. HibinoS. ChoshiT. Concise synthesis of carbazole-1,4-quinones and evaluation of their antiproliferative activity against HCT-116 and HL-60 cells.Eur. J. Med. Chem.201612156157710.1016/j.ejmech.2016.05.065 27318980
     [Google Scholar]
  39. BeckD.E. AbdelmalakM. LvW. ReddyP.V.N. TenderG.S. O’NeillE. AgamaK. MarchandC. PommierY. CushmanM. Discovery of potent indenoisoquinoline topoisomerase I poisons lacking the 3-nitro toxicophore.J. Med. Chem.20155893997401510.1021/acs.jmedchem.5b00303 25909279
     [Google Scholar]
  40. AbeT. TerasakiM. Synthesis of phaitanthrin E and tryptanthrin through amination/cyclization cascade.Helv. Chim. Acta20181012e170028410.1002/hlca.201700284
     [Google Scholar]
  41. Muthu RamalingamB. Dhatchana MoorthyN. ChowdhuryS.R. MageshwaranT. VellaichamyE. SahaS. GanesanK. RajeshB.N. IqbalS. MajumderH.K. GunasekaranK. SivaR. MohanakrishnanA.K. Synthesis and biological evaluation of calothrixins B and their deoxygenated analogues.J. Med. Chem.20186131285131510.1021/acs.jmedchem.7b01797 29313676
     [Google Scholar]
  42. Dhatchana MoorthyN. Muthu RamalingamB. IqbalS. MohanakrishnanA.K. GunasekaranK. VellaichamyE. Novel isothiacalothrixin B analogues exhibit cytotoxic activity on human colon cancer cells in vitro by inducing irreversible DNA damage.PLoS One2018139e020290310.1371/journal.pone.0202903 30188913
     [Google Scholar]
  43. ChoiS.J. LeeJ.E. JeongS.Y. Im, I.; Lee, S.D.; Lee, E.J.; Lee, S.K.; Kwon, S.M.; Ahn, S.G.; Yoon, J.H.; Han, S.Y.; Kim, J.I.; Kim, Y.C. 5,5′-substituted indirubin-3′-oxime derivatives as potent cyclin-dependent kinase inhibitors with anticancer activity.J. Med. Chem.20105393696370610.1021/jm100080z 20361800
     [Google Scholar]
  44. RakhaT.H. El-GammalO.A. MetwallyH.M. Abu El-ReashG.M. Synthesis, characterization, DFT and biological studies of (Z)-N′-(2-oxoindolin-3-ylidene)picolino- hydrazide and its Co(II), Ni(II) and Cu(II) complexes.J. Mol. Struct.201410629610910.1016/j.molstruc.2013.12.086
     [Google Scholar]
  45. Al-OmaryF.A.M. RajA. RajuK. PanickerC.Y. HaressN.G. El-EmamA.A. El-AshmawyM.B. Al-SaadiA.A. Van AlsenoyC. WarJ.A. Spectroscopic investigation (FT-IR, FT-Raman), HOMO–LUMO, NBO analysis and molecular docking study of 2-[(4-chlorobenzyl)sulfanyl]-4-(2-methylpropyl)-6-[3-trifluoromethyl)-anilino]pyrimidine-5-carbonitrile, a potential chemotherapeutic agent.Spectrochim. Acta A Mol. Biomol. Spectrosc.2015136Pt B52053310.1016/j.saa.2014.09.066 25448953
     [Google Scholar]
  46. ArasuN. AsirvathamP.S. PriyaM.K. RevathiB.K. Spectroscopic (FT-IR, Raman, 13C and 1H NMR) investigation, molecular orbital calculation and thermal properties of novel piperidine derivative compound by quantum chemical calculation.Mater. Today Proc.20198475610.1016/j.matpr.2019.02.079
     [Google Scholar]
  47. AlzomanN.Z. MaryY.S. PanickerC.Y. Al-SwaidanI.A. El-EmamA.A. Al-DeebO.A. Al-SaadiA.A. Van AlsenoyC. WarJ.A. Spectroscopic investigation (FT-IR and FT-Raman), vibrational assignments, HOMO–LUMO, NBO, MEP analysis and molecular docking study of 2-[(4-chlorobenzyl)sulfanyl]-4-(2-methylpropyl)-6-(phenylsulfanyl)-pyrimidine-5-carbonitrile, a potential chemotherapeutic agent.Spectrochim. Acta A Mol. Biomol. Spectrosc.201513941342410.1016/j.saa.2014.12.043 25576938
     [Google Scholar]
  48. Ríos-GutiérrezM. Saz SousaA. DomingoL.R. Electrophilicity and nucleophilicity scales at different DFT computational levels.J. Phys. Org. Chem.2023367e450310.1002/poc.4503
     [Google Scholar]
/content/journals/cmc/10.2174/0109298673346612250320080402
Loading
Ab-initio Molecular Dynamics and Density Functional Theory Study of Amodiaquine Analogues as Potential Inhibitors of β-haematin Crystallization
Curr. Med. Chem. 32, 8466 (2025); https://doi.org/10.2174/0109298673346612250320080402
/content/journals/cmc/10.2174/0109298673346612250320080402
/content/journals/cmc/10.2174/0109298673346612250320080402
Loading

Data & Media loading...

Supplements

Supplementary material is available on the publisher's website along with the published article.

file format download Download

  • Article Type:     Research Article
Keyword(s): Ab-initio; amodiaquine analogues; crystallization; density; molecular dynamics; β-haematin

Most Cited Most Cited RSS feed

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