Chemistry:Lumefantrine

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Lumefantrine (or benflumetol) is an antimalarial drug. It is only used in combination with artemether. This combination is frequently the first-line medication for Plasmodium falciparum malaria.[1] Lumefantrine has a much longer half-life compared to artemether (3-6 days vs. 2 hours[2]), and is therefore thought to clear any residual parasites that remain after combination treatment.[3]

Mechanism of action

The exact mechanism by which lumefantrine acts on erythrocytic stages of Plasmodium falciparum is unknown. However, it was shown to exert its action through possible two mechanisms:[3][2][4]

  • inhibiting β-hematin formation by creating complexes with hemin
  • inhibiting nucleic acid and protein synthesis

Moreover, it was shown to interact with human sodium/potassium ATPase subunit α1.[4]

Metabolism

Lumefantrine is metabolised in the liver by cytochrome P450 3A4 isoenzyme (CYP3A4) and 2D6 (CYP2D6), yielding desbutyl-lumefantrine as a major metabolite.[5][2]

Adverse effects

Lumefantrine, as used in combination with artemether, was shown to induce the following side effects:

People taking efavirenz as a part of HIV therapy should be wary of potential deviations during treatment, due to a decrease of AUC of this antiretroviral.[6][7]

History

Lumefantrine, along with pyronaridine and naphthoquine, were synthesized during the Chinese Project 523 antimalaria drug research effort initiated in 1967; these compounds are all used in combination antimalaria therapies.[8][9][10]

Research

Lumefantrine is being investigated as a part of a regimen with ganaplacide for the treatment of Plasmodium falciparum malaria.[11]

O-choline

Along with O-choline (octadecyl 2-(trimethylammonio)ethyl phosphate), lumefantrine inhibits in vivo growth of Theileria equi and Babesia caballi, due to inhibition of membrane phospholipid synthesis, hemoglobin digestion and targeting lactate metabolism.[12] Additionally, it can inhibit Babesia gibsoni growth in vitro (synergistically with artemisinin derivatives).[13]

It may exert negative effects on aquatic ecosystems by adversely acting on Chlorella vulgaris, Raphidocelis subcapitata, Lemna minor and Microcystis aeruginosa.[14][15] Moreover, it is classified as a potential endocrine disrupting compound by decreasing FSHB and increasing prolactin secretion.[16][17]

Lumefantrine and calcium phosphate-loaded lipid nanoparticles or cubosomes were investigated as a potential treatment of lung cancer due to probable antiangiogenic and anti-inflammatory properties of this combination.[18][19]

General structure of selene-containing lumefantrine derivatives[20]

Selenium-containing lumefantrine derivatives synthesised through Knoevenagel condensation (which itself is used to synthesise lumefantrine) exhibit potential antibacterial and antifungal activity. Compared with ciprofloxacin, they were shown to more potently bind to E. coli MurB enzyme – an enzyme participating in cell cycle and cell wall synthesis.[20]

See also

References

  1. ↑ CDC (2025-06-24). "Treatment of Uncomplicated Malaria" (in en-us). https://www.cdc.gov/malaria/hcp/clinical-guidance/treatment-uncomplicated.html. 
  2. ↑ 2.0 2.1 2.2 "Coartem - Highlights of prescribing information". August 2019. https://www.novartis.com/us-en/sites/novartis_us/files/coartem.pdf. 
  3. ↑ 3.0 3.1 "Clinical pharmacokinetics and pharmacodynamics and pharmacodynamics of artemether-lumefantrine". Clinical Pharmacokinetics 37 (2): 105–125. August 1999. doi:10.2165/00003088-199937020-00002. PMID 10496300. 
  4. ↑ 4.0 4.1 "Lumefantrine" (in en). https://go.drugbank.com/drugs/DB06708. 
  5. ↑ "Lumefantrine" (in en). https://go.drugbank.com/drugs/DB06708. 
  6. ↑ "Effect of nevirapine, efavirenz and lopinavir/ritonavir on the therapeutic concentration and toxicity of lumefantrine in people living with HIV at Lagos University Teaching Hospital, Nigeria". Journal of Pharmacological Sciences 144 (3): 95–101. November 2020. doi:10.1016/j.jphs.2020.07.013. PMID 32921396. 
  7. ↑ "The impact of CYP2B6 polymorphisms on the interactions of efavirenz with lumefantrine: Implications for paediatric antimalarial therapy". European Journal of Pharmaceutical Sciences 119: 90–101. July 2018. doi:10.1016/j.ejps.2018.04.012. PMID 29635009. https://publications.aston.ac.uk/id/eprint/33195/1/1_s2.0_S0928098718301696_main.pdf. 
  8. ↑ "Discovery, mechanisms of action and combination therapy of artemisinin". Expert Review of Anti-Infective Therapy 7 (8): 999–1013. October 2009. doi:10.1586/eri.09.68. PMID 19803708. 
  9. ↑ "Artemisinin-naphthoquine combination therapy for uncomplicated pediatric malaria: a tolerability, safety, and preliminary efficacy study". Antimicrobial Agents and Chemotherapy 56 (5): 2465–2471. May 2012. doi:10.1128/AAC.06248-11. PMID 22330921. 
  10. ↑ "Artemisinin-naphthoquine versus artemether-lumefantrine for uncomplicated malaria in Papua New Guinean children: an open-label randomized trial". PLOS Medicine 11 (12). December 2014. doi:10.1371/journal.pmed.1001773. PMID 25549086. 
  11. ↑ "Ganaplacide (KAF156) plus lumefantrine solid dispersion formulation combination for uncomplicated Plasmodium falciparum malaria: an open-label, multicentre, parallel-group, randomised, controlled, phase 2 trial" (in English). The Lancet. Infectious Diseases 23 (9): 1051–1061. September 2023. doi:10.1016/S1473-3099(23)00209-8. PMID 37327809. 
  12. ↑ "Lumefantrine and o-choline - Parasite metabolism specific drug molecules inhibited in vitro growth of Theileria equi and Babesia caballi in MASP culture system". Ticks and Tick-Borne Diseases 10 (3): 568–574. April 2019. doi:10.1016/j.ttbdis.2019.01.004. PMID 30733146. 
  13. ↑ "The efficacy of artemisinin, artemether, and lumefantrine against Babesia gibsoni in vitro". Parasitology International 64 (2): 190–193. April 2015. doi:10.1016/j.parint.2014.12.006. PMID 25523292. 
  14. ↑ "Effects of the antimalarial lumefantrine on Lemna minor, Raphidocelis subcapitata and Chlorella vulgaris". Environmental Toxicology and Pharmacology 85. July 2021. doi:10.1016/j.etap.2021.103635. PMID 33716093. Bibcode: 2021EnvTP..8503635C. 
  15. ↑ "Allelopathic interactions between Lemna minor and Microcystis aeruginosa are influenced by the antimalarial drug lumefantrine". Aquatic Botany 192. 2024-05-01. doi:10.1016/j.aquabot.2024.103759. ISSN 0304-3770. Bibcode: 2024AqBot.19203759D. https://linkinghub.elsevier.com/retrieve/pii/S0304377024000111. 
  16. ↑ (in en) S109 | PARCEDC | List of 7074 potential endocrine disrupting compounds (EDCs) by PARC T4.2, 2024-04-08, doi:10.5281/ZENODO.10944198, https://zenodo.org/records/10944199, retrieved 2025-02-26 
  17. ↑ "Endocrine disruption and oxidative stress implications of artemether-lumefantrine combination therapy in the ovary and uterus of rats". Human & Experimental Toxicology 35 (11): 1173–1182. November 2016. doi:10.1177/0960327115626580. PMID 26811345. Bibcode: 2016HETox..35.1173A. 
  18. ↑ "In vivo synergistic anti-tumor effect of lumefantrine combined with pH responsive behavior of nano calcium phosphate based lipid nanoparticles on lung cancer". European Journal of Pharmaceutical Sciences 158. March 2021. doi:10.1016/j.ejps.2020.105657. PMID 33271276. 
  19. ↑ "pH responsive delivery of lumefantrine with calcium phosphate nanoparticles loaded lipidic cubosomes for the site specific treatment of lung cancer". Chemistry and Physics of Lipids. Practical insights into drug delivery systems 224. November 2019. doi:10.1016/j.chemphyslip.2019.03.016. PMID 30951710. 
  20. ↑ 20.0 20.1 "Design, synthesis, molecular docking, and biological evaluation of novel selenium containing lumefantrine analogues" (in en). Journal of Heterocyclic Chemistry 57 (3): 1319–1329. 2020. doi:10.1002/jhet.3868. ISSN 1943-5193. https://onlinelibrary.wiley.com/doi/10.1002/jhet.3868. 



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