Identification

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Name
Artesunate
Accession Number
DB09274
Type
Small Molecule
Groups
Approved, Investigational
Description

Artesunate is part of the artemisinin group of drugs that treat malaria. It is a semi-synthetic derivative of artemisinin that is water-soluble and may therefore be given by injection. It is on the World Health Organization's List of Essential Medicines. It has been made available in the US under the investigational new drug protocol 2. Artesunate is provided by the Centers for Disease Control and Prevention on an emergency basis.

Structure
Thumb
Synonyms
  • Artesunate
  • artesunato
  • artesunatum
  • artesunic acid
  • AS
  • butanedioic acid, 1-[(3R,5aS,6R,8aS,9R,10S,12R,12aR)-decahydro-3,6,9-trimethyl-3,12-epoxy-12H-pyrano[4,3-j]-1,2-benzodioxepin-10-yl] ester
  • dihydroqinghasu hemsuccinate
External IDs
182824-33-5 / NSC-712571
Product Ingredients
IngredientUNIICASInChI Key
Artesunate sodiumNot Available80155-81-3ZISJLHQNEVGTIU-AZISKZOLSA-M
Categories
UNII
60W3249T9M
CAS number
88495-63-0
Weight
Average: 384.425
Monoisotopic: 384.178417862
Chemical Formula
C19H28O8
InChI Key
FIHJKUPKCHIPAT-AHIGJZGOSA-N
InChI
InChI=1S/C19H28O8/c1-10-4-5-13-11(2)16(23-15(22)7-6-14(20)21)24-17-19(13)12(10)8-9-18(3,25-17)26-27-19/h10-13,16-17H,4-9H2,1-3H3,(H,20,21)/t10-,11-,12+,13+,16-,17-,18-,19-/m1/s1
IUPAC Name
4-oxo-4-{[(1R,4S,5R,8S,9R,10S,12R,13R)-1,5,9-trimethyl-11,14,15,16-tetraoxatetracyclo[10.3.1.0⁴,¹³.0⁸,¹³]hexadecan-10-yl]oxy}butanoic acid
SMILES
[H][C@@]12CC[C@@H](C)[C@]3([H])CC[C@@]4(C)OO[C@@]13[C@]([H])(O[C@@H](OC(=O)CCC(O)=O)[C@@H]2C)O4

Pharmacology

Indication

For the treatment of severe malaria caused by Plasmodium falciparum in adults and children 3

Pharmacodynamics

Artesunate is an artemisinin drug capable of killing all erythrocytic stages of the malaria parasite including the ring stage, late schizonts, and the gametocytes responsible for transmission of malaria 3. It also increases splenic clearance of infected erythrocytes by reducing cytoadherence. Artesunate and the artemisinins are the most rapid acting anti-malarial drugs. This class of drugs is ineffective against extra-erythrocytic forms, sporozoites, liver schizonts, and merozoites.

Mechanism of action

The mechanism of artesunate is thought to involve cleavage of the endoperoxide bond through reaction with haeme 3. This produces free radicals which alkylate parasitic proteins. It has been shown to inhibit an essential parasite calcium adenosine triphosphatase enzyme. Artesunate inhibits malaria proteins EXP1, a glutathione S-transferase, responsible for breaking down cytotoxic hematin 1. It is unknown to what extent this inhibition contributes to the action of artesunate.

TargetActionsOrganism
AMalaria protein EXP-1
inhibitor
Plasmodium falciparum
Absorption

After intravenous administration artesunate is rapidly metabolized to its active metabolite, dihydroartemisinin (DHA) 3. Tmax for DHA is 0.5-15 min. After intramuscular administration Tmax is 8-12 min. Cmax was observed to be 45-fold and 20-fold lower in children and adults respectively with intramuscular versus intravenous administration. Elimination was observed to be 32-fold and 13-fold slower in children and adults respectively with intramuscular versus intravenous administration.

Volume of distribution
Not Available
Protein binding

DHA accumulates significantly in parasite infected erythrocytes producing 93% plasma protein binding in malaria patients and 88% in healthy subjects 3.

Metabolism

Artesunate is rapidly metabolized to DHA by plasma esterases 3. A small amount may undergo metabolism by CYP2A6. DHA is further metabolized by glucuronidation in the liver. α-dihydroartemisinin-β-glucuronide has been identified as a mjor metabolite in the urine.

Route of elimination
Not Available
Half life

Half life of elimination after intravenous bolus was observed to be less than 5 min for artesunate and 21-64 min for DHA 3. Half life after intramuscular administration is 48 min in children and 41 min in adults.

Clearance
Not Available
Toxicity
Not Available
Affected organisms
Not Available
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
4-hydroxycoumarinThe metabolism of 4-hydroxycoumarin can be decreased when combined with Artesunate.
6-Deoxyerythronolide BThe metabolism of Artesunate can be decreased when combined with 6-Deoxyerythronolide B.
7-ethyl-10-hydroxycamptothecinThe metabolism of Artesunate can be decreased when combined with 7-ethyl-10-hydroxycamptothecin.
9-aminocamptothecinThe metabolism of 9-aminocamptothecin can be decreased when combined with Artesunate.
AbataceptThe metabolism of Artesunate can be increased when combined with Abatacept.
AcalabrutinibThe metabolism of Artesunate can be decreased when combined with Acalabrutinib.
AcenocoumarolThe metabolism of Acenocoumarol can be decreased when combined with Artesunate.
AcepromazineThe risk or severity of QTc prolongation can be increased when Artesunate is combined with Acepromazine.
AceprometazineThe risk or severity of QTc prolongation can be increased when Artesunate is combined with Aceprometazine.
AcetaminophenThe metabolism of Artesunate can be decreased when combined with Acetaminophen.
Additional Data Available
  • Extended Description
    Extended Description

    Extended description of the mechanism of action and particular properties of each drug interaction.

    Learn more
  • Severity
    Severity

    A severity rating for each drug interaction, from minor to major.

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  • Evidence Level
    Evidence Level

    A rating for the strength of the evidence supporting each drug interaction.

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  • Action
    Action

    An effect category for each drug interaction. Know how this interaction affects the subject drug.

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Food Interactions
Not Available

References

General References
  1. Lisewski AM, Quiros JP, Ng CL, Adikesavan AK, Miura K, Putluri N, Eastman RT, Scanfeld D, Regenbogen SJ, Altenhofen L, Llinas M, Sreekumar A, Long C, Fidock DA, Lichtarge O: Supergenomic network compression and the discovery of EXP1 as a glutathione transferase inhibited by artesunate. Cell. 2014 Aug 14;158(4):916-28. doi: 10.1016/j.cell.2014.07.011. [PubMed:25126794]
  2. CDC: Artesunate [Link]
  3. Artesunate Product Information [Link]
External Links
Human Metabolome Database
HMDB0240267
KEGG Drug
D02482
PubChem Compound
6917864
PubChem Substance
310265169
ChemSpider
5293084
ChEBI
63918
ChEMBL
CHEMBL361497
HET
D95
Wikipedia
Artesunate
ATC Codes
P01BE03 — ArtesunateP01BF02 — Artesunate and mefloquineP01BF03 — Artesunate and amodiaquineP01BF06 — Artesunate and pyronaridineP01BF04 — Artesunate, sulphamethopyrazine and pyrimethamine
PDB Entries
6fgc

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedNot AvailablePlasmodium Infections1
1CompletedBasic ScienceMalaria caused by Plasmodium falciparum1
1CompletedPreventionPlasmodium Falciparum Infection2
1CompletedTreatmentCervical Intraepithelial Neoplasia Grade 2/3 / High-risk HPV (Any Strain)1
1CompletedTreatmentHealthy Volunteers1
1CompletedTreatmentHepatocellular,Carcinoma1
1CompletedTreatmentHuman Immunodeficiency Virus (HIV) / Plasmodium Infections1
1CompletedTreatmentLocally Advanced Breast Cancer (LABC) / Metastatic Breast Cancer1
1CompletedTreatmentMalaria, Cerebral / Plasmodium Infections2
1CompletedTreatmentPlasmodium Infections5
1CompletedTreatmentTumors, Solid1
1RecruitingTreatmentAIN2/3 / Alternative Treatment / Anal Intraepithelial Neoplasia (AIN) / Artesunate / HPV-Related Anal Intraepithelial Neoplasia / Human Papilloma Virus (HPV) / Precancerous Conditions1
1RecruitingTreatmentHPV-Related Vulvar Intraepithelial Neoplasia / Preinvasive Vulvar Disease / Vulva Intraepithelial Neoplasia / Vulvar Diseases / Vulvar Dysplasia1
1, 2CompletedPreventionPlasmodium Infections / Sickle Cell Crisis1
2Active Not RecruitingTreatmentMalaria caused by Plasmodium falciparum1
2CompletedBasic SciencePlasmodium Infections1
2CompletedTreatmentMalaria caused by Plasmodium falciparum2
2CompletedTreatmentMalaria caused by Plasmodium falciparum / Uncomplicated Malaria1
2CompletedTreatmentMalaria caused by plasmodium vivax1
2CompletedTreatmentPlasmodium Falciparum Malaria2
2CompletedTreatmentPlasmodium Infections7
2CompletedTreatmentPlasmodium Infections / Severe Malaria1
2CompletedTreatmentUncomplicated Falciparum Malaria3
2CompletedTreatmentUncomplicated Plasmodium Falciparum Malaria1
2Not Yet RecruitingTreatmentCervical Dysplasia / CIN 2/3 / HPV Infections / Pre-Cancerous Dysplasia1
2RecruitingTreatmentColorectal Cancers1
2RecruitingTreatmentColorectal Cancers / Malignant intestinal neoplasms1
2TerminatedTreatmentPlasmodium Falciparum Infection1
2, 3Active Not RecruitingTreatmentMalaria caused by Plasmodium falciparum1
2, 3CompletedPreventionPlasmodium Infections2
2, 3CompletedTreatmentMalaria caused by Plasmodium falciparum1
2, 3CompletedTreatmentPlasmodium Falciparum Malaria1
2, 3CompletedTreatmentSchistosoma Haematobium1
2, 3WithdrawnTreatmentPlasmodium Infections / Pregnancy1
2, 3WithdrawnTreatmentUncomplicated Falciparum Malaria1
3Active Not RecruitingTreatmentPlasmodium Infections1
3CompletedNot AvailableAntimalarials / Malaria caused by Plasmodium falciparum / Plasmodium Infections1
3CompletedPreventionPlasmodium Infections1
3CompletedTreatmentAnemias / Plasmodium Infections / Pregnancy1
3CompletedTreatmentAsymptomatic P.Falciparum Malaria1
3CompletedTreatmentAsymptomatic Parataemia / Plasmodium Falciparum / Sub Patent Parasitaemia1
3CompletedTreatmentDrug Resistant Malaria Due to Plasmodium Falciparum1
3CompletedTreatmentFevers / Plasmodium Infections1
3CompletedTreatmentInfections, Cytomegalovirus1
3CompletedTreatmentMalaria caused by Plasmodium falciparum / Malaria caused by plasmodium vivax / Plasmodium Infections1
3CompletedTreatmentMalaria caused by Plasmodium falciparum / Plasmodium Infections2
3CompletedTreatmentMalaria caused by plasmodium vivax2
3CompletedTreatmentMalaria caused by plasmodium vivax / Uncomplicated Falciparum Malaria1
3CompletedTreatmentMalaria in Pregnancy1
3CompletedTreatmentPlasmodium Falciparum Infection1
3CompletedTreatmentPlasmodium Infections19
3CompletedTreatmentPregnancy Complicated by Malaria as Antepartum Condition1
3CompletedTreatmentSchistosoma Mansoni1
3CompletedTreatmentUncomplicated Plasmodium Knowlesi Malaria1
3Not Yet RecruitingPreventionAnemias / Malaria caused by Plasmodium falciparum1
3Not Yet RecruitingTreatmentPlasmodium Falciparum Malaria (Uncomplicated)2
3RecruitingTreatmentSchistosoma Haematobium / Schistosoma Mansoni1
3Unknown StatusTreatmentUncomplicated Malaria1
4Active Not RecruitingTreatmentPlasmodium Infections2
4CompletedNot AvailableHealthy Volunteers1
4CompletedNot AvailableMalaria Falciparum1
4CompletedHealth Services ResearchPlasmodium Infections1
4CompletedPreventionPlasmodium Infections1
4CompletedTreatmentAnemias1
4CompletedTreatmentFalciparum / Plasmodium Infections1
4CompletedTreatmentMalaria (Uncomplicated)1
4CompletedTreatmentMalaria caused by Plasmodium falciparum5
4CompletedTreatmentPlasmodium Falciparum Malaria3
4CompletedTreatmentPlasmodium Infections14
4CompletedTreatmentUncomplicated Falciparum Malaria1
4CompletedTreatmentUncomplicated Malaria1
4CompletedTreatmentUncomplicated P. Falciparum Malaria in Children1
4RecruitingPreventionParasitic Diseases / Plasmodium Infections1
4RecruitingTreatmentDrug Resistant Malaria Due to Plasmodium Falciparum1
4RecruitingTreatmentNephritis, Lupus1
4RecruitingTreatmentPlasmodium Falciparum Malaria (Drug Resistant)1
4SuspendedNot AvailablePlasmodium Infections1
4TerminatedTreatmentMalaria caused by Plasmodium falciparum1
4TerminatedTreatmentMalaria caused by plasmodium vivax1
4TerminatedTreatmentPlasmodium Infections1
4Unknown StatusTreatmentAcute Uncomplicated Malaria With P.Vivax Infection1
4Unknown StatusTreatmentMalaria caused by Plasmodium falciparum1
4Unknown StatusTreatmentPlasmodium Infections2
4Unknown StatusTreatmentUncomplicated Falciparum Malaria1
4WithdrawnTreatmentChildren / Malaria caused by Plasmodium falciparum / Malnutrition1
Not AvailableCompletedNot AvailableDrug Resistance / Plasmodium Falciparum Malaria1
Not AvailableCompletedNot AvailableFevers / Suspected Malaria1
Not AvailableCompletedNot AvailableHuman Immunodeficiency Virus (HIV) Infections / Plasmodium Infections1
Not AvailableCompletedNot AvailableMalaria caused by Plasmodium falciparum1
Not AvailableCompletedNot AvailablePlasmodium Infections1
Not AvailableCompletedPreventionAnemias / Plasmodium Infections1
Not AvailableCompletedPreventionMalaria caused by Plasmodium falciparum1
Not AvailableCompletedPreventionPlasmodium Infections2
Not AvailableCompletedTreatmentMalaria caused by Plasmodium falciparum5
Not AvailableCompletedTreatmentMalaria caused by Plasmodium falciparum / Malaria caused by plasmodium vivax1
Not AvailableCompletedTreatmentP. Falciparum Malaria1
Not AvailableCompletedTreatmentPlasmodium Falciparum Malaria1
Not AvailableCompletedTreatmentPlasmodium Infections7
Not AvailableCompletedTreatmentUncomplicated Malaria1
Not AvailableTerminatedTreatmentPlasmodium Infections1
Not AvailableUnknown StatusNot AvailableSevere Malaria1
Not AvailableUnknown StatusTreatmentUncomplicated P. Falciparum Malaria1
Not AvailableWithdrawnNot AvailablePlasmodium Infections1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
Not Available
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)131-135MSDS
Predicted Properties
PropertyValueSource
Water Solubility0.678 mg/mLALOGPS
logP2.35ALOGPS
logP3.1ChemAxon
logS-2.8ALOGPS
pKa (Strongest Acidic)3.77ChemAxon
pKa (Strongest Basic)-4.2ChemAxon
Physiological Charge-1ChemAxon
Hydrogen Acceptor Count7ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area100.52 Å2ChemAxon
Rotatable Bond Count5ChemAxon
Refractivity89.95 m3·mol-1ChemAxon
Polarizability39.46 Å3ChemAxon
Number of Rings4ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Taxonomy

Description
This compound belongs to the class of organic compounds known as artemisinins. These are sesquiterpenoids originally isolated from the herb Artemisia annua. Their structure is based on artemisinin, a tetracyclic compound that contains a 1,2-dioxepane fused to an octahydrobenzopyran moiety. The internal peroxide bridge is believed to be a key to the mode of action of artemisinins.
Kingdom
Organic compounds
Super Class
Lipids and lipid-like molecules
Class
Prenol lipids
Sub Class
Sesquiterpenoids
Direct Parent
Artemisinins
Alternative Parents
Oxepanes / Heterocyclic fatty acids / Fatty acid esters / Trioxanes / Oxanes / Dicarboxylic acids and derivatives / Dialkyl peroxides / Carboxylic acid esters / Oxacyclic compounds / Carboxylic acids
show 3 more
Substituents
Artemisinin skeleton / Fatty acid ester / Heterocyclic fatty acid / Oxepane / Dicarboxylic acid or derivatives / Oxane / Fatty acyl / 1,2,4-trioxane / Carboxylic acid ester / Dialkyl peroxide
show 11 more
Molecular Framework
Aliphatic heteropolycyclic compounds
External Descriptors
dicarboxylic acid monoester, semisynthetic derivative, sesquiterpenoid, artemisinin derivative, cyclic acetal (CHEBI:63918)

Targets

Kind
Protein
Organism
Plasmodium falciparum
Pharmacological action
Yes
Actions
Inhibitor
General Function
Not Available
Specific Function
Not Available
Gene Name
EXP-1
Uniprot ID
P04926
Uniprot Name
Malaria protein EXP-1
Molecular Weight
17449.565 Da
References
  1. Lisewski AM, Quiros JP, Ng CL, Adikesavan AK, Miura K, Putluri N, Eastman RT, Scanfeld D, Regenbogen SJ, Altenhofen L, Llinas M, Sreekumar A, Long C, Fidock DA, Lichtarge O: Supergenomic network compression and the discovery of EXP1 as a glutathione transferase inhibited by artesunate. Cell. 2014 Aug 14;158(4):916-28. doi: 10.1016/j.cell.2014.07.011. [PubMed:25126794]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Steroid hydroxylase activity
Specific Function
Exhibits a high coumarin 7-hydroxylase activity. Can act in the hydroxylation of the anti-cancer drugs cyclophosphamide and ifosphamide. Competent in the metabolic activation of aflatoxin B1. Const...
Gene Name
CYP2A6
Uniprot ID
P11509
Uniprot Name
Cytochrome P450 2A6
Molecular Weight
56501.005 Da
References
  1. Phompradit P, Muhamad P, Cheoymang A, Na-Bangchang K: Preliminary investigation of the contribution of CYP2A6, CYP2B6, and UGT1A9 polymorphisms on artesunate-mefloquine treatment response in Burmese patients with Plasmodium falciparum malaria. Am J Trop Med Hyg. 2014 Aug;91(2):361-6. doi: 10.4269/ajtmh.13-0531. Epub 2014 Jun 2. [PubMed:24891466]
  2. Artesunate and Amiodiquine FDA Label [File]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
References
  1. Banda CG, Dzinjalamala F, Mukaka M, Mallewa J, Maiden V, Terlouw DJ, Lalloo DG, Khoo SH, Mwapasa V: Pharmacokinetics and Safety Profile of Artesunate-Amodiaquine Coadministered with Antiretroviral Therapy in Malaria-Uninfected HIV-Positive Malawian Adults. Antimicrob Agents Chemother. 2018 Jun 26;62(7). pii: AAC.00412-18. doi: 10.1128/AAC.00412-18. Print 2018 Jul. [PubMed:29760133]
  2. FDA Label: Nevirapine [File]

Drug created on October 28, 2015 15:21 / Updated on December 02, 2019 08:41