Identification

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
  • 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

Pharmacology

Indication

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

Structured Indications
Not Available
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
DrugInteractionDrug group
AcepromazineThe serum concentration of Acepromazine can be increased when it is combined with Artesunate.Approved, Vet Approved
AceprometazineThe serum concentration of Aceprometazine can be increased when it is combined with Artesunate.Approved
AlimemazineThe serum concentration of Alimemazine can be increased when it is combined with Artesunate.Approved, Vet Approved
AmiodaroneThe serum concentration of the active metabolites of Artesunate can be reduced when Artesunate is used in combination with Amiodarone resulting in a loss in efficacy.Approved, Investigational
AmlodipineThe serum concentration of the active metabolites of Artesunate can be reduced when Artesunate is used in combination with Amlodipine resulting in a loss in efficacy.Approved
AmphetamineThe serum concentration of the active metabolites of Artesunate can be reduced when Artesunate is used in combination with Amphetamine resulting in a loss in efficacy.Approved, Illicit
ArtemetherThe risk or severity of adverse effects can be increased when Artemether is combined with Artesunate.Approved
AzelastineThe serum concentration of the active metabolites of Artesunate can be reduced when Artesunate is used in combination with Azelastine resulting in a loss in efficacy.Approved
AzithromycinThe serum concentration of the active metabolites of Artesunate can be reduced when Artesunate is used in combination with Azithromycin resulting in a loss in efficacy.Approved
BL-1020The serum concentration of BL-1020 can be increased when it is combined with Artesunate.Investigational
BuprenorphineThe serum concentration of the active metabolites of Artesunate can be reduced when Artesunate is used in combination with Buprenorphine resulting in a loss in efficacy.Approved, Illicit, Investigational, Vet Approved
ChlorproethazineThe serum concentration of Chlorproethazine can be increased when it is combined with Artesunate.Experimental
ChlorpromazineThe serum concentration of Chlorpromazine can be increased when it is combined with Artesunate.Approved, Vet Approved
ClofibrateThe serum concentration of the active metabolites of Artesunate can be reduced when Artesunate is used in combination with Clofibrate resulting in a loss in efficacy.Approved, Investigational
ClomifeneThe serum concentration of the active metabolites of Artesunate can be reduced when Artesunate is used in combination with Clomifene resulting in a loss in efficacy.Approved, Investigational
ClotrimazoleThe serum concentration of the active metabolites of Artesunate can be reduced when Artesunate is used in combination with Clotrimazole resulting in a loss in efficacy.Approved, Vet Approved
DapsoneThe risk or severity of adverse effects can be increased when Artesunate is combined with Dapsone.Approved, Investigational
DesipramineThe serum concentration of the active metabolites of Artesunate can be reduced when Artesunate is used in combination with Desipramine resulting in a loss in efficacy.Approved
DexfenfluramineThe serum concentration of the active metabolites of Artesunate can be reduced when Artesunate is used in combination with Dexfenfluramine resulting in a loss in efficacy.Approved, Illicit, Investigational, Withdrawn
DiethylstilbestrolThe serum concentration of the active metabolites of Artesunate can be reduced when Artesunate is used in combination with Diethylstilbestrol resulting in a loss in efficacy.Approved, Investigational
EzogabineThe serum concentration of the active metabolites of Artesunate can be reduced when Artesunate is used in combination with Ezogabine resulting in a loss in efficacy.Approved
FluphenazineThe serum concentration of Fluphenazine can be increased when it is combined with Artesunate.Approved
FomepizoleThe serum concentration of the active metabolites of Artesunate can be reduced when Artesunate is used in combination with Fomepizole resulting in a loss in efficacy.Approved, Vet Approved
IsoniazidThe serum concentration of the active metabolites of Artesunate can be reduced when Artesunate is used in combination with Isoniazid resulting in a loss in efficacy.Approved
KetoconazoleThe serum concentration of the active metabolites of Artesunate can be reduced when Artesunate is used in combination with Ketoconazole resulting in a loss in efficacy.Approved, Investigational
LetrozoleThe serum concentration of the active metabolites of Artesunate can be reduced when Artesunate is used in combination with Letrozole resulting in a loss in efficacy.Approved, Investigational
LumefantrineThe risk or severity of adverse effects can be increased when Artesunate is combined with Lumefantrine.Approved
MemantineThe serum concentration of the active metabolites of Artesunate can be reduced when Artesunate is used in combination with Memantine resulting in a loss in efficacy.Approved, Investigational
MenadioneThe serum concentration of the active metabolites of Artesunate can be reduced when Artesunate is used in combination with Menadione resulting in a loss in efficacy.Approved, Nutraceutical
MesoridazineThe serum concentration of Mesoridazine can be increased when it is combined with Artesunate.Approved, Investigational
MethimazoleThe serum concentration of the active metabolites of Artesunate can be reduced when Artesunate is used in combination with Methimazole resulting in a loss in efficacy.Approved
MethotrimeprazineThe serum concentration of Methotrimeprazine can be increased when it is combined with Artesunate.Approved
MethoxsalenThe serum concentration of the active metabolites of Artesunate can be reduced when Artesunate is used in combination with Methoxsalen resulting in a loss in efficacy.Approved
Methylene blueThe serum concentration of Methylene blue can be increased when it is combined with Artesunate.Approved, Investigational
MetyraponeThe serum concentration of the active metabolites of Artesunate can be reduced when Artesunate is used in combination with Metyrapone resulting in a loss in efficacy.Approved
MiconazoleThe serum concentration of the active metabolites of Artesunate can be reduced when Artesunate is used in combination with Miconazole resulting in a loss in efficacy.Approved, Investigational, Vet Approved
MoricizineThe serum concentration of Moricizine can be increased when it is combined with Artesunate.Approved, Investigational, Withdrawn
NevirapineThe serum concentration of the active metabolites of Artesunate can be reduced when Artesunate is used in combination with Nevirapine resulting in a loss in efficacy.Approved
NicotineThe serum concentration of the active metabolites of Artesunate can be reduced when Artesunate is used in combination with Nicotine resulting in a loss in efficacy.Approved
NilvadipineThe serum concentration of the active metabolites of Artesunate can be reduced when Artesunate is used in combination with Nilvadipine resulting in a loss in efficacy.Approved, Investigational
NorfloxacinThe serum concentration of the active metabolites of Artesunate can be reduced when Artesunate is used in combination with Norfloxacin resulting in a loss in efficacy.Approved
PerazineThe serum concentration of Perazine can be increased when it is combined with Artesunate.Investigational
PerphenazineThe serum concentration of Perphenazine can be increased when it is combined with Artesunate.Approved
PhenobarbitalThe serum concentration of the active metabolites of Artesunate can be reduced when Artesunate is used in combination with Phenobarbital resulting in a loss in efficacy.Approved
PilocarpineThe serum concentration of the active metabolites of Artesunate can be reduced when Artesunate is used in combination with Pilocarpine resulting in a loss in efficacy.Approved
PrednisoloneThe serum concentration of the active metabolites of Artesunate can be reduced when Artesunate is used in combination with Prednisolone resulting in a loss in efficacy.Approved, Vet Approved
ProchlorperazineThe serum concentration of Prochlorperazine can be increased when it is combined with Artesunate.Approved, Vet Approved
PromazineThe serum concentration of Promazine can be increased when it is combined with Artesunate.Approved, Vet Approved
PromethazineThe serum concentration of Promethazine can be increased when it is combined with Artesunate.Approved
PropericiazineThe serum concentration of Propericiazine can be increased when it is combined with Artesunate.Approved
PropiopromazineThe serum concentration of Propiopromazine can be increased when it is combined with Artesunate.Vet Approved
RifampicinThe serum concentration of the active metabolites of Artesunate can be reduced when Artesunate is used in combination with Rifampicin resulting in a loss in efficacy.Approved
RosiglitazoneThe serum concentration of the active metabolites of Artesunate can be reduced when Artesunate is used in combination with Rosiglitazone resulting in a loss in efficacy.Approved, Investigational
SeratrodastThe serum concentration of the active metabolites of Artesunate can be reduced when Artesunate is used in combination with Seratrodast resulting in a loss in efficacy.Approved
SulfaphenazoleThe serum concentration of the active metabolites of Artesunate can be reduced when Artesunate is used in combination with Sulfaphenazole resulting in a loss in efficacy.Approved
ThiazinamThe serum concentration of Thiazinam can be increased when it is combined with Artesunate.Experimental
ThiethylperazineThe serum concentration of Thiethylperazine can be increased when it is combined with Artesunate.Withdrawn
ThioproperazineThe serum concentration of Thioproperazine can be increased when it is combined with Artesunate.Approved
ThioridazineThe serum concentration of Thioridazine can be increased when it is combined with Artesunate.Approved, Withdrawn
TranylcypromineThe serum concentration of the active metabolites of Artesunate can be reduced when Artesunate is used in combination with Tranylcypromine resulting in a loss in efficacy.Approved
TrifluoperazineThe serum concentration of Trifluoperazine can be increased when it is combined with Artesunate.Approved
TriflupromazineThe serum concentration of Triflupromazine can be increased when it is combined with Artesunate.Approved, Vet Approved
TroleandomycinThe serum concentration of the active metabolites of Artesunate can be reduced when Artesunate is used in combination with Troleandomycin resulting in a loss in efficacy.Approved
VemurafenibThe risk or severity of QTc prolongation can be increased when Vemurafenib is combined with Artesunate.Approved
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
KEGG Drug
D02482
PubChem Compound
6917864
PubChem Substance
310265169
ChemSpider
5293084
ChEBI
63918
ChEMBL
CHEMBL361497
Wikipedia
Artesunate
ATC Codes
P01BF03 — Artesunate and amodiaquineP01BF04 — Artesunate, sulphamethopyrazine and pyrimethamineP01BF02 — Artesunate and mefloquineP01BE03 — ArtesunateP01BF06 — Artesunate and pyronaridine

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1Active Not RecruitingPreventionPlasmodium Falciparum Infection1
1CompletedNot AvailablePlasmodium Infections1
1CompletedBasic ScienceMalaria caused by Plasmodium falciparum1
1CompletedTreatmentHepatocellular,Carcinoma1
1CompletedTreatmentLocally Advanced Breast Cancer (LABC) / Metastatic Breast Cancer (MBC)1
1CompletedTreatmentMalaria, Cerebral / Plasmodium Infections2
1CompletedTreatmentPlasmodium Infections2
1CompletedTreatmentTumors, Solid1
1RecruitingPreventionPlasmodium Falciparum Infection1
2CompletedBasic SciencePlasmodium Infections1
2CompletedTreatmentMalaria caused by Plasmodium falciparum1
2CompletedTreatmentMalaria caused by Plasmodium falciparum / Uncomplicated Malaria1
2CompletedTreatmentMalaria caused by plasmodium vivax1
2CompletedTreatmentPlasmodium Falciparum Malaria2
2CompletedTreatmentPlasmodium Infections3
2CompletedTreatmentPlasmodium Infections / Severe Malaria1
2CompletedTreatmentUncomplicated Falciparum Malaria2
2Not Yet RecruitingTreatmentColorectal Cancers1
2RecruitingTreatmentColorectal Cancers / Malignant intestinal neoplasms1
2TerminatedTreatmentPlasmodium Falciparum Infection1
2, 3CompletedPreventionPlasmodium Infections1
2, 3CompletedTreatmentSchistosoma Haematobium1
2, 3WithdrawnTreatmentUncomplicated Falciparum Malaria1
3CompletedNot AvailableAntimalarials / Malaria caused by Plasmodium falciparum / Plasmodium Infections1
3CompletedPreventionPlasmodium Infections1
3CompletedTreatmentInfections, Cytomegalovirus1
3CompletedTreatmentMalaria caused by Plasmodium falciparum / Malaria caused by plasmodium vivax / Plasmodium Infections1
3CompletedTreatmentMalaria caused by plasmodium vivax1
3CompletedTreatmentPlasmodium Falciparum Infection1
3CompletedTreatmentPlasmodium Infections9
3CompletedTreatmentSchistosoma Mansoni1
3Unknown StatusTreatmentUncomplicated Malaria1
4Active Not RecruitingTreatmentPlasmodium Infections1
4CompletedTreatmentAnemias1
4CompletedTreatmentPlasmodium Infections6
4CompletedTreatmentUncomplicated Malaria1
4Not Yet RecruitingTreatmentNephritis, Lupus1
4RecruitingPreventionParasitic Diseases / Plasmodium Infections1
4SuspendedNot AvailablePlasmodium Infections1
4Unknown StatusTreatmentAcute Uncomplicated Malaria With P.Vivax Infection1
4Unknown StatusTreatmentMalaria caused by Plasmodium falciparum1
4Unknown StatusTreatmentPlasmodium Infections1
Not AvailableCompletedNot AvailableHuman Immunodeficiency Virus (HIV) Infections / Plasmodium Infections1
Not AvailableCompletedPreventionMalaria caused by Plasmodium falciparum1
Not AvailableCompletedPreventionPlasmodium Infections1
Not AvailableCompletedTreatmentMalaria caused by Plasmodium falciparum3
Not AvailableCompletedTreatmentP. Falciparum Malaria1
Not AvailableCompletedTreatmentPlasmodium Falciparum Malaria1
Not AvailableCompletedTreatmentPlasmodium Infections3
Not AvailableUnknown StatusNot AvailableSevere Malaria1
Not AvailableUnknown StatusTreatmentUncomplicated P. Falciparum Malaria1

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]

Drug created on October 28, 2015 15:21 / Updated on December 01, 2017 17:22