FOSMIDOMYCIN

Details

Stereochemistry	ACHIRAL
Molecular Formula	C4H10NO5P
Molecular Weight	183.0997
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

ON(CCCP(O)(O)=O)C=O

InChI

InChIKey=GJXWDTUCERCKIX-UHFFFAOYSA-N

InChI=1S/C4H10NO5P/c6-4-5(7)2-1-3-11(8,9)10/h4,7H,1-3H2,(H2,8,9,10)

HIDE SMILES / InChI

Molecular Formula	C4H10NO5P
Molecular Weight	183.0997
Charge	0
Count

Stereochemistry	ACHIRAL
Additional Stereochemistry	No
Defined Stereocenters	0 / 0
E/Z Centers	0
Optical Activity	NONE

Description
Sources: https://www.ncbi.nlm.nih.gov/pubmed/12937969
Curator's Comment: The description was created based on several sources, including https://www.drugbank.ca/drugs/DB02948 | https://clinicaltrials.gov/ct2/show/NCT00214643 | https://clinicaltrials.gov/ct2/show/NCT00217451 | https://www.ncbi.nlm.nih.gov/pubmed/21866890

Fosmidomycin (3-(formylhydroxyamino)-propylphosphonic acid mono-sodium salt, 3-(N-formyl-N-hydroxyamino)-propylphosphonic acid mono-sodium salt, FR-31564) is a potent inhibitor of P. falciparum 1-deoxy-D-xylulose-5-phosphate reductoisomerase (PfDXR), developed by Albert Schweitzer Hospital for P. falciparum malaria treatment. Fosmidomycin was originally isolated as natural antibiotic from Streptomyces lavendulae. Fosmidomycin is active against a broad range of enterobacteria, but not against Gram-positive organisms or anaerobes. Fosmidomycin was developed as far as an early phase II study for the treatment of urinary tract infections by Fujisawa Pharmaceutical Company (Osaka, Japan) in the early eighties, but these trials have been discontinued. In recent clinical studies, it was shown that fosmidomycin is effective in curing uncomplicated Plasmodium falciparum malaria in humans. The treatment was well tolerated and resulted in a fast parasite and fever clearance. However, the high rate of recrudescence precludes the use of fosmidomycin as a monotherapy. In drug combination studies, the synergy of fosmidomycin with clindamycin was observed. Clinical studies with a fosmidomycin-clindamycin combination are currently ongoing.

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
1-deoxy-D-xylulose 5-phosphate reductoisomerase, apicoplastic 2 Target ID: O96693 Gene ID: NA Gene Symbol: DXR Target Organism: Plasmodium falciparum (isolate HB3) Sources: https://www.ncbi.nlm.nih.gov/pubmed/12937969	Inhibitor 8297		28.0 nM [IC50]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Malaria 95 Sources: https://clinicaltrials.gov/ct2/show/NCT00214643	Primary		Phase III 656	Unknown Approved Use Unknown
Urinary tract infections 205 Sources: https://www.ncbi.nlm.nih.gov/pubmed/12937969	Primary		Phase II 1132	Unknown Approved Use Unknown

C_max

Value	Dose	Analyte	Population
4.58 μg/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/17531088	1200 mg 3 times / day multiple, oral dose: 1200 mg route of administration: Oral experiment type: MULTIPLE co-administered:	FOSMIDOMYCIN plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
2.33 μg/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/7073262	500 mg single, oral dose: 500 mg route of administration: Oral experiment type: SINGLE co-administered:	FOSMIDOMYCIN serum	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: UNKNOWN
11.1 μg/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/7073262	7.5 mg/kg single, intramuscular dose: 7.5 mg/kg route of administration: Intramuscular experiment type: SINGLE co-administered:	FOSMIDOMYCIN serum	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: UNKNOWN

AUC

Value	Dose	Analyte	Population
27.67 μg × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/17531088	1200 mg 3 times / day multiple, oral dose: 1200 mg route of administration: Oral experiment type: MULTIPLE co-administered:	FOSMIDOMYCIN plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
210 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/7073262	30 mg/kg single, intravenous dose: 30 mg/kg route of administration: Intravenous experiment type: SINGLE co-administered:	FOSMIDOMYCIN serum	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: UNKNOWN
14 μg × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/7073262	500 mg single, oral dose: 500 mg route of administration: Oral experiment type: SINGLE co-administered:	FOSMIDOMYCIN serum	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: UNKNOWN
42.2 μg × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/7073262	7.5 mg/kg single, intramuscular dose: 7.5 mg/kg route of administration: Intramuscular experiment type: SINGLE co-administered:	FOSMIDOMYCIN serum	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: UNKNOWN

T_1/2

Value	Dose	Analyte	Population
0.5 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/17531088	1200 mg 3 times / day multiple, oral dose: 1200 mg route of administration: Oral experiment type: MULTIPLE co-administered:	FOSMIDOMYCIN plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
1.65 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/7073262	30 mg/kg single, intravenous dose: 30 mg/kg route of administration: Intravenous experiment type: SINGLE co-administered:	FOSMIDOMYCIN serum	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: UNKNOWN
1.87 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/7073262	500 mg single, oral dose: 500 mg route of administration: Oral experiment type: SINGLE co-administered:	FOSMIDOMYCIN serum	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: UNKNOWN
1.58 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/7073262	7.5 mg/kg single, intramuscular dose: 7.5 mg/kg route of administration: Intramuscular experiment type: SINGLE co-administered:	FOSMIDOMYCIN serum	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: UNKNOWN

F_unbound

Value	Dose	Co-administered	Analyte	Population
99% EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/17531088	1200 mg 3 times / day multiple, oral dose: 1200 mg route of administration: Oral experiment type: MULTIPLE co-administered:		FOSMIDOMYCIN plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

Sourcing

Vendor/Aggregator	ID	URL
AK Scientific	R980	https://aksci.com/item_detail.php?cat=R980
ApexBio Technology	C4898	https://www.apexbt.com/catalogsearch/result/?q=C4898
BOC Sciences	66508-53-0	http://www.bocsci.com/description.asp?cas=66508-53-0
Cayman Chemical	16000	http://www.caymanchem.com/app/template/Product.vm/catalog/16000
Chemspace	CSC000076817	https://chem-space.com/CSC000076817
Enamine	BBV-38278542	http://www.enaminestore.com/catalog/BBV-38278542
MuseChem	I006850	https://www.musechem.com/product/I006850.html
Toronto Research Chemicals	C176670	https://www.trc-canada.com/product-detail/?CatNum=C176670
Toronto Research Chemicals	F728500	https://www.trc-canada.com/product-detail/?CatNum=F728500
eMolecules	300143136	https://orderbb.emolecules.com/search/#?query=300143136
eMolecules	50153329	https://orderbb.emolecules.com/search/#?query=50153329
eMolecules	8321444	https://orderbb.emolecules.com/search/#?query=8321444

PubMed

Title	Date	PubMed
The plastid of Plasmodium spp.: a target for inhibitors.	2005	16265894
Fosmidomycin analogues as inhibitors of monoterpenoid indole alkaloid production in Catharanthus roseus cells.	2005 Aug	16054176
Bacterial genome adaptation to niches: divergence of the potential virulence genes in three Burkholderia species of different survival strategies.	2005 Dec 7	16336651
Alkoxycarbonyloxyethyl ester prodrugs of FR900098 with improved in vivo antimalarial activity.	2005 Jul	15996004
[Prevalence of nonmevalonate and mevalonate pathways for isoprenoid biosynthesis among bacteria of different systematic groups].	2005 Mar-Apr	15938394
AFMoC enhances predictivity of 3D QSAR: a case study with DOXP-reductoisomerase.	2005 May 19	15887963
[Isoprenoid pigments in representatives of the family Microbacteriaceae].	2005 May-Jun	16119846
The Arabidopsis csb3 mutant reveals a regulatory link between salicylic acid-mediated disease resistance and the methyl-erythritol 4-phosphate pathway.	2005 Oct	16167903
A fragment-based approach to understanding inhibition of 1-deoxy-D-xylulose-5-phosphate reductoisomerase.	2005 Oct	16116659
The capacity for thermal protection of photosynthetic electron transport varies for different monoterpenes in Quercus ilex.	2005 Sep	16126854
Synthesis of alpha-substituted fosmidomycin analogues as highly potent Plasmodium falciparum growth inhibitors.	2006 Apr 1	16439126
Evaluation of fosmidomycin analogs as inhibitors of the Synechocystis sp. PCC6803 1-deoxy-D-xylulose 5-phosphate reductoisomerase.	2006 Apr 1	16310360
Synthesis and biological evaluation of cyclopropyl analogues of fosmidomycin as potent Plasmodium falciparum growth inhibitors.	2006 Apr 20	16610809
The relationship between the methyl-erythritol phosphate pathway leading to emission of volatile isoprenoids and abscisic acid content in leaves.	2006 Aug	16766667
Dynamic pathway allocation in early terpenoid biosynthesis of stress-induced lima bean leaves.	2006 Aug	16580034
Synthesis and antimalarial activity of chain substituted pivaloyloxymethyl ester analogues of Fosmidomycin and FR900098.	2006 Aug 1	16679022
Arylmethyl substituted derivatives of Fosmidomycin: synthesis and antimalarial activity.	2006 Dec	17055117
Isoprenoid biosynthesis as a drug target: bisphosphonate inhibition of Escherichia coli K12 growth and synergistic effects of fosmidomycin.	2006 Dec 14	17149863
Kinetic characterization of Synechocystis sp. PCC6803 1-deoxy-D-xylulose 5-phosphate reductoisomerase mutants.	2006 Feb	16219495
An alternative high-performance liquid chromatographic method for determination of clindamycin in plasma.	2006 Jan	16771232
Involvement of 2-C-methyl-D-erythritol-4-phosphate pathway in biosynthesis of aphidicolin-like tetracyclic diterpene of Scoparia dulcis.	2006 May	16651787
Plastid cues posttranscriptionally regulate the accumulation of key enzymes of the methylerythritol phosphate pathway in Arabidopsis.	2006 May	16531478
Enhanced flux through the methylerythritol 4-phosphate pathway in Arabidopsis plants overexpressing deoxyxylulose 5-phosphate reductoisomerase.	2006 Nov	16941216
Isoprenoid biosynthesis in plants - 2C-methyl-D-erythritol-4-phosphate synthase (IspC protein) of Arabidopsis thaliana.	2006 Oct	16972937
Targeting the methyl erythritol phosphate (MEP) pathway for novel antimalarial, antibacterial and herbicidal drug discovery: inhibition of 1-deoxy-D-xylulose-5-phosphate reductoisomerase (DXR) enzyme.	2007	17430177
Bioassay for determination of fosmidomycin in plasma and urine: application for pharmacokinetic dose optimisation.	2007 Apr	17258829
Molecular epidemiology of malaria in Cameroon. XXV. In vitro activity of fosmidomycin and its derivatives against fresh clinical isolates of Plasmodium falciparum and sequence analysis of 1-deoxy-D-xylulose 5-phosphate reductoisomerase.	2007 Aug	17690389
An Escherichia coli undecaprenyl-pyrophosphate phosphatase implicated in undecaprenyl phosphate recycling.	2007 Aug	17660416
The methylerythritol phosphate pathway for isoprenoid biosynthesis in coccidia: presence and sensitivity to fosmidomycin.	2007 Aug	17399705
gamma-Substituted bis(pivaloyloxymethyl)ester analogues of fosmidomycin and FR900098.	2007 Dec	17994605
Evidence of artemisinin production from IPP stemming from both the mevalonate and the nonmevalonate pathways.	2007 Dec	17710406
Isoprenoid biosynthesis of the apicoplast as drug target.	2007 Jan	17266527
Conformationally restrained aromatic analogues of fosmidomycin and FR900098.	2007 Jul	17611943
Structures of Mycobacterium tuberculosis 1-deoxy-D-xylulose-5-phosphate reductoisomerase provide new insights into catalysis.	2007 Jul 6	17491006
Effect of fosmidomycin on metabolic and transcript profiles of the methylerythritol phosphate pathway in Plasmodium falciparum.	2007 Jun	17568945
Structure of 1-deoxy-D-xylulose 5-phosphate reductoisomerase in a quaternary complex with a magnesium ion, NADPH and the antimalarial drug fosmidomycin.	2007 Jun 1	17554164
Plants used traditionally to treat malaria in Brazil: the archives of Flora Medicinal.	2007 May 1	17472740
Divergent strategy for the synthesis of alpha-aryl-substituted fosmidomycin analogues.	2007 May 11	17428097
Pharmacokinetics and pharmacodynamics of fosmidomycin monotherapy and combination therapy with clindamycin in the treatment of multidrug resistant falciparum malaria.	2007 May 25	17531088
Organocatalytic asymmetric direct phosphonylation of alpha,beta-unsaturated aldehydes: mechanism, scope, and application in synthesis.	2007 Nov 9	17927255
The structure of Mycobacteria 2C-methyl-D-erythritol-2,4-cyclodiphosphate synthase, an essential enzyme, provides a platform for drug discovery.	2007 Oct 23	17956607
Assessment of in vitro antimalarial interactions between dihydroartemisinin and fosmidomycin.	2007 Sep	18041293
Gateways to clinical trials.	2007 Sep	17982511
Novel deoxyxylulosephosphate-reductoisomerase inhibitors: fosmidomycin derivatives with spacious acyl residues.	2007 Sep	17806130
Elicitor induced activation of the methylerythritol phosphate pathway toward phytoalexins biosynthesis in rice.	2007 Sep	17634747
Synthesis and evaluation of alpha,beta-unsaturated alpha-aryl-substituted fosmidomycin analogues as DXR inhibitors.	2007 Sep 1	17583502
Towards new antimalarial drugs: synthesis of non-hydrolyzable phosphate mimics as feed for a predictive QSAR study on 1-deoxy-D-xylulose-5-phosphate reductoisomerase inhibitors.	2008 Apr	18421757
Significance of terpenoids in induced indirect plant defence against herbivorous arthropods.	2008 Apr	18208515
Herbivore-induced terpenoid emission in Medicago truncatula: concerted action of jasmonate, ethylene and calcium signaling.	2008 Jan	17924138
Synthesis of beta- and gamma-oxa isosteres of fosmidomycin and FR900098 as antimalarial candidates.	2008 Mar 15	18158249

Patents

Sample Use Guides

In Vivo Use Guide

Fosmidomycin-clindamycin (30 mg/kg and 10 mg/kg) given twice daily for three days

Route of Administration: Oral

In Vitro Use Guide

Assay mixtures (total volume: 200 mL) contained 100 mm Tris hydrochloride (pH 7.6), 4 mm MnCl2, 0.5 mm dithiothreitol (DTT), 0.5 mm NADPH, 10–30 nm of recombinant IspC protein (P. falciparum) or 100 mm Tris hydrochloride (pH 8.0), 10 mm MgCl2, 1mm NADPH, 27 nm of recombinant IspC protein (E. coli). Dilution series (1:2) of inhibitor 1 (Fosmidomycin) covered the concentration range of 200 mm to 1 nm. The reaction was started by addition of 1-deoxyxylulose 5-phosphate to a final concentration of 1 mm. The reaction was monitored photometrically (room temperature for P. falciparum or 37C for E. coli) at 340 nm in a microplate reader

Substance Class	Chemical Created by `admin` on `Fri Dec 15 15:46:57 UTC 2023` Edited by `admin` on `Fri Dec 15 15:46:57 UTC 2023`
Record UNII	5829E3D9I9
Record Status	`Validated (UNII)`
Record Version

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Name

Type

Language

FOSMIDOMYCIN

Official Name

English

fosmidomycin [INN]

Common Name

English

FOSMIDOMYCIN [MART.]

Common Name

English

FOSMIDOMYCIN [MI]

Common Name

English

(3-(N-HYDROXYFORMAMIDO)PROPYL)PHOSPHONIC ACID

Systematic Name

English

Classification Tree Code System Code

NCI_THESAURUS

C258