Identification

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Name
Rifalazil
Accession Number
DB04934
Type
Small Molecule
Groups
Investigational
Description

Rifalazil is a derivative of the antibiotic rifamycin. It is being investigated by ActivBiotics for the treatment of various bacterial infections.

Structure
Thumb
Synonyms
  • 3'-hydroxy-5'-(4-isobutyl-1-piperazinyl)benzoxazinorifamycin
External IDs
KRM-1648
International/Other Brands
Rifalazil
Categories
UNII
S1976TE8QK
CAS number
129791-92-0
Weight
Average: 941.088
Monoisotopic: 940.446988137
Chemical Formula
C51H64N4O13
InChI Key
UEFHFKKWYKVLDC-HTQYORAHSA-N
InChI
InChI=1S/C51H64N4O13/c1-24(2)23-54-16-18-55(19-17-54)32-21-33(57)39-35(22-32)67-48-40(52-39)36-37-44(60)30(8)47-38(36)49(62)51(10,68-47)65-20-15-34(64-11)27(5)46(66-31(9)56)29(7)43(59)28(6)42(58)25(3)13-12-14-26(4)50(63)53-41(48)45(37)61/h12-15,20-22,24-25,27-29,34,42-43,46,57-60H,16-19,23H2,1-11H3,(H,53,63)/b13-12+,20-15+,26-14-/t25-,27+,28+,29+,34-,42-,43+,46+,51-/m0/s1
IUPAC Name
(7S,9E,11S,12R,13S,14R,15R,16R,17S,18S,19E,21Z)-2,15,17,32-tetrahydroxy-11-methoxy-3,7,12,14,16,18,22-heptamethyl-30-[4-(2-methylpropyl)piperazin-1-yl]-6,23,37-trioxo-8,27,38-trioxa-24,34-diazahexacyclo[23.11.1.1⁴,⁷.0⁵,³⁶.0²⁶,³⁵.0²⁸,³³]octatriaconta-1,3,5(36),9,19,21,25,28(33),29,31,34-undecaen-13-yl acetate
SMILES
CO[C@H]1\C=C\O[C@@]2(C)OC3=C(C)C(O)=C4C(=O)C(NC(=O)\C(C)=C/C=C/[C@H](C)[C@H](O)[C@@H](C)[C@@H](O)[C@@H](C)[C@H](OC(C)=O)[C@@H]1C)=C1OC5=C(N=C1C4=C3C2=O)C(O)=CC(=C5)N1CCN(CC(C)C)CC1

Pharmacology

Indication

Investigated for use/treatment in atherosclerosis, bacterial infection, and peripheral vascular disease.

Pharmacodynamics

Rifalazil represents a new generation of ansamycins that contain a unique four-ring structure. Originally rifalazil was developed as a therapeutic agent to replace rifampin as part of a multiple drug regimen in the treatment of tuberculosis. As a result of its superior antimicrobial activity and high intracellular levels, rifalazil has potential to treat indications caused by the intracellular pathogen, Chlamydia trachomatis, which causes non-gonococcal urethritis and cervicitis, often leading to pelvic inflammatory disease. Rifalazil also has potential to treat the related microorganism, Chlamydia pneumoniae, which may be involved in chronic inflammatory processes thought to be partly responsible for atherosclerosis. Due to its favourable antimicrobial spectrum and other positive attributes, rifalazil may also prove valuable in the treatment of gastric ulcer disease, caused by Helicobacter pylori, and antibiotic-associated colitis, the result of toxin production following the growth of Clostridium difficile in the colon. The potential value of rifalazil in the treatment of these indications will be assessed in human clinical trials.

Mechanism of action

The potent antimycobacterial activity of rifalazil is due to inhibition of bacterial RNA polymerase.

TargetActionsOrganism
UDNA-directed RNA polymerase subunit betaNot AvailableEscherichia coli (strain K12)
Absorption
Not Available
Volume of distribution
Not Available
Protein binding
Not Available
Metabolism

The major metabolites of rifalazil in human are 25-deacetyl-benzoxazinorifamycin and 32-hydroxy-benzoxazinorifamycin. The enzyme responsible for the benzoxazinorifamycin-25-deacetylation is a B-esterase while the enzyme responsible for the benzoxazinorifamycin-32-hydroxylation is CYP3A4.

Route of elimination
Not Available
Half life
Not Available
Clearance
Not Available
Toxicity
Not Available
Affected organisms
  • Bacteria
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
(R)-warfarinThe risk or severity of bleeding can be increased when Rifalazil is combined with (R)-warfarin.
(S)-WarfarinThe risk or severity of bleeding can be increased when Rifalazil is combined with (S)-Warfarin.
4-hydroxycoumarinThe risk or severity of bleeding can be increased when Rifalazil is combined with 4-hydroxycoumarin.
AcenocoumarolThe risk or severity of bleeding can be increased when Rifalazil is combined with Acenocoumarol.
Adenovirus type 7 vaccine liveThe therapeutic efficacy of Adenovirus type 7 vaccine live can be decreased when used in combination with Rifalazil.
Anthrax immune globulin humanThe therapeutic efficacy of Anthrax immune globulin human can be decreased when used in combination with Rifalazil.
Anthrax vaccineThe therapeutic efficacy of Anthrax vaccine can be decreased when used in combination with Rifalazil.
Bacillus calmette-guerin substrain connaught live antigenThe therapeutic efficacy of Bacillus calmette-guerin substrain connaught live antigen can be decreased when used in combination with Rifalazil.
Bacillus calmette-guerin substrain danish 1331 live antigenThe therapeutic efficacy of Bacillus calmette-guerin substrain danish 1331 live antigen can be decreased when used in combination with Rifalazil.
Bacillus calmette-guerin substrain tice live antigenThe therapeutic efficacy of Bacillus calmette-guerin substrain tice live antigen can be decreased when used in combination with Rifalazil.
Additional Data Available
  • Extended Description
    Extended Description

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

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  • 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. Mae T, Inaba T, Konishi E, Hosoe K, Hidaka T: Identification of enzymes responsible for rifalazil metabolism in human liver microsomes. Xenobiotica. 2000 Jun;30(6):565-74. [PubMed:10923859]
  2. Rothstein DM, Hartman AD, Cynamon MH, Eisenstein BI: Development potential of rifalazil. Expert Opin Investig Drugs. 2003 Feb;12(2):255-71. [PubMed:12556219]
External Links
KEGG Drug
D02550
PubChem Compound
6540558
PubChem Substance
175426909
ChemSpider
16736451
ChEMBL
CHEMBL236297
Wikipedia
Rifalazil

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
2CompletedTreatmentChlamydia Trachomatis Infection1
2Unknown StatusNot AvailableCerebrovascular Diseases / Coronary Artery Disease / Peripheral Vascular Disease (PVD)1
3Unknown StatusTreatmentIntermittent Claudication / Peripheral Vascular Disease (PVD)1

Pharmacoeconomics

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

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.0116 mg/mLALOGPS
logP5.16ALOGPS
logP4.48ChemAxon
logS-4.9ALOGPS
pKa (Strongest Acidic)4.52ChemAxon
pKa (Strongest Basic)8.63ChemAxon
Physiological Charge-1ChemAxon
Hydrogen Acceptor Count15ChemAxon
Hydrogen Donor Count5ChemAxon
Polar Surface Area226.22 Å2ChemAxon
Rotatable Bond Count6ChemAxon
Refractivity260.84 m3·mol-1ChemAxon
Polarizability100.52 Å3ChemAxon
Number of Rings7ChemAxon
Bioavailability0ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption-0.7494
Blood Brain Barrier-0.9076
Caco-2 permeable-0.5979
P-glycoprotein substrateSubstrate0.7333
P-glycoprotein inhibitor IInhibitor0.5525
P-glycoprotein inhibitor IINon-inhibitor0.7461
Renal organic cation transporterNon-inhibitor0.89
CYP450 2C9 substrateNon-substrate0.801
CYP450 2D6 substrateNon-substrate0.8338
CYP450 3A4 substrateSubstrate0.6903
CYP450 1A2 substrateNon-inhibitor0.5611
CYP450 2C9 inhibitorNon-inhibitor0.5582
CYP450 2D6 inhibitorNon-inhibitor0.8682
CYP450 2C19 inhibitorNon-inhibitor0.6166
CYP450 3A4 inhibitorNon-inhibitor0.7363
CYP450 inhibitory promiscuityHigh CYP Inhibitory Promiscuity0.7914
Ames testNon AMES toxic0.5689
CarcinogenicityNon-carcinogens0.8451
BiodegradationNot ready biodegradable1.0
Rat acute toxicity2.6963 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9942
hERG inhibition (predictor II)Non-inhibitor0.8326
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

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 phenoxazines. These are polycyclic aromatic compounds containing a phenoxazine moiety, which is a linear tricyclic system that consists of a two benzene rings joined by a 1,4-oxazine ring.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Benzoxazines
Sub Class
Phenoxazines
Direct Parent
Phenoxazines
Alternative Parents
Macrolactams / Naphthofurans / N-arylpiperazines / Naphthols and derivatives / Benzofurans / Coumarans / Aryl alkyl ketones / Dialkylarylamines / 1-hydroxy-2-unsubstituted benzenoids / 1-hydroxy-4-unsubstituted benzenoids
show 18 more
Substituents
Phenoxazine / Naphthofuran / Macrolactam / N-arylpiperazine / 1-naphthol / Naphthalene / Benzofuran / Coumaran / Tertiary aliphatic/aromatic amine / Aryl ketone
show 39 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Escherichia coli (strain K12)
Pharmacological action
Unknown
General Function
Ribonucleoside binding
Specific Function
DNA-dependent RNA polymerase catalyzes the transcription of DNA into RNA using the four ribonucleoside triphosphates as substrates.
Gene Name
rpoB
Uniprot ID
P0A8V2
Uniprot Name
DNA-directed RNA polymerase subunit beta
Molecular Weight
150631.165 Da
References
  1. Fujii K, Saito H, Tomioka H, Mae T, Hosoe K: Mechanism of action of antimycobacterial activity of the new benzoxazinorifamycin KRM-1648. Antimicrob Agents Chemother. 1995 Jul;39(7):1489-92. [PubMed:7492091]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
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. Mae T, Hosoe K, Fujii K, Yamashita K, Yamane T, Hidaka T, Ohashi T: In vitro metabolism of a rifamycin derivative by animal and human liver microsomes, whole blood and expressed human CYP3A isoform. Xenobiotica. 1996 Aug;26(8):793-802. [PubMed:8879143]

Drug created on October 21, 2007 16:23 / Updated on June 04, 2019 06:13