molecular formula C46H62N4O11 B1679326 Rifabutin CAS No. 72559-06-9

Rifabutin

Cat. No.: B1679326
CAS No.: 72559-06-9
M. Wt: 847 g/mol
InChI Key: ATEBXHFBFRCZMA-NYGPAKPVSA-N
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Scientific Research Applications

Rifabutin has a wide range of scientific research applications, including:

Safety and Hazards

Rifabutin can cause skin irritation and serious eye irritation. It may also cause respiratory irritation. It is recommended to avoid dust formation, breathing mist, gas or vapors, and contact with skin and eyes. Use of personal protective equipment, wearing chemical impermeable gloves, and ensuring adequate ventilation are advised .

Preparation Methods

Synthetic Routes and Reaction Conditions

Rifabutin is synthesized through a semisynthetic process starting from rifamycin S. The process involves several steps, including the modification of the rifamycin S structure to introduce the spiropiperidyl group . The reaction conditions typically involve the use of organic solvents and catalysts to facilitate the chemical transformations.

Industrial Production Methods

Industrial production of this compound involves large-scale synthesis using optimized reaction conditions to ensure high yield and purity. The process is carefully controlled to maintain the quality and consistency of the final product. The production involves multiple purification steps, including crystallization and chromatography, to achieve the desired purity levels .

Chemical Reactions Analysis

Types of Reactions

Rifabutin undergoes various chemical reactions, including:

Common Reagents and Conditions

Common reagents used in these reactions include oxidizing agents like potassium permanganate, reducing agents like sodium borohydride, and various organic solvents. The reactions are typically carried out under controlled temperature and pressure conditions to ensure the desired outcomes .

Major Products Formed

The major products formed from these reactions include various derivatives of this compound with modified antimicrobial properties. These derivatives are often studied for their potential use in treating different bacterial infections .

Comparison with Similar Compounds

Similar Compounds

    Rifampin: Another ansamycin antibiotic with a similar mechanism of action but different spectrum of activity.

    Rifapentine: A derivative of rifamycin with a longer half-life and different pharmacokinetic properties.

    Rifamycin S: The parent compound from which Rifabutin is synthesized.

Uniqueness

This compound is unique in its enhanced activity against Mycobacterium avium complex and its ability to induce cytochrome P-450 3A at lower levels compared to Rifampin . This makes this compound a valuable option for treating infections caused by resistant mycobacteria and for use in combination therapy with other antimicrobial agents .

Properties

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-1'-(2-methylpropyl)-6,23-dioxospiro[8,33-dioxa-24,27,29-triazapentacyclo[23.6.1.14,7.05,31.026,30]tritriaconta-1(32),2,4,9,19,21,24,26,30-nonaene-28,4'-piperidine]-13-yl] acetate
Source PubChem
URL https://pubchem.ncbi.nlm.nih.gov
Description Data deposited in or computed by PubChem

InChI

InChI=1S/C46H62N4O11/c1-22(2)21-50-18-16-46(17-19-50)48-34-31-32-39(54)28(8)42-33(31)43(56)45(10,61-42)59-20-15-30(58-11)25(5)41(60-29(9)51)27(7)38(53)26(6)37(52)23(3)13-12-14-24(4)44(57)47-36(40(32)55)35(34)49-46/h12-15,20,22-23,25-27,30,37-38,41,48,52-55H,16-19,21H2,1-11H3/b13-12+,20-15+,24-14-,47-36?/t23-,25+,26+,27+,30-,37-,38+,41+,45-/m0/s1
Source PubChem
URL https://pubchem.ncbi.nlm.nih.gov
Description Data deposited in or computed by PubChem

InChI Key

ZWBTYMGEBZUQTK-PVLSIAFMSA-N
Source PubChem
URL https://pubchem.ncbi.nlm.nih.gov
Description Data deposited in or computed by PubChem

Canonical SMILES

CC1C=CC=C(C(=O)N=C2C(=C3C(=C4C2=NC5(N4)CCN(CC5)CC(C)C)C6=C(C(=C3O)C)OC(C6=O)(OC=CC(C(C(C(C(C(C1O)C)O)C)OC(=O)C)C)OC)C)O)C
Source PubChem
URL https://pubchem.ncbi.nlm.nih.gov
Description Data deposited in or computed by PubChem

Isomeric SMILES

C[C@H]1/C=C/C=C(\C(=O)N=C2C(=C3C(=C4C2=NC5(N4)CCN(CC5)CC(C)C)C6=C(C(=C3O)C)O[C@@](C6=O)(O/C=C/[C@@H]([C@H]([C@H]([C@@H]([C@@H]([C@@H]([C@H]1O)C)O)C)OC(=O)C)C)OC)C)O)/C
Source PubChem
URL https://pubchem.ncbi.nlm.nih.gov
Description Data deposited in or computed by PubChem

Molecular Formula

C46H62N4O11
Source PubChem
URL https://pubchem.ncbi.nlm.nih.gov
Description Data deposited in or computed by PubChem

Molecular Weight

847.0 g/mol
Source PubChem
URL https://pubchem.ncbi.nlm.nih.gov
Description Data deposited in or computed by PubChem

Solubility

Minimally soluble (0.19 mg/mL)
Record name Rifabutin
Source DrugBank
URL https://www.drugbank.ca/drugs/DB00615
Description The DrugBank database is a unique bioinformatics and cheminformatics resource that combines detailed drug (i.e. chemical, pharmacological and pharmaceutical) data with comprehensive drug target (i.e. sequence, structure, and pathway) information.
Explanation Creative Common's Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/legalcode)

Mechanism of Action

Rifabutin acts via the inhibition of DNA-dependent RNA polymerase in gram-positive and some gram-negative bacteria, leading to a suppression of RNA synthesis and cell death.
Record name Rifabutin
Source DrugBank
URL https://www.drugbank.ca/drugs/DB00615
Description The DrugBank database is a unique bioinformatics and cheminformatics resource that combines detailed drug (i.e. chemical, pharmacological and pharmaceutical) data with comprehensive drug target (i.e. sequence, structure, and pathway) information.
Explanation Creative Common's Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/legalcode)

CAS No.

72559-06-9
Record name Rifabutin [USAN:USP:INN:BAN:JAN]
Source ChemIDplus
URL https://pubchem.ncbi.nlm.nih.gov/substance/?source=chemidplus&sourceid=0072559069
Description ChemIDplus is a free, web search system that provides access to the structure and nomenclature authority files used for the identification of chemical substances cited in National Library of Medicine (NLM) databases, including the TOXNET system.
Record name Rifabutin
Source DrugBank
URL https://www.drugbank.ca/drugs/DB00615
Description The DrugBank database is a unique bioinformatics and cheminformatics resource that combines detailed drug (i.e. chemical, pharmacological and pharmaceutical) data with comprehensive drug target (i.e. sequence, structure, and pathway) information.
Explanation Creative Common's Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/legalcode)

Retrosynthesis Analysis

AI-Powered Synthesis Planning: Our tool employs the Template_relevance Pistachio, Template_relevance Bkms_metabolic, Template_relevance Pistachio_ringbreaker, Template_relevance Reaxys, Template_relevance Reaxys_biocatalysis model, leveraging a vast database of chemical reactions to predict feasible synthetic routes.

One-Step Synthesis Focus: Specifically designed for one-step synthesis, it provides concise and direct routes for your target compounds, streamlining the synthesis process.

Accurate Predictions: Utilizing the extensive PISTACHIO, BKMS_METABOLIC, PISTACHIO_RINGBREAKER, REAXYS, REAXYS_BIOCATALYSIS database, our tool offers high-accuracy predictions, reflecting the latest in chemical research and data.

Strategy Settings

Precursor scoring Relevance Heuristic
Min. plausibility 0.01
Model Template_relevance
Template Set Pistachio/Bkms_metabolic/Pistachio_ringbreaker/Reaxys/Reaxys_biocatalysis
Top-N result to add to graph 6

Feasible Synthetic Routes

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Q & A

A: [] Rifabutin, similar to Rifampicin, acts by inhibiting the bacterial DNA-dependent RNA polymerase, specifically targeting the beta subunit (rpoB) of the enzyme. This inhibition effectively blocks the initiation of RNA synthesis, ultimately leading to bacterial cell death.

ANone: this compound has the molecular formula C46H56N4O11 and a molecular weight of 849.0 g/mol.

A: While the provided research does not include specific spectroscopic data, techniques like nuclear magnetic resonance (NMR) spectroscopy and mass spectrometry have been used to characterize this compound and its metabolites in various studies. []

ANone: The provided research primarily focuses on the pharmacological and pharmacokinetic aspects of this compound. Information regarding its material compatibility with various substances is limited within these studies.

ANone: this compound is primarily known for its antimicrobial properties and is not reported to exhibit significant catalytic activity. Its primary mode of action involves binding to a specific target protein rather than catalyzing chemical reactions.

ANone: While the provided research does not detail specific computational studies, techniques like quantitative structure-activity relationship (QSAR) modeling could be employed to explore the relationship between this compound's structure and its biological activity.

A: [] Structural modifications, particularly around the rifamycin core structure, are known to influence this compound's activity, potency, and selectivity. For example, modifications influencing the interaction with the rpoB binding site can significantly impact its ability to inhibit bacterial RNA polymerase.

A: [] this compound exhibits stability challenges and can degrade under various conditions, potentially affecting its efficacy. Formulation strategies are crucial to enhance its stability, solubility, and bioavailability.

ANone: The provided research primarily focuses on the clinical and pharmacological aspects of this compound. Detailed information regarding SHE regulations and compliance requirements would necessitate consulting relevant regulatory guidelines and agencies.

A: [, ] this compound exhibits low oral bioavailability due to significant first-pass metabolism. It is extensively metabolized, primarily by CYP3A4 enzymes in the liver and intestines. The major active metabolite, 25-O-Desacetyl-Rifabutin, contributes to its antimicrobial activity. this compound is excreted in both urine and feces.

A: [, ] this compound has demonstrated clinical efficacy in preventing and treating Mycobacterium avium complex (MAC) infections, especially in individuals with HIV. Its efficacy against other mycobacterial species and in specific patient populations, like children, is being actively researched. [, ]

A: [, ] In vitro susceptibility testing, typically using broth microdilution methods, is commonly employed to determine the minimum inhibitory concentration (MIC) of this compound against various mycobacterial strains.

A: [] Mouse models, particularly the beige mouse model, have been utilized to evaluate the in vivo activity of this compound against disseminated MAC infection. These models help assess the efficacy of different doses and treatment regimens.

A: [, ] Yes, several clinical trials have evaluated this compound's safety and efficacy for preventing and treating mycobacterial infections, notably in individuals with HIV.

A: [, ] Resistance to this compound primarily arises from mutations in the rpoB gene, encoding the beta subunit of RNA polymerase, the drug's target. These mutations often alter the drug's binding site, reducing its efficacy.

A: [, ] Cross-resistance, particularly with Rifampicin, is a significant concern. Mutations in the rpoB gene can confer resistance to both drugs, limiting treatment options, especially for multidrug-resistant tuberculosis.

ANone: While the provided research does not detail specific drug delivery approaches for this compound, research into targeted delivery strategies, such as liposomal formulations or nanoparticle-based systems, could be explored to enhance its efficacy and potentially minimize side effects.

A: [] While therapeutic drug monitoring of this compound levels is not routinely performed, measuring plasma concentrations could be beneficial in specific clinical situations, such as suspected drug interactions or treatment failures.

A: [] High-performance liquid chromatography (HPLC), often coupled with UV detection or mass spectrometry, is a common method for quantifying this compound and its metabolites in biological matrices like plasma and urine.

ANone: The provided research focuses primarily on the clinical aspects of this compound. Information regarding its environmental fate, persistence, and potential ecotoxicological effects is limited within these studies and would require further investigation.

A: [, ] this compound exhibits limited aqueous solubility, which can affect its dissolution rate and, consequently, its bioavailability. Formulation strategies are crucial to address these challenges and improve its therapeutic efficacy.

A: [] Validation of analytical methods for this compound involves establishing and documenting method performance characteristics such as accuracy, precision, specificity, linearity, range, limit of detection (LOD), and limit of quantification (LOQ). These parameters ensure the reliability and reproducibility of the analytical data.

ANone: The provided research primarily focuses on this compound's antimicrobial activity and pharmacokinetic properties. Information regarding its potential to induce an immune response or elicit hypersensitivity reactions is limited within these studies.

ANone: While the provided research does not extensively explore this compound's interactions with drug transporters, further investigation into its potential to interact with efflux transporters, like P-glycoprotein (P-gp), is warranted. Such interactions could impact its absorption and distribution within the body.

A: [, ] Yes, this compound is known to induce the activity of specific drug-metabolizing enzymes, particularly CYP3A4. This induction can lead to increased metabolism and reduced plasma concentrations of co-administered drugs that are substrates of these enzymes.

ANone: While this compound is used clinically, suggesting a degree of biocompatibility, the provided research primarily focuses on its antimicrobial activity and pharmacokinetic properties. Detailed information regarding its biocompatibility profile and potential for biodegradation is limited within these studies and would require further investigation.

A: [, ] Alternatives to this compound include Rifampicin (although cross-resistance is a concern), macrolides like Clarithromycin and Azithromycin, and fluoroquinolones like Moxifloxacin. The choice of treatment depends on the specific mycobacterial species, drug susceptibility patterns, patient-specific factors, and potential drug interactions.

ANone: The provided research primarily focuses on the clinical aspects of this compound. Information regarding specific guidelines for its disposal and waste management practices is limited within these studies and would necessitate consulting relevant regulatory guidelines and local regulations.

A: [, ] Key milestones include its initial development as a rifamycin derivative, recognition of its activity against MAC, approval for the prevention of disseminated MAC in individuals with HIV, and exploration of its use in combination therapies for various mycobacterial infections.

A: [] this compound research benefits from the contributions of various disciplines, including microbiology, pharmacology, medicinal chemistry, pharmaceutics, and clinical medicine. Understanding its mechanism of action, resistance mechanisms, pharmacokinetic properties, formulation strategies, and clinical efficacy requires a multidisciplinary approach.

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