Ethambutol synthesis

Because they are similar, the aLkanolamines often can be used interchangeably. However, cost/perfomiance considerations generally dictate a best choice for specific appHcations. AMPD is manufactured in very low volumes for use as a reagent in certain medical diagnostic tests, although some is used in certain cosmetic products. 2-Ainino-1-butanol is used primarily as a taw material for the synthesis of ethambutol [74-55-5] an antituberculosis dmg. The first step in the synthesis of this dmg is the resolution of AB into its optical isomers because only (i)-2-amino-l-butanol, [5856-62-2] is utilized in this synthesis. 

Bacterial cell wall j3-Lactams Glyoopeptides Cycloserine Isoniazid Ethambutol Inhibit peptidoglycan synthesis Inhibit peptidoglycan synthesis Inhibits peptidoglycan synthesis Inhibits mycolic acid synthesis Inhibits arabinogalactan synthesis None in mammalian cells None in mammalian cells None in mammalian cells None in mammalian cells None in mammalian cells... 

Mutations resulting in ethambutol resistance can arise spontaneously. The exact changes are unknown but may involve enzymes in carbohydrate synthesis pathways. 

An alternative method of synthesis consists of preparing (+) 2-aminobutanol (34.1.3) by redncing ethyl ester of L-2-aminobutyric acid hydrochloride with hydrogen nsing simnlta-neonsly Raney nickel and platinum oxide catalysts. This gives pure (+) 2-aminobutanol. Reacting this with 1,2-dichloroethane in the presence of sodium hydroxide gives the desired ethambutol (34.1.4) [16,17]. 

Pharmacology Ethambutol diffuses into actively growing mycobacterium cells such as tubercle bacilli. It inhibits the synthesis of at least 1 metabolite, thus causing impairment of cell metabolism, arrest of multiplication, and cell death. No cross-resistance with other agents has been demonstrated. 

Ethambutol is a synthetic agent and not related to any of the other tuberculostatics. Its mechanism of action is not well understood but in actively dividing mycobacteria it appears to be an inhibitor of mycobacterial RNA synthesis. It also has effects on bacterial phosphate metabolism and on polyamine synthesis. It is an bacteriostatic agent and its main function in combination therapy is to delay the occurrence of resistance, mainly against isoniazid and rifampicin. It is well absorbed after oral administration. It is widely distributed, except to the CNS. Protein binding is about 20-30%. It is mainly excreted unchanged in the bile and urine with an elimination half-life of 3 h. Ethambutol is concentrated in erythrocytes and thus provides a depot for continuous release. 

Ethambutol is a water-soluble, heat-stable compound that acts by inhibition of arabinosyl transferase enzymes that are involved in cell wall biosynthesis. Nearly all strains of M tuberculosis and M. kansasii and most strains of Mycobacterium avium-intracellulare are sensitive to ethambutol. Drug resistance relates to point mutations in the gene (EmbB) that encodes the arabinosyl transferases that are involved in mycobacterial cell wall synthesis. 

DNA synthesis inhibitors Fluoroquinolones Antimycobacterials Isoniazid Rifampin Ethambutol Pyrizinamide Streptomycin... 

The mechanism of ethambutol (Myambutol) is not fully understood. This drug apparently suppresses RNA synthesis in susceptible bacteria, but it is not known how this occurs. Ethambutol is primarily effective against M. tuberculosis infections and is a secondary agent in the treatment of tuberculosis.61 Adverse effects associated with this drug include joint pain, nausea, skin rash and itching, and CNS abnormalities (dizziness, confusion, hallucinations). 

B. Blessington and A. Beiraghi, Study of thesterochemistry of ethambutol using chiral liquid chromatography and synthesis, /. Chromatogr., 522 195 (1990). 

The synthetic application of the a-chloro aldehydes has been demonstrated by the preparation of a variety of important chiral building blocks (Scheme 2.35) [26b]. The a-chloro aldehydes could be reduced to the corresponding optically active a-chloro alcohols in more than 90% yield, maintaining the enantiomeric excess by using NaBFU. It was also shown that optically active 2-aminobutanol - a key intermediate in the synthesis of the tuberculostatic, ethambutol - could be obtained in high yields by standard transformations from 2-chlorobutanol. Furthermore, the synthesis of an optically active terminal epoxide was demonstrated. The 2-chloro aldehydes could also be oxidized to a-chloro carboxylic acids in high yields without loss of optical purity, and further transformations were also presented. 

Ethambutol Mutation of target enzyme involved in arabinogalactan synthesis... 

The Sn2 reaction is a key step in the laboratory synthesis of many drugs including ethambutol (trade name Myambutol), used in the treatment of tuberculosis, and fluoxetine (trade name Prozac), an antidepressant, as illustrated in Figure 7.13. 

Underexcretion of urate is caused by all diuretics (except spironolactone), aspirin, ethambutol, pyr-azinamide, nicotinic acid, and alcohol (which increases urate synthesis and also causes a rise in blood lactic acid that inhibits tubular secretion of urate). The diagnosis of gout ideally requires the demonstration of negatively birefringent needle-shaped crystals in synovial fluid (monosodium urate monohydrate crystals), not just elevated serum urate. 

Several currently used TB drugs target the biosynthesis of the unique mycobacterial cell wall structures (O Fig. 23). Ethambutol is an arabinosyltransferase inhibitor [305], and mycolic acid synthesis is targeted by several commonly used antituberculosis drugs, including isoniazid, ethionamide, isoxyl, thiolactomycin, and triclosan. In addition, pyrazinamide was shown to inhibit the s)mthesis of mycolic acid precursors [306]. 

Ethambutol i Inhibits synthesis of arabinogalactan (cell-wall component) Dose-dependent retrobulbar neuritis visual acuity and red-green discrimination... 

Mechanisms Ethambutol inhibits arabinosyl transferases (encoded by the emhCAB operon) involved in the synthesis of arabinogalactan, a component of mycobacterial cell walls. Resistance occurs rapidly via mutations in the emb gene if the drug is used alone. 

Ethambutol Inhibits mycolic acid synthesis in bacterial cell wall (mechanism not confirmed) Reversible retrobulbar neuritis. Loss of central vision. Patients must have ophthalmogic exam prior to treatment to determine baseline vision. PO. Wide distribution. Reaches 50% concentration in CNS. Concentrated in tubercles. 

The a-aminoxylation of aldehydes has been successfully applied by different groups to the synthesis of biologically important compounds such as (+)-strictifo-lione [21], brasoside and littoralisone [22], ethambutol [23], levetiracetam [24], halipeptin A [25], brevicomin [26], linezolid [27], (+)-harzialactone A [28], tarchonanthuslactone [29], (+)-neosymbioimine [30], propranolol [31], thysanone [32], and (-l-)-disparlure [33]. 

An improved synthesis of mefloquine has been advanced [149]. Also the asymmetric total synthesis of the (+)-enantiomer of mefloquine hydrochloride has been described [150]. Modifications of mefloquine aimed at development of novel biologically active compounds, including antituberculosis drugs, have extensively been performed (Scheme 92) [ 151 ]. Compounds 215,216 were more active than mefloquine against M. tuberculosis (MIC 11.9-33 pM), some of derivatives have a better tuberculostatic activity than the first line tnbercnlostatic agent ethambutol (MIC = 15.9) [151]. 

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