Cycloserine

Other Infections. The slowly excreted sulfonamides (eg, sulfamethoxypyrida2ine, sulfadimethoxine) are used for treatment of minor infections such as sinusitis or otitis, or for prolonged maintenance therapy. Soluble sulfonamides are sometimes used for proto2oal infections in combination with other agents. Pyrimethamine, combined with sulfonamides, has been used for toxoplasmosis or leishmaniasis, and trimethoprim with sulfonamides has been used in some types of malaria. In nocardiosis, sulfonamides have been used with cycloserine [68-41-7] (17). 

Antituberculin Agents. Rifampin [13292-46-17, a semisynthetic derivative of rifamycin SV, is a most valuable dmg for treatment of tuberculosis, an infection caused by mycobacteria, leprosy, and an expanding range of other infections (23). Cycloserine [64-41-7] has been used to a limited extent for treatment of tuberculosis as a reserve dmg. Although cycloserine inhibits bacteria by interfering with their cell wall biosynthesis, it has toxic side effects in humans in the form of neurotoxicity. Capreomycin [11003-38-6] and to a much lesser extent viomycin [32988-50-4] both of which are peptides, have also been used for treatment of this disease. 

Over 250 analogues of the B vitamers have been reported (11,100). Nearly all have low vitamin B activity and some show antagonism. Among these are the 4-deshydroxy analogue, pyridoxine 4-ethers, and 4-amino-5-hydroxymeth5i-2-methyipyrimidine, a biosynthetic precursor to thiamine. StmcturaHy unrelated antagonists include dmgs such as isoniazid, cycloserine, and penicillamine, which are known to bind to pyridoxal enzyme active sites (4). 

With 3- and 4-substituted isoxazoles the tautomeric form normally present is the XH tautomer, (13 X = O) and (14 X = O, N) respectively. However, other influences need to be considered as in cycloserine (IS), which exists as a zwitterion, as does 5-amino-3-hydroxy-isoxazole (16). 

Some products are precipitated from the fermentation broth. The insoluble calcium salts of some organic acids precipitate and are col-lec ted, and adding sulfuric acid regenerates the acid while forming gypsum (calcium sulfate) that constitutes a disposal problem. An early process for recovering the antibiotic cycloserine added silver nitrate to the fermentation broth to precipitate an insoluble silver salt. This process was soon obsolete because of poor economics and because the silver salt, when diy, exploded easily. 

The investigation of UV and IR spectra of isoxazolines has shown them to be the A -isomers. The IR spectra of isoxazolidin-3-ones were investigated in connection with the chemistry of cycloserine. ... 

Biologically, the most important compound of this series proved to be the antituberculosis antibiotic, cycloserine or 4-aminoisoxazolid-3-one (202). After this compound had been isolated and its struc-... 

At present, several syntheses of cycloserine are known, and a number of its analogs have been prepared. These investigations have been reviewed recently. ... 

SO that the necessary reactions occur at what is judged to be the best possible pace. The process is shown schematically above to for the drug fludalanine (56). In practice, the drug is combined with the 2,4-pentanedione enamine of cyc-loserine. The combination is synergistic as cycloserine in-... 

Cycle pent hi azide 1, 368 Cyclophosphamide 3, 161 Cycl opryazate 1, 5 2 Cycloserine 14 Cyclothiazide 358 Cycrimine U 47 Cyheptamide 222 Cypenamine 2, 7 Cyprazepam 7, 402 Cyproheptadine 161... 

One of the problems with cycloserine (57) as an antibacterial agent is its tendency to dimenze In an attempt to overcome this, the prodrug penti/idone (59) has been prepared The primary amino group essential for the dimenzation reacnon is reversibly blocked to prevent this Penti/idone is synthesized conveniently from cycloserine (57) by merely mixing it with acetyl acetone (58) and storing for two days to achieve the dehydration The resulting pentizidone apparently requires enzymic assistance to release cycloserine in vivo [20]... 

Cycloserine may be made by a fermentation process or by direct synthesis. The fermentation process is described in U.S. Patent 2,773,878. A fermentation medium containing the following proportions of ingredients was prepared ... 

This material was made up with distilled water to provide 41 g per liter, and the mixture was adjusted to pH 7.0 with potassium hydroxide solution. To the mixture were added per liter 5.0 g of calcium carbonate and 7.5 ml of soybean oil. 2,000 ml portions of this medium were then added to fermentation vessels, equipped with stirrers and aeration spargers, and sterilized at 121°C for 60 minutes. After cooling the flasks were inoculated with a suspension of strain No. ATCC 11924 of Streptomyces lavendulae, obtained from the surface of agar slants. The flasks were stirred for 4 days at 28°C at approximately 1,700 rpm. At the end of this period the broth was found to contain cycloserine in the amount of about 250 C.D.U./ml of broth. The mycelium was separated from the broth by filtration. The broth had a pH of about 7.5. Tests showed it to be highly active against a variety of microorganisms. 

Streptomyces kanamycetius Bekanamycin sulfate Kanamycin sulfate Streptomyces layendulae Cycloserine... 

Soybean meal, by fermentation Bacitracin Clavulanic acid Cycloserine Erythromycin Gentamicin sulfate Kanamycin sulfate Micronomicin Novobiocin Oleandomycin Oxamniquine Oxytetracycline Paromomycin Ribostamicin Sisomicin... 

Lactams Penicillins Cephalosporins Monobactams Carbapenems Vancomycin Bacitracin Cycloserin Fosfomycin Inhibition of synthesis of, or damage to, cell wall... 

D D-Cycloserin "Roche" GB Cycloserine Roche Orientmycin (Kayaku-... 

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