Paromomycin derivatives

Recently, Tor and co-workers have analysed the interaction between the cyclic analog 2 and the corresponding paromomycin derivative with the A-site sequence and also with the HIV TAR RNA fragment [47]. At pH 7.5, the decrease in affinity for the locked derivatives with respect to the parent aminoglycosides is 22-14 fold for the A-site and 11-2 fold for the HIV TAR sequence. The differences with respect to the natural ligands are significantly reduced at acid pH. 

Derivatives Containing a 4,5-Disubstituted-2-deoxystreptamine Moiety. The first of this subclass to be isolated were the neomycins (B (9) and C), followed by paromomycin I [7542-37-2] 023114 X 024, and paromomycin 11 [51795-47-2] C23II43X3O24. The paromomycins are... 

G. lamblia is treated with 5-nitroimidazole derivates. Paromomycin is a second choice in specific circumstances (e.g. pregnancy). In a Cochrane review, where 34 trials were included and where only one trial was without significant methodological flaws, the authors concluded that a single dose of tinidazole can provide the highest clinical cure rate with relatively few adverse effects. The high recun ence rate of disease after initial diug therapy is a problem. 

Commercial neomycin is a complex mixture of aminoglycoside antibiotics originally isolated from a culture of Stn.tptomyc.zi, ( n.adiaz by Waksman and his co-workers in 1949. The principle components of the mixture are neomycin B(I) and neomycin C(II) together with a small quantity of neaminel, a degradation product of neomycin formerly known as neomycin A. Table 1 shows the content variability of neomycin B and C and neamine in commercial samples of neomycin as reported in the literature. Neomycins LP-A, LP-B and LP-C which chemically are the mono N-acetyl derivatives of neomycins A, B and C may also be present in small amounts. Several other minor components have recently been identified as paromamine, paromomycin I and paromomycin II. (Also known as neomycins D, E and F respectively). 

Fig. 10 a MD-tar ensembles of conformers for 2-4. The experimental ensemble corresponding to 1 in the free state (reft) is shown for comparison, b Structures representative of the main conformational families present in solution for neomycin-B derivatives 2 (left) and 3 (right) superimposed on the X-Ray structure of paromomycin in the complex with ribosomal RNA, according to X-Ray data. The maximum 4>/ U deviations (for each glycosidic linkage) is shown. Unit IV is omitted for simplicity... 

Hepatic foetor The sweet aromatic smell of the exhaled breath (mercaptan derivatives) is accepted as a reliable sign of acute liver failure, but it is not always present. The administration of poorly absorbable antibiotics (e.g. paromomycin) usually improves the condition of hepatic foetor or even eliminates it temporarily, (s. pp 87, 267)... 

The 4-0-glucosamine unit of paromomycin was replaced with glucose, mannose and galactose, with only the glucosyl derivative retaining activity. ... 

Two pseudopentasaccharides, lividomycin A and mannosylparomomycin, and 4" -0-a-D-mannopyranosyl-substituted derivatives of lividomycin B (27) and paromomycin I (25), respectively. They are produced by the same organism that produces... 

Wong and coworkers in a recent investigation [163] studied the A-site-binding aminoglycosides, including the 4,5-disubstituted 2-deoxystreptamine derivatives (neomycin B, paromomycin, and ribostamycin) and the 4,6-disubstituted 2-deoxystrep-... 

Diazotization by sodium nitrite in a dilute solution of sulfuric acid has been used to convert amino groups of neomycin B at the 6 - and 6" -positions to a hydroxyl group to make paromomycin 1 (120), the 6" -deamino-6" -hydroxyparomomycin 1 (121), and the 6" -deamino-6" -hydroxyneomycin B (122). These compounds were found to be less active than the parent antibiotic, particularly the tetra-amino derivative 121, which was the least active compound, showing about one-tenth the activity of penta-amino derivative 120 or 122 (compounds 120-122 ). These results indicated... 

A mass-spectrometric investigation of the antibiotics Paromomycin and Paromomycin II as their per(trimethylsilyl) derivatives has been made. A molecular ion was found in these tetrasaccharides containing amino sugars. The A-series of fragments was found to establish the sequence of the monosaccharide residues in the oligosaccharide. Essentially the same technique was used in a study of antibiotics from Streptomyces fradiae these were found to be tetrasaccharides containing an amino-deoxycyditol residue. " ... 

Neomycins, Paromomycins, Lividomycins. Although the tetra- and pen-tacyclic aminoglycosides have been known for some time (neomycin 1949, paromomycin 1959, lividomycin 1967), only a few chemical modifications have been carried out. Not until after the discovery of the enzymatic inactivation mechanisms were several deoxy compounds and acylated derivatives (HABA, etc.) prepared. 

The poly-N-alkyl- and hexa-N-acyl derivatives of neomycin and paromomycin fail to show activity, but the hexa-N-methane-sulfonates and -sulfina-tes are claimed to be active and less toxic. 6 - and 6" -N alkyl- and N-alkylaryl-neomycins and -paromomycins have been prepared from the Schiffs bases by reduction with NaBH4 Some of the alkylaryl compounds show a slightly improved activity the alkyl derivatives are ineffective. The hexa-N-benzylneomydns prepared from neomycin, aromatic aldehydes and NaBH4, as well as the corresponding paromomycins, synthesized by means of catalytic reduction of the Schiffs bases, have reduced antibacterial activity. The Schiffs bases of paromomycin show in vitro the same activity as the parent compoimd, obviously because of the ease of hydrolysis. 

The controlled synthesis of 2 -N-aralkylparomomycin succeeded through the conversion of paromomycin to the l,3,2", 6" -tetra-N-acetyl derivative, followed by reaction with an aldehyde and reduction of the resulting Schiffs base with NaBH4 >. 

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