Pristinamycin water soluble derivatives

Until now, pristinamycin has not found more general therapeutic use because of its lack of water solubility. It was, therefore, decided to initiate a semisynthetic programme with the objective of synthesising novel water soluble derivatives of both components of pristinamycin such that a mixture of these derivatives retained all the biological properties of the natural mixture. This new association would be required for a worldwide development of this class of antibiotics. 

In oxidized pristinamycin (80) the activated double bond of the dehydro-proline residue displayed the same reactivity towards thiols. Some water soluble derivatives of (80) were prepared by this route, but they were devoid of antibacterial activity. 

Pristinamycin the major component (> 80%) of natural pristinamycin I was chosen for semi-synthetic studies. The majority of reactions described hereafter were equally applicable to semi-synthetic modifications of virginiamycin Si. One of the major targets was to find water soluble pristinamycin 1 derivatives retaining all the biological and pharmacological properties of the parent... 

Table 4. Comparison of the water solubility and antibacterial activity of pristinamycin with one of the 5y-amino 5y-desoxy pristinamycin Ia derivatives...

Both diastereomeric 26-dialkylaminoalkylsulfinyl pristinamycin lie displayed excellent antibacterial activity. Examples of this class of semi-synthetic derivatives of pristinamycin IIb were water soluble as their acid salts and were as active as the parent molecule in the in vitro tests. Due to their water solubility, they were more active than the parent compound in the in vivo tests. Table 10 gives an example of biological results for this family. 

This approach to the synthesis of the 4-dimethylaminobutyrate ester (50, R = (CH2)3NMe2) involved initial reaction of pristinamycin 11 with 4-chloro-butyroyl chloride in the presence of dimethylaniline yielding the 4-chlorobutyr-ate ester (50, R = (CH2)3C1, 32%), followed by reaction with dimethylamine in methanol at 40 °C. This did indeed provide the required semi-synthetic pristinamycin 11 derivative (50, R = (CH2)3NMe2), which was soluble in water as its hydrochloride salt, but the yield was low (5%). The use of alternative secondary amines in the final reaction did not result in any improvement in the yield. 

More than fifty 26-dialkylaminoalkyl derivatives obtained from pristinamycin IIA [130] were prepared and were soluble in water as their acid salts. They showed only slight in vitro activity, but were effective against experimental... 

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