Stability of some novel thymidine, 5-bromo-2'-deoxyuridine and 3'-azido-2'-3'-dideoxythymidine analogues

In the search of new prodrugs effective against herpes simplex virus series of thymidine, 5-bromo-2'-deoxyuridine esters with amino acid and peptide chains and 3'-azido-2',3'-dideoxythymidine derivatives have been synthesized and evaluated for antiviral activity. The chemical stability of some of them containing different residues was studied at pH 1 and 7.4 and temperature of 37 degrees C. An HPLC method was developed for quantification of the unchanged ester concentration. It was proved that esters with simple aliphatic straight side chain (containing alanyl-, glycyl-, or glycyl-glycyl-glycyl-residues) are relatively stable both at acidic and neutral media, 37 degrees C. Some of them undergo negligible hydrolysis with half lifes ranging between 6 and 23 h. In contrast, more complex esters with branched side chain (valyl-), with phenyl residue (phenylalanyl-), as well as containing thiazol ring are rather unstable especially at acidic conditions and undergo rapid hydrolysis resulting in the respective chemical precursor. The stability of the former group esters outlines them as suitable candidates for prodrugs: with higher lipophilicity facilitating po absorption, satisfying chemical stability and possibility to release the active moiety following enzymatic hydrolysis.