SYNTHESIS AND IN-VITRO INVESTIGATIONS OF NALIDIXIC-ACID AMIDES OF AMINO-ACID ESTERS AS PRODRUGS

For a new DDS of nalidixic acid (1) to overcome its therapeutic drawba cks, amides of glycine ethyl ester and the methyl esters of alanine, p henylalanine, leucine, isoleucine and valine, 2(a-f), were synthesized as prodrugs, The stability of the prepared prodrugs in pH 1.2, 7.4 an d 80% human plasma was investigated and showed higher stability in the buffers than in the plasma. It was noticed that the reversion of the parent drug from the synthesized prodrugs occurred through two steps, the first was hydrolysis of the ester moiety with formation of nalidix ic acid amides of the amino acids as intermediates. The second step wa s the hydrolysis of these intermediates to 1 and the corresponding ami no acid. The prodrugs showed an increase in the lipophilicity compared with 1 as indicated from the log P values. The plasma protein binding potency was studied in vitro using BSA and revealed a decrease in the percentage bound in case of glycine and alanine derivatives (of low l ipophilicity) and increase in the percentage bound of phenylalanine, l eucine and isoleucine derivatives (of high lipophilicity). Lower bindi ng potency and higher lipophilicity was observed in the case of valine derivative, that was suggested to be owed to some steric hindrance wi th the binding sites.