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 drawbacks, amides of glycine ethyl ester and the methyl esters of alanine, phenylalanine, leucine, isoleucine and valine, 2(a-f), were synthesized as prodrugs. The stability of the prepared prodrugs in pH 1.2, 7.4 and 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 nalidixic acid amides of the amino acids as intermediates. The second step was the hydrolysis of these intermediates to 1 and the corresponding amino 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 lipophilicity) and increase in the percentage bound of phenylalanine, leucine and isoleucine derivatives (of high lipophilicity). Lower binding potency and higher lipophilicity was observed in the case of valine derivative, that was suggested to be owed to some steric hindrance with the binding sites.
Aboul-Fadl
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Department of Pharmaceutical Medicinal Chemistry, Assiut University, Egypt.
Fouad
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EA
D000577:Amides / Q000097:blood / Q000737:chemistry; D000596:Amino Acids / Q000097:blood / Q000737:chemistry*; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D004952:Esters / Q000097:blood / Q000737:chemistry; D006801:Humans; D006868:Hydrolysis; D007700:Kinetics; D009268:Nalidixic Acid / Q000097:blood / Q000138:chemical synthesis* / Q000737:chemistry; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry; D011485:Protein Binding; D012710:Serum Albumin, Bovine / Q000378:metabolism
D000577:Amides; D000596:Amino Acids; D004952:Esters; D011355:Prodrugs; D012710:Serum Albumin, Bovine; D009268:Nalidixic Acid