Biomaterial Database

Synthesis and in vitro investigations of nalidixic acid amides of amino acid esters as prodrugs. 1996

T Aboul-Fadl, and E A Fouad

Department of Pharmaceutical Medicinal Chemistry, Assiut University, Egypt.

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.

UI	MeSH Term	Description	Entries
D007700	Kinetics	The rate dynamics in chemical or physical systems.
D009268	Nalidixic Acid	A synthetic 1,8-naphthyridine antimicrobial agent with a limited bacteriocidal spectrum. It is an inhibitor of the A subunit of bacterial DNA GYRASE.	Nalidixin,Nalidixate Sodium,Nalidixate Sodium Anhydrous,Nevigramon,Sodium Nalidixic Acid, Anhydrous,Sodium Nalidixic Acid, Monohydrate,Acid, Nalidixic,Anhydrous, Nalidixate Sodium,Sodium Anhydrous, Nalidixate,Sodium, Nalidixate
D011355	Prodrugs	A compound that, on administration, must undergo chemical conversion by metabolic processes before becoming the pharmacologically active drug for which it is a prodrug.	Drug Precursor,Drug Precursors,Pro-Drug,Prodrug,Pro-Drugs,Precursor, Drug,Precursors, Drug,Pro Drug,Pro Drugs
D011485	Protein Binding	The process in which substances, either endogenous or exogenous, bind to proteins, peptides, enzymes, protein precursors, or allied compounds. Specific protein-binding measures are often used as assays in diagnostic assessments.	Plasma Protein Binding Capacity,Binding, Protein
D002627	Chemistry, Physical	The study of CHEMICAL PHENOMENA and processes in terms of the underlying PHYSICAL PHENOMENA and processes.	Physical Chemistry,Chemistries, Physical,Physical Chemistries
D004952	Esters	Compounds derived from organic or inorganic acids in which at least one hydroxyl group is replaced by an –O-alkyl or another organic group. They can be represented by the structure formula RCOOR’ and are usually formed by the reaction between an acid and an alcohol with elimination of water.	Ester
D006801	Humans	Members of the species Homo sapiens.	Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D006868	Hydrolysis	The process of cleaving a chemical compound by the addition of a molecule of water.
D000577	Amides	Organic compounds containing the -CO-NH2 radical. Amides are derived from acids by replacement of -OH by -NH2 or from ammonia by the replacement of H by an acyl group. (From Grant & Hackh's Chemical Dictionary, 5th ed)	Amide
D000596	Amino Acids	Organic compounds that generally contain an amino (-NH2) and a carboxyl (-COOH) group. Twenty alpha-amino acids are the subunits which are polymerized to form proteins.	Amino Acid,Acid, Amino,Acids, Amino