Synthesis, characterization and in-vitro antitubercular activity of isoniazid-gelatin conjugate

• Published in: Journal of pharmacy and pharmacology Vol. 64; no. 5; p. 712
• Main Authors: Cassano, Roberta, Trombino, Sonia, Ferrarelli, Teresa, Cavalcanti, Paolina, Giraldi, Cristina, Lai, Francesco, Loy, Giuseppe, Picci, Nevio
• Format: Journal Article
• Language: English
• Published: England 01.05.2012
• Subjects: Antitubercular Agents - administration & dosage; Antitubercular Agents - pharmacology; Chemistry, Pharmaceutical; Gelatin; Isoniazid - administration & dosage; Isoniazid - pharmacology; Mycobacterium tuberculosis - drug effects; Prodrugs - chemical synthesis; Prodrugs - pharmacology; Solid-Phase Synthesis Techniques - methods
• ISSN: 2042-7158
• DOI: 10.1111/j.2042-7158.2012.01461.x

A novel and simple method to synthesize antitubercular-protein conjugate by solid phase synthesis was developed employing a carboxypolystyrene resin. The aim was to covalently bind a drug with antitubercular activity, isoniazid, to a biomacromolecule, gelatin, widely used in the pharmaceutical, cosmetic and food industry. Calorimetric and (1) H NMR analyses were performed to verify the bond formation between the antitubercular drug and gelatin. After absorption isoniazid delivers toxic metabolites and so an oxidation test with tert-butyl hydroperoxide was performed to assess the amount of toxic metabolites released from the prodrug (gelatin linked to isoniazid), compared with isoniazid itself.   Spectrophotometric analysis revealed that the protein derivative was an excellent isoniazid prodrug since there was a 40% reduction in release of toxic metabolites (isonicotinic acid) by the prodrug. The results clearly showed that antitubercular moieties, covalently linked to a natural polymer, allowed the introduction of peculiar features for specific pharmaceutical applications into the macromolecule. In addition, antitubercular activity of the new polymer was determined by Middlebrook 7H11 medium against Mycobacterium tuberculosis complex. The new isoniazid-gelatin conjugate showed significant antitubercular activity and for this reason should be useful as an efficacious tool in the treatment of tuberculosis.