title: Lipophilic pyrazinoic acid amide and ester prodrugs stability, activation and activity against M. tuberculosis.
abstract: Pyrazinamide (PZA) is active against M. tuberculosis and is a first line agent for the treatment of human tuberculosis. PZA is itself a prodrug that requires activation by a pyrazinamidase to form its active metabolite pyrazinoic acid (POA). Since the specificity of cleavage is dependent on a single bacterial enzyme, resistance to PZA is often found in tuberculosis patients. Esters of POA have been proposed in the past as alternatives to PZA however the most promising compounds were rapidly degraded in the presence of serum. In order to obtain compounds that could survive during the transport phase, we synthesized lipophilic ester and amide POA derivatives, studied their activity against M. tuberculosis, their stability in plasma and rat liver homogenate and also their activation by a mycobacterial homogenate. The new lipophilic ester prodrugs were found to be active in concentrations 10-fold lower than those needed for PZA to kill sensitive M. tuberculosis and also have a suitable stability in the presence of plasma. Amides of POA although more stable in plasma have lower activity. The reason can probably be found in the rate of activation of both types of prodrugs; while esters are easily activated by mycobacterial esterases, amides are resistant to activation and are not transformed into POA at a suitable rate.
authors.affiliation: iMed.UL, Faculty of Pharmacy, University of Lisbon, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal.
authors.forename: Marta Filipa
authors.initials: MF
authors.lastname: Simões
authors.forename: Emília
authors.initials: E
authors.lastname: Valente
authors.forename: M José Rodríguez
authors.initials: MJ
authors.lastname: Gómez
authors.forename: Elsa
authors.initials: E
authors.lastname: Anes
authors.forename: Luís
authors.initials: L
authors.lastname: Constantino
mesh_terms: D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000995:Antitubercular Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D002021:Buffers; D002460:Cell Line; D002851:Chromatography, High Pressure Liquid; D004355:Drug Stability; D004952:Esters / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D006868:Hydrolysis; D066298:In Vitro Techniques; D007202:Indicators and Reagents; D008055:Lipids / Q000737:chemistry; D008099:Liver / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects; D008826:Microbial Sensitivity Tests; D020102:Mycobacterium smegmatis / Q000187:drug effects; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000201:enzymology; D010587:Phagocytosis / Q000187:drug effects; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry*; D011718:Pyrazinamide / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D012995:Solubility; D012996:Solutions; D013056:Spectrophotometry, Ultraviolet
chemical_list: D000577:Amides; D000995:Antitubercular Agents; D002021:Buffers; D004952:Esters; D007202:Indicators and Reagents; D008055:Lipids; D011355:Prodrugs; D012996:Solutions; D011718:Pyrazinamide; C005296:pyrazinoic acid