title: Lipophilic N-acylpyrazinamide derivatives: synthesis, physicochemical characterization, liposome incorporation, and in vitro activity against Mycobacterium avium-intracellulare.
abstract: N-acetyl-(2), N-caproyl-(3), N-capryl-(4) and N-palmitoyl-pyrazinamide (5) were synthesized by reacting pyrazinamide (1) with acetic anhydride to prepare (2), or by reacting (1) in chloroform with the corresponding acid chlorides to prepare (3-5). Products were identified by high resolution mass spectroscopy, elemental analysis, and 1H NMR. Melting points, enthalpies of fusion, solubility and octanol-water partition coefficients were determined. Hydrolysis of (2) indicated a pseudo first-order, pH-dependent degradation reaction. Apparent half life times of degradation ranged from 74.2 hours at pH 3 to 5.4 hours at pH 7.34. Derivative (5) was incorporated in liposomes consisting of soy phosphatidylcholine and dipalmitoylphosphatidylglycerol (7:3 molar ratio). The in vitro susceptibility of Mycobacterium avium-intracellulare (MAI) to the liposomal compound containing (5) was tested. MAI was susceptible to (5) at concentrations of 12.5-25 micrograms/ml, although MAI is not susceptible to the parent drug (1). Thus, a new class of antimycobacterial agents with physicochemical properties suitable for stable incorporation within liposomes and high antibiotic efficacy against MAI is presented.
authors.affiliation: Department of Pharmaceutics Drug Delivery Laboratory, University of Florida, Gainesville.
authors.forename: Z Z
authors.initials: ZZ
authors.lastname: Liu
authors.forename: X D
authors.initials: XD
authors.lastname: Guo
authors.forename: L E
authors.initials: LE
authors.lastname: Straub
authors.forename: G
authors.initials: G
authors.lastname: Erdos
authors.forename: R J
authors.initials: RJ
authors.lastname: Prankerd
authors.forename: R J
authors.initials: RJ
authors.lastname: Gonzalez-Rothi
authors.forename: H
authors.initials: H
authors.lastname: Schreier
mesh_terms: D000107:Acetylation; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000995:Antitubercular Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D006801:Humans; D008081:Liposomes; D015269:Mycobacterium avium Complex / Q000187:drug effects*; D015270:Mycobacterium avium-intracellulare Infection / Q000188:drug therapy*; D011718:Pyrazinamide / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011719:Pyrazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; D000995:Antitubercular Agents; D008081:Liposomes; D011719:Pyrazines; C074305:N-palmitoylpyrazinamide; D011718:Pyrazinamide