Lipophilic N-acylpyrazinamide derivatives: synthesis, physicochemical characterization, liposome incorporation, and in vitro activity against Mycobacterium avium-intracellulare.

: 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.