1. Preparation and antitubercular activities in vitro and in vivo of novel Schiff bases of isoniazid.
- Author
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Hearn MJ, Cynamon MH, Chen MF, Coppins R, Davis J, Joo-On Kang H, Noble A, Tu-Sekine B, Terrot MS, Trombino D, Thai M, Webster ER, and Wilson R
- Subjects
- Animals, Antitubercular Agents pharmacology, Female, Isoniazid analogs & derivatives, Isoniazid pharmacology, Macrophages drug effects, Macrophages microbiology, Mice, Mice, Inbred C57BL, Microbial Sensitivity Tests, Structure-Activity Relationship, Antitubercular Agents chemistry, Antitubercular Agents therapeutic use, Isoniazid chemistry, Isoniazid therapeutic use, Mycobacterium tuberculosis drug effects, Schiff Bases chemistry, Tuberculosis drug therapy
- Abstract
Structural modification of the frontline antitubercular isonicotinic acid hydrazide (INH) provides lipophilic adaptations (3-46) of the drug in which the hydrazine moiety of the parent compound has been chemically blocked from the deactivating process of N(2)-acetylation by N-arylaminoacetyl transferases. As a class, these compounds show high levels of activity against Mycobacterium tuberculosis in vitro and in tuberculosis-infected macrophages. They provide strong protection in tuberculosis-infected mice and have low toxicity. With some representatives of this class achieving early peak plasma concentrations approximately three orders of magnitude above minimum inhibitory concentration, they may serve as tools for improving our understanding of INH-based treatment modalities, particularly for those patients chronically underdosed in conventional INH therapy.
- Published
- 2009
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