JAC Advance Access originally published online on December 19, 2003
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Journal of Antimicrobial Chemotherapy (2004) 53, 185-191
© 2004 The British Society for Antimicrobial Chemotherapy
Design and synthesis of antituberculars: preparation and evaluation against Mycobacterium tuberculosis of an isoniazid Schiff base
1 Department of Chemistry, Wellesley College, 106 Central Street, Wellesley, MA 02481; 2 Department of Microbiology and Immunology, Upstate Medical University, State University of New York, Syracuse, New York; 3 Department of Medicine, Veterans Affairs Medical Center, Syracuse, New York, USA
Received 22 July 2003; returned 1 October 2003; revised 8 October 2003; accepted 29 October 2003
Objectives: Enzymatic acetylation of the antitubercular isoniazid (INH) by N-acetyltransferase represents a major metabolic pathway for INH in human beings. Acetylation greatly reduces the therapeutic activity of the drug, resulting in underdosing, decreased bioavailability and acquired INH resistance. Chemical modification of INH with a functional group that blocks acetylation, while maintaining strong antimycobacterial action, may improve clinical outcomes and help reduce the rise of INH resistance. The goal of this study was to probe activities, toxicity and bioavailability of an investigational compound prepared by this chemical modification.
Methods: The investigational compound was chosen from a cohort of lipophilic antitubercular INH Schiff bases based on its strong activity in primary assays. The compound was evaluated in vitro, in vivo in mice, in mutagenicity tests and in rats for bioavailability.
Results: The INH Schiff base acts against both intracellular and extracellular organisms in vitro, with a wide range between active and cytotoxic concentrations. The material is active against non-tubercular mycobacteria. The INH Schiff base is non-mutagenic in the Ames test and has excellent bioavailability in Sprague–Dawley rats, achieving early peak plasma concentrations approximately three orders of magnitude above its MIC when administered orally. In tuberculosis-infected mice the compound is well tolerated and in a 4 week study provides 3 log cfu reduction in spleens and 4 log cfu reduction in lungs.
Conclusion: The results demonstrate that investigational compounds in which N-acetylation of INH is blocked by chemical modification can display strong activity, low toxicity and excellent bioavailability, making them suitable for further exploration.
Keywords: N-acetyltransferase, fast acetylators, bioavailability, acquired resistance
* Corresponding author. Tel: +1-781-283-3036; Fax: +1-781-283-3642; E-mail: MHearn{at}Wellesley.edu