JAC Advance Access published online on December 19, 2003
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkh041
© 2003 by The British Society for Antimicrobial Chemotherapy
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Original article
1 Department of Chemistry,
Wellesley College, 106 Central Street, Wellesley, MA 02481;
* Corresponding author. E-mail: MHearn{at}Wellesley.edu.
Received 22 July 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
Design and synthesis of antituberculars: preparation
and evaluation against Mycobacterium tuberculosis of
an isoniazid Schiff base
2 Department of Microbiology and
Immunology, Upstate Medical University, State University of New
York,
Syracuse, New York; Department
of Medicine, Veterans Affairs Medical Center, Syracuse, New York,
USA
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