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. 2009 Oct;44(10):4169-78.
doi: 10.1016/j.ejmech.2009.05.009. Epub 2009 May 21.

Preparation and antitubercular activities in vitro and in vivo of novel Schiff bases of isoniazid

Michael J Hearn  1 , Michael H Cynamon, Michaeline F Chen, Rebecca Coppins, Jessica Davis, Helen Joo-On Kang, Abigail Noble, Becky Tu-Sekine, Marianne S Terrot, Daniella Trombino, Minh Thai, Eleanor R Webster, Rebecca Wilson
Affiliations

Preparation and antitubercular activities in vitro and in vivo of novel Schiff bases of isoniazid

Michael J Hearn et al. Eur J Med Chem. 2009 Oct.

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.

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Figures

Figure 1
Figure 1
The antitubercular isonicotinic acid hydrazide (1) and its Schiff base congeners (2). Position N2 of 1 is subject to deactivating acetylation by the class of enzymes known as N-arylaminoacetyl transferases (NATs). The deactivation phenomenon is associated with the rise of resistance. Compounds 2 are blocked towards this enzymatic process.
Figure 2
Figure 2
Preparation of Schiff bases from carbonyl precursors.
Figure 3
Figure 3
With alkyl groups larger than methyl in the ketone component, nucleophilic attack by the hydrazide moiety is hindered.
Figure 4
Figure 4
Bar graph depicting the relative lipophilicities of INH and its Schiff bases of benzaldehyde, citronellal and tridecanal.
See this image and copyright information in PMC

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