European Journal of Medicinal Chemistry 2009-10-01

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

Michael J Hearn, 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

Index: Eur. J. Med. Chem. 44 , 4169-78, (2009)

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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.