In vitro and in vivo activities of acylated derivatives of isoniazid against mycobacterium tuberculosis.

Enzymatic acylation of the antitubercular isoniazid (INH) by N-acetyl transferases reduces the therapeutic effectiveness of the drug. Because it represents a major metabolic pathway for INH in human beings, such acetylation has serious consequences for tuberculosis treatment regimens. Among patients in whom this process is efficient, the "rapid acetylators," the resultant chronic underdosing of INH may give rise to the development of resistance, as well as inadequate therapy. Not much work has been done previously to characterize the antitubercular properties of other N2-acylisoniazids. In order to address the fundamental issue of the activities of these acylated derivatives of INH, a number of such compounds 1a-f were chemically synthesized for investigation by a method providing good yield and purity. In experiments in vitro against Mycobacterium tuberculosis, these compounds displayed minimum inhibitory concentration (MIC) values between several fold and several hundred fold greater than that of INH itself, on a molar basis, with some of the more active compounds having higher calculated values of log P. Among these derivatives, compound 1b, closely homologous to the INH metabolite 1a, N2-acetylisoniazid, provided unexpected protection in tuberculosis-infected mice. The authors conclude that such close structural congeners of metabolites of INH may serve as significant leads in antitubercular drug discovery and in the exploration of the mode of action of INH.