Isoniazid is Not a Lead Compound for its Pyridyl Ring Derivatives,Isonicotinoyl Amides, Hydrazides, and Hydrazones: A Critical Review

Author(s): T. Scior, S. J. Garces-Eisele.

Journal Name: Current Medicinal Chemistry

Volume 13 , Issue 18 , 2006

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Abstract:

The relationships between structure, disintegration and antituberculotic in vitro activity were studied for over 200 derivatives of isonicotinic acid hydrazide (isoniazid, INH). Conclusive evidence reflects that many compounds do not withstand the in vitro conditions. A pH dependant partial hydrolysis to INH occurs in the case of hydrazones, in analogy to well-known benzoic acid esters. Hydrazides and amides are cleaved into isonicotinic acid. In general, antimycobacterial potencies drop against INH except for two outliers probably with additional unspecific toxicity of their residues. Analyzing the complexity and heterogeneity of molecular events, trends linked to hydrolysis are found when structural features are clustered. Hammett sigma constants correlate to pKα values possessing a twofold descriptive meaning: (i) the cardinal increase of partial positive charge of the reaction center towards nucleophilic water attack and (ii) the ionization crucial for mycobacterial cell permeation through porins or lipid barriers. We review the literature concluding that many so-called "novel leads" are nothing else than precursors of an INH-based scaffold. In addition, INH ringsubstitution or analogous backbones never achieve the efficiency of INH, itself a prodrug, which accumulates in Mycobacterium tuberculosis in form of its intrabacterial active principle(s) to which it is an optimal transport vehicle, evidencing that INH is not a promising lead compound at all.

Keywords: Hydrazones, Hydrazides, Hydrolysis, Isoniazid, Mycobacterium, Tuberculosis, QSAR

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Article Details

VOLUME: 13
ISSUE: 18
Year: 2006
Page: [2205 - 2219]
Pages: 15
DOI: 10.2174/092986706777935249
Price: $58

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