Mode of action and quantitative structure-activity correlations of tuberculostatic drugs of the isonicotinic acid hydrazide type

• Published in: Journal of medicinal chemistry 1976-04, Vol.19 (4), p.483-492
• Main Authors: Seydel, Joachim K, Schaper, Klaus J, Wempe, Ellen, Cordes, Hans P
• Format: Article
• Language: English
• Subjects: Antitubercular Agents - chemical synthesis; Antitubercular Agents - pharmacology; Isoniazid - analogs & derivatives; Isoniazid - chemical synthesis; Isoniazid - pharmacology; Kinetics; Microbial Sensitivity Tests; Mycobacterium tuberculosis - drug effects; Regression Analysis; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00226a007

Quantitative structure-activity studies have been performed for a series of 2-substituted isonicotinic acid hydrazides by correlating electronic, steric, and lipophilic properties of the substituents with the biological activity date (MIC) from serial dilution tests with Mycobacterium tuberculosis (strain H 37 Rv). The reaction rates for the quaternization of 2-substituted pyridines with methyl iodide were also determined. The rate constants show a similar dependence on the steric and electronic effects of the substituents as the antibacterial activities of the corresponding pyridine-4-carboxylic acid hydrazides. The obtained correlations give evidence that the reactivity of the pyridine nitrogen atom is essential for the biological activity of 2-substituted isonicotinic acid hydrazides and seem to support the hypothesis that isonicotinic acid derivatives are incorporated into an NAD analogue.