Synthesis and Investigation of Phthalazinones as Antitubercular Agents

Abstract

A series of 2- and 7-substituted phthalazinones was synthesised and their potential as anti-tubercular drugs assessed via Mycobacterium tuberculosis (mc² 6230) growth inhibition assays. All phthalazinones tested showed growth inhibitory activity (MIC <100 μm), and those compounds containing lipophilic and electron-withdrawing groups generally exhibited better anti-tubercular activity. Several lead compounds were identified, including 7-((2-amino-6-(4-fluorophenyl)pyrimidin-4-yl)amino)-2-heptylphthalazin-1(2H)-one (MIC=1.6 μm), 4-tertbutylphthalazin-2(1H)-one (MIC=3 μm), and 7-nitro-phthalazin-1(2H)-one (MIC=3 μm). Mode of action studies indicated that selected pyrimidinyl-phthalazinones may interfere with NADH oxidation, however, the mode of action of the lead compound is independent of this enzyme. MIC=minimum inhibitory concentration.

Keywords: Medicinal Chemistry; Nitrogen Heterocycles; Phthalazinones; Tuberculosis.