Abstract
A series of 2‐ and 7‐substituted phthalazinones was synthesised and their potential as anti‐tubercular drugs assessed via Mycobacterium tuberculosis (mc26230) 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.
A library of phthalazinones was synthesised and screened for antituberculosis activity. All phthalazinones inhibited mycobacterial growth (MIC<100 μm), with the lead compound, 7‐((2‐amino‐4‐(4‐fluorophenyl)pyrimidin‐4‐yl)amino)‐2‐heptylphthalazin‐1‐(2H)one exhibiting an MIC value of 1.6 μm. Mode of action studies suggest that some phthalazinones interact with the respiratory chain to cause dysregulation of NADH oxidation.