School of Chemical and Physical Sciences, Victoria University of Wellington, P.O. Box 600, 6140, Wellington, New Zealand.
Centre for Biodiscovery, Victoria University of Wellington, P.O. Box 600, 6140, Wellington, New Zealand.
Chem Asian J. 2019 Apr 15;14(8):1278-1285. doi: 10.1002/asia.201801805. Epub 2019 Feb 13.
A series of 2- and 7-substituted phthalazinones was synthesised and their potential as anti-tubercular drugs assessed via Mycobacterium tuberculosis (mc 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.
合成了一系列 2-和 7-取代的酞嗪酮，并通过结核分枝杆菌（mc6230）生长抑制试验评估了它们作为抗结核药物的潜力。所有测试的酞嗪酮都显示出生长抑制活性（MIC<100μm），并且那些含有亲脂性和吸电子基团的化合物通常表现出更好的抗结核活性。鉴定出了几种先导化合物，包括 7-((2-氨基-6-(4-氟苯基)嘧啶-4-基)氨基)-2-庚基酞嗪-1(2H)-酮（MIC=1.6μm）、4-叔丁基酞嗪-2(1H)-酮（MIC=3μm）和 7-硝基-酞嗪-1(2H)-酮（MIC=3μm）。作用机制研究表明，某些嘧啶基酞嗪酮可能干扰 NADH 氧化，但先导化合物的作用机制与此酶无关。MIC=最小抑菌浓度。
