Search for NADH-fumarate reductase produced by microorganisms

NADH-富马酸还原酶(复合体I+II)是许多成虫无氧能量代谢的关键酶。在筛选猪蛔虫成虫NADH-富马酸还原酶抑制剂的过程中，我们从木霉中分离到了哈茨吡啶酮。FTD-0795。我们用三尖杉酯苷类似物的一种更有效的抑制剂atpenin A5来研究靶标酶，发现它特异性地抑制复合体II。虽然atpenin A5对蠕虫和哺乳动物没有显示出选择性，但它对复合体II的抑制作用是已知的最有效的复合体II的抑制剂卡宾的300倍。因此，atpenin A5可能是复合体II的生化研究的有用工具。我们连续筛选发现了另外五种抑制物，Gisoprenin A，Paecilamol，Verticipyrorie，Decursin和Decursinol angelate。其中对苯丙胺酚和马鞭草酮为新化合物，马鞭草酮对猪链霉菌NADH-富马酸还原酶有较强的抑制作用，IC_(50)为4.1 nM，对哺乳动物心脏NADH氧化酶(复合体I+III+IV)的抑制作用较弱，IC_(50)为56.0 nM。我们现在正在评估这些化合物的驱虫活性。我们之前发现了选择性的蠕虫复合体I抑制剂，那福瑞丁。碱处理制得一种新的化合物γ，其抑制活性和驱虫活性与化合物I几乎相同。我们已经完成了那福瑞丁-γ的全合成，我们还将制备更多有效的那福瑞丁-γ类似物。

NADH-fumarate reductase (complex I+II) is a key enzyme of anaerobic energy metabolism in many adult helminths. In the course of the, screening of NADH-fumarate reductase inhibitors from adult roundworm, Ascaris suum, we have isolated harzianopyridone from Trichoderma sp. FTD-0795. We studied the target enzyme using atpenin A5, a more potent inhibitor of harzianopyridone analog, and found that it specifically inhibited complex II. Though atpenin A5 did not show selectivity between helminths and mammals, it showed 300 times more potent complex II inhibition than carboxin the most potent known inhibitor of complex II. Therefore, atpenin A5 may be a useful tool for biochemical study of complex II.Our continuous screening achieved the finding of another five inhibitors, glisoprenin A, paecilaminol, verticipyrorie, decursin, and decursinol angelate. Among them, paecilaminol and verticipyrone are new compounds, and verticipyrone showed potent inhibition against A. suum NADH-fumarate reductase with IC_<50> value of 4.1 nM and weak inhibition to mammal bovine heart NADH oxidase (complex I+III+IV) with IC_<50> value of 56.0 nM. We are evaluating anthelmintic activities of these compounds now.We found selective helminth complex I inhibitor, nafuredin, previously. Alkaline treatment of nafuredin yielded a new compound nafuredin-γ that showed almost the same complex I inhibition and anthelmintic activity as nafuredin. We have already finished the total synthesis of nafuredin-γ, and we will prepare more potent analogs of nafuredin-γ.