Search for NADH-fumarate reductase produced by microorganisms

NADH-延胡索酸还原酶（复合物I+II）是许多蠕虫成虫无氧能量代谢的关键酶。在从成虫（猪蛔虫）中筛选NADH-延胡索酸还原酶抑制剂的过程中，我们从木霉属FTD-0795中分离出哈茨酰吡啶酮。我们研究了目标酶使用atpenin A5，一个更有效的抑制剂harzianopyridone类似物，并发现它特异性抑制复合物II。虽然atpenin A5并没有显示蠕虫和哺乳动物之间的选择性，它显示了300倍更有效的复合物II抑制比carboxin的最有效的复合物II的抑制剂。因此，atpenin A5可能是一个有用的工具，为复杂II的生化研究。我们的连续筛选实现了另外五个抑制剂，glisoprenin A，paecilaminol，verticipyrorie，decursin，decursinol angelate的发现。其中，对乙酰氨基酚和维替吡酮为新化合物，其中维替吡酮对A.对猪NADH-延胡索酸还原酶的IC<50>值为4.1 nM，对哺乳动物牛心脏NADH氧化酶（复合物I+III+IV）的IC<50>值为56.0 nM。我们正在评价这些化合物的抗蠕虫活性，以前发现了选择性蠕虫复合物I抑制剂萘呋啶。碱处理萘呋啶得到一个新的化合物萘呋啶-γ，其表现出与萘呋啶几乎相同的复合物I抑制和驱虫活性。我们已经完成了萘呋啶-γ的全合成，并将进一步合成更有效的萘呋啶-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.