Institute of Organic Chemistry and Chemical Biology, Center for Biomolecular Magnetic Resonance, Johann Wolfgang Goethe-University Frankfurt , Max-von-Laue-Straße 7, D-60438 Frankfurt am Main, Germany.
J Med Chem. 2013 Dec 12;56(23):9530-41. doi: 10.1021/jm400978u. Epub 2013 Dec 3.
Novel naphthoquinones were designed, synthesized, and tested as substrate-based inhibitors against the membrane-embedded protein quinol/fumarate reductase (QFR) from Wolinella succinogenes, a target closely related to QFRs from the human pathogens Helicobacter pylori and Campylobacter jejuni. For a better understanding of the hitherto structurally unexplored substrate binding pocket, a structure-activity relationship (SAR) study was carried out. Analogues of lawsone (2-hydroxy-1,4-naphthoquinone 3a) were synthesized that vary in length and size of the alkyl side chains (3b-k). A combined study on the prototropic tautomerism of 2-hydroxy-1,4-naphthoquinones series indicated that the 1,4-tautomer is the more stable and biologically relevant isomer and that the presence of the hydroxyl group is crucial for inhibition. Furthermore, 2-bromine-1,4-naphthoquinone (4a-c) and 2-methoxy-1,4-naphthoquinone (5a-b) series were also discovered as novel and potent inhibitors. Compounds 4a and 4b showed IC50 values in low micromolar range in the primary assay and no activity in the counter DT-diaphorase assay.
新型萘醌类化合物被设计、合成并测试为基于底物的抑制剂，以抑制来自沃林氏梭菌的膜嵌入蛋白喹诺/延胡索酸盐还原酶（QFR），该目标与幽门螺杆菌和空肠弯曲菌等人类病原体的 QFR 密切相关。为了更好地了解迄今为止在结构上未被探索的底物结合口袋，进行了一项结构-活性关系（SAR）研究。合成了 Lawsone（2-羟基-1,4-萘醌 3a）的类似物，其烷基侧链的长度和大小各异（3b-k）。对 2-羟基-1,4-萘醌系列的质子互变异构体的综合研究表明，1,4-互变异构体是更稳定和更相关的生物异构体，并且羟基的存在对于抑制至关重要。此外，还发现了 2-溴-1,4-萘醌（4a-c）和 2-甲氧基-1,4-萘醌（5a-b）系列作为新型强效抑制剂。化合物 4a 和 4b 在初步测定中表现出低微摩尔范围内的 IC50 值，并且在反 DT-二氢吡啶酶测定中没有活性。
