Structure-activity relationships among DNA gyrase inhibitors. Synthesis and biological evaluation of 1,2-dihydro-4, 4-dimethyl-1-oxo-2-naphthalenecarboxylic acids as 1-carba bioisosteres of oxolinic acid.
Structure-activity relationships among DNA gyrase inhibitors. Synthesis and biological evaluation of 1,2-dihydro-4, 4-dimethyl-1-oxo-2-naphthalenecarboxylic acids as 1-carba bioisosteres of oxolinic acid.
复制标题
DNA 旋转酶抑制剂之间的结构-活性关系。
DOI：
10.1021/jm00369a013
复制
发表时间：
1984
影响因子：
7.3
通讯作者：
Shen,LL
中科院分区：
文献类型：
--
作者：
Högberg,T;Khanna,I;Drake,SD;Mitscher,LA;Shen,LL
合成了一系列恶唑啉酸类似物，试图评估NL原子在抗微生物DNA旋转酶抑制剂的可能作用模式中所起的作用。制备Carba类似物是因为它们不可能是氮原子的内部共振贡献，而且还可以满足假定作用模式的电子要求。成功的路线包括Friedel-Craft将合适的芳香族化合物与4，4-二甲基丁内酯环加成，然后乙氧基化，二氯二氰基对苯二酚氧化，以及仔细的皂化。这些类似物的宝石-二甲基团以非平面性为代价防止了芳构化。只有未被取代的母体化合物L，即2-二氢-4，4-二甲基-L-氧代-2-萘甲酸(9E)，具有明显的体外抑菌活性。然而，这可能是由于不同的作用模式所致，因为9E在体外对DNA旋转酶没有明显的抑制作用。因此，NL原子在酶和细菌抑制中发挥着重要作用，而C-6氧原子的存在无法弥补这一点。
A series of oxolinic acidanalogues was synthesized in an attempt to evaluate the role, if any, played by the Nl atom in putative modes of action of antimicrobialDNA gyrase inhibitors. Carba analogues were prepared because these have no possibility of an internal resonance contribution of the nitrogen atom and yet could otherwise satisfy electronic requirements of putative modes of action. Successful routes were developed involvingFriedel-Craft’s cycloaddition of suitable aromatic compounds with 4, 4-dimethylbutyrolactone, followed by ethoxycarbonylation, oxidation with dichlorodicyanobenzoquinone, and careful saponification. The gem-dimethyl group of these analogues prevents aromatization at the cost of nonplanarity. Only the unsubstituted parent compound, l, 2-dihydro-4, 4-dimethyl-l-oxo-2-naphthalenecarboxylic acid (9e), possessed any appreciable antimicrobial activity in vitro. This may be due to a different mode of action, however, since9e gave no measurable inhibition of DNA gyrase in vitro. Thus, the Nl atom plays a significant role in enzymic and bacteriological inhibition that cannot be compensated for by the presence of C-6 oxygen atoms.