Mielczarek Marcin, Devakaram Ruth V, Ma Cong, Yang Xiao, Kandemir Hakan, Purwono Bambang, Black David StC, Griffith Renate, Lewis Peter J, Kumar Naresh
School of Chemistry, The University of New South Wales, Sydney, NSW 2052, Australia.
Org Biomol Chem. 2014 May 14;12(18):2882-94. doi: 10.1039/c4ob00460d.
The increasing resistance of bacteria against clinically approved antibiotics is resulting in an alarming decrease in therapeutic options for today's clinicians. We have targeted the essential interaction between bacterial RNA polymerase and σ(70)/σ(A) for the development of lead molecules exhibiting a novel mechanism of antibacterial activity. Several classes of structurally related bis-indole inhibitors of bacterial transcription initiation complex formation were synthesized and their antimicrobial activities were evaluated. Condensation of indole-7- and indole-2-carbohydrazides with 7- and 2-trichloroacetylindoles or indole-7- and indole-2-glyoxyloyl chlorides resulted in the successful synthesis of 7,7'-, 2,2'-, 2,7'- and 3,2'-linked bis-indole derivatives with -CO-NH-NH-CO- and -CO-CO-NH-NH-CO- linkers. Indole-7-glyoxyloyl chlorides were reacted with hydrazine hydrate in different ratios to afford respective -CO-CO-NH-NH-CO-CO- bis-indole or hydrazide derivatives. The resulting compounds were found to be active against the β'-CH-σ(70)/σ interaction in ELISA assays and inhibited the growth of both Gram-positive and Gram-negative bacteria. Structure-activity relationship (SAR) studies were performed in order to identify the structural features of the synthesized inhibitors required for biological activity.
细菌对临床批准的抗生素的耐药性不断增加，导致当今临床医生的治疗选择急剧减少。我们针对细菌RNA聚合酶与σ(70)/σ(A)之间的关键相互作用，开发具有新型抗菌活性机制的先导分子。合成了几类结构相关的细菌转录起始复合物形成的双吲哚抑制剂，并评估了它们的抗菌活性。吲哚-7-和吲哚-2-碳酰肼与7-和2-三氯乙酰吲哚或吲哚-7-和吲哚-2-乙二酰氯缩合，成功合成了具有-CO-NH-NH-CO-和-CO-CO-NH-NH-CO-连接基的7,7'-、2,2'-、2,7'-和3,2'-连接的双吲哚衍生物。吲哚-7-乙二酰氯与水合肼以不同比例反应，得到相应的-CO-CO-NH-NH-CO-CO-双吲哚或酰肼衍生物。在ELISA试验中发现所得化合物对β'-CH-σ(70)/σ相互作用有活性，并抑制革兰氏阳性菌和革兰氏阴性菌的生长。进行了构效关系（SAR）研究，以确定合成抑制剂具有生物活性所需的结构特征。
