School of Chemistry, The University of New South Wales, Sydney, NSW 2052, Australia.
Department of Infectious Diseases and Immunology, School of Medical Sciences, The University of Sydney, Sydney, NSW 2006, Australia.
Molecules. 2021 Jun 19;26(12):3745. doi: 10.3390/molecules26123745.
Rottlerin is a natural product consisting of chalcone and flavonoid scaffolds, both of which have previously shown quorum sensing (QS) inhibition in various bacteria. Therefore, the unique rottlerin scaffold highlights great potential in inhibiting the QS system of Rottlerin analogues were synthesised by modifications at its chalcone- and methylene-bridged acetophenone moieties. The synthesis of analogues was achieved using an established five-step synthetic strategy for chalcone derivatives and utilising the Mannich reaction at C6 of the chromene to construct morpholine analogues. Several pyranochromene chalcone derivatives were also generated using aldol conditions. All the synthetic rottlerin derivatives were screened for QS inhibition and growth inhibition against the related LasR QS system. The pyranochromene chalcone structures displayed high QS inhibitory activity with the most potent compounds, and , achieving QS inhibition of 49.4% and 40.6% and no effect on bacterial growth inhibition at 31 µM, respectively. Both compounds also displayed moderate biofilm inhibitory activity and reduced the production of pyocyanin.
罗特林是一种由查耳酮和黄酮骨架组成的天然产物，这两种骨架都曾在各种细菌中表现出群体感应（QS）抑制作用。因此，罗特林独特的骨架突出了其抑制罗特林类似物 QS 系统的巨大潜力，通过对其查耳酮和亚甲基桥接苯乙酮部分进行修饰合成了类似物。类似物的合成采用了已建立的查耳酮衍生物的五步合成策略，并利用曼尼希反应在色烯的 C6 位构建吗啉类似物。还使用醛醇条件生成了几种吡喃色烯查耳酮衍生物。所有合成的罗特林衍生物都进行了 QS 抑制筛选和对相关 LasR QS 系统的生长抑制筛选。吡喃色烯查耳酮结构表现出高 QS 抑制活性，最有效的化合物和 ，分别实现了 49.4%和 40.6%的 QS 抑制，在 31 µM 时对细菌生长抑制没有影响。这两种化合物还表现出中等的生物膜抑制活性，并减少了绿脓菌素的产生。
