Shandil Sahil, Yu Tsz Tin, Sabir Shekh, Black David StC, Kumar Naresh
School of Chemistry, The University of New South Wales, Sydney, NSW 2052, Australia.
Antibiotics (Basel). 2023 Jul 24;12(7):1227. doi: 10.3390/antibiotics12071227.
As bacteria continue to develop resistance mechanisms against antimicrobials, an alternative method to tackle this global concern must be developed. As the system is the most well-known and responsible for biofilm and pyocyanin production, quinazolinone inhibitors of the system in were developed. Molecular docking following a rationalised medicinal chemistry approach was adopted to design these analogues. An analysis of docking data suggested that compound could bind with the key residues in the ligand binding domain of PqsR in a similar fashion to the known antagonist M64. The modification of cyclic groups at the 3-position of the quinazolinone core, the introduction of a halogen at the aromatic core and the modification of the terminal group with aromatic and aliphatic chains were investigated to guide the synthesis of a library of 16 quinazolinone analogues. All quinazolinone analogues were tested in vitro for inhibition, with the most active compounds and being tested for biofilm and growth inhibition in (PAO1). Compound displayed the highest inhibitory activity (73.4%, 72.1% and 53.7% at 100, 50 and 25 µM, respectively) with no bacterial growth inhibition. However, compounds and only inhibited biofilm formation by 10% and 5%, respectively.
随着细菌对抗菌药物的耐药机制不断发展，必须开发一种解决这一全球问题的替代方法。由于该系统是最广为人知且与生物膜和绿脓菌素产生有关的系统，因此开发了该系统的喹唑啉酮抑制剂。采用合理的药物化学方法进行分子对接以设计这些类似物。对接数据分析表明，化合物可以与铜绿假单胞菌喹诺酮信号受体（PqsR）配体结合域中的关键残基结合，其方式与已知拮抗剂M64类似。研究了喹唑啉酮核心3位环基团的修饰、芳香核上卤素的引入以及末端基团用芳香链和脂肪链的修饰，以指导16种喹唑啉酮类似物库的合成。所有喹唑啉酮类似物均在体外进行了对绿脓菌素抑制的测试，其中活性最高的化合物和在铜绿假单胞菌（PAO1）中进行了生物膜和生长抑制测试。化合物表现出最高的绿脓菌素抑制活性（在100、50和25µM时分别为73.4%、72.1%和53.7%），且无细菌生长抑制。然而，化合物和仅分别抑制生物膜形成10%和5%。
