Rising numbers of cases of multidrug- and extensively drug-resistant Pseudomonas aeruginosa over recent years have created an urgent need for novel therapeutic approaches to cure potentially fatal infections. One such approach is virulence attenuation where anti-virulence compounds, designed to reduce pathogenicity without affording bactericidal effects, are employed to treat infections. P. aeruginosa uses the pqs quorum sensing (QS) system, to coordinate the expression of a large number of virulence determinants as well as bacterial-host interactions and hence represents an excellent anti-virulence target.

We report the synthesis and identification of a new series of thiazole-containing quinazolinones capable of inhibiting PqsR, the transcriptional regulator of the pqs QS system. The compounds demonstrated high potency (IC₅₀ < 300 nM) in a whole-cell assay, using a mCTX:P_pqsA-lux-based bioreporter for the P. aeruginosa PAO1-L and PA14 strains. Structural evaluation defined the binding modes of four analogues in the ligand-binding domain of PqsR through X-ray crystallography. Further work showed the ability of 6-chloro-3((2-pentylthiazol-4-yl)methyl)quinazolin-4(3H)-one (18) and 6-chloro-3((2-hexylthiazol-4-yl)methyl)quinazolin-4(3H)-one (19) to attenuate production of the PqsR-regulated virulence factor pyocyanin. Compounds 18 and 19 showed a low cytotoxic profile in the A549 human epithelial lung cell line making them suitable candidates for further pre-clinical evaluation.

近年来，多重耐药和广泛耐药的铜绿假单胞菌病例数量不断增加，迫切需要新的治疗方法来治愈潜在的致命感染。其中一种方法是毒力减弱，其中抗毒力化合物旨在降低致病性而不提供杀菌作用，用于治疗感染。铜绿假单胞菌使用pqs群体感应 (QS) 系统来协调大量毒力决定簇的表达以及细菌与宿主的相互作用，因此是一种出色的抗毒力靶标。

我们报告了一系列新的含噻唑喹唑啉酮类化合物的合成和鉴定，这些化合物能够抑制 PqsR（ pqs QS 系统的转录调节因子）。使用基于 mCTX:P _pqsA -lux的生物报告基因对铜绿假单胞菌PAO1-L 和 PA14 菌株进行全细胞测定，这些化合物显示出高效力 (IC ₅₀ < 300 nM)。结构评估通过 X 射线晶体学确定了 PqsR 配体结合域中四种类似物的结合模式。进一步的工作显示了 6-氯-3((2-戊基噻唑-4-基)甲基)喹唑啉-4(3 H )-酮 ( 18 ) 和 6-氯-3((2-己基噻唑-4-基)的能力)甲基)喹唑啉-4(3 H )-酮 ( 19 ) 可减弱 PqsR 调节的毒力因子绿脓素的产生。化合物18和19在 A549 人上皮肺细胞系中表现出低细胞毒性，使其成为进一步临床前评估的合适候选者。