Benzofuranyl-tethered 1,3,4-oxadiazoles as quorum-sensing inhibitors targeting Pseudomonas aeruginosa pathogenicity.

Abstract

Two series of benzofuran-2-yl-1,3,4-oxadiazoles, 9 (9a-h) and 10 (a-d, f, h), were synthesized and evaluated in vitro as potential quorum-sensing inhibitors and antivirulence agents against Pseudomonas aeruginosa (PA), PAO1. Several compounds showed activity comparable to or greater than that of azithromycin at ¼ MIC. The compounds reduced biofilm formation by 32.7-70.5%, motility by 24.2-56.7%, hemolysin production by 29.1-55.6%, and protease production by 29.7-59.7%. 5-(Benzofuran-2-yl)-N-phenyl-1,3,4-oxadiazol-2-amine (9c) and its 5-bromo congener (10c) showed the highest inhibitory activities. In a mouse infection model using PA pretreated with 9c or 10c, both compounds conferred 43% protection and reduced bacterial loads in the kidney and liver by up to 50% relative to the untreated control group. Cytotoxicity testing in the WI-38 human lung cell line indicated lower cytotoxicity for 9c and 10c (CC50 = 153.75 ± 5.11 and 194.62 ± 6.03 μg mL-1, respectively) than for ciprofloxacin (CC50 = 132.87 ± 4.87 μg mL-1). Molecular docking within the PqsR ligand-binding domain (PqsR-LBD) revealed interactions analogous to those of the co-crystallized inhibitor. Accelerated molecular dynamics (aMD) simulations showed that 9c selectively modulated the Ile186-containing region while stabilizing the overall receptor conformation, a dynamic profile compatible with an inverse agonist-like binding mode. Collectively, these findings identify benzofuran-oxadiazole hybrids as a potential scaffold for developing novel non-bactericidal therapies aimed at attenuating the pathogenicity of multidrug-resistant (MDR) PA infections.

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