Polarity-Driven Scaffold Optimization of Diaryl Ether FabV Inhibitors to Enhance Aqueous Solubility

The continuous rise and spread of antimicrobial resistance poses a severe threat to global health and creates an urgent need for the development of new classes of antibiotics. One promising target is FabV, an enoyl-acyl carrier protein reductase that is crucial for the survival of certain pathogenic Gram-negative species such as the opportunistic nosocomial bacterium P. aeruginosa. Previously, our group investigated the structure-activity relationship of diaryl ether-based inhibitors of FabV and uncovered p-N,N-dimethylsulfamoyl phenyl substitution as a privileged motif, exemplified by compounds 1a (IC₅₀ = 0.25 μM) and 1e (IC₅₀ = 0.19 μM). In the present study, we explored skeletal modifications of the diaryl ether scaffold with the aim of improving aqueous solubility of the compounds while maintaining potent activity. Our efforts uncovered compound 6k (IC₅₀ = 0.53 μM), in which the alkyl chain is replaced by a 3-cyanocyclobutyl group and which shows a fivefold increase in kinetic solubility compared to the parent compound 1a. Similarly, benzene-to-pyridine replacement in the A-ring led to significant solubility gains with minimal loss of potency. These results showcase an effective strategy for optimizing solubility in inhibitors targeting enzymes with highly lipophilic natural substrates.