Discovery of 4-hydroxy-2-oxo-1,2-dihydroquinolines as potential inhibitors of Streptococcus pneumoniae, including drug-resistant strains.

Discovery of 4-hydroxy-2-oxo-1,2-dihydroquinolines as potential inhibitors of Streptococcus pneumoniae, including drug-resistant strains. Bioorg Med Chem Lett. 2020 Feb 29;:127071 Authors: Huddar S, Park CM, Kim HJ, Jang S, Lee S Abstract New therapies for treating drug-resistant pneumococcal infections are urgently needed. The novel scaffold 6-hydroxy-4-oxo-1,2-dihydro-4H-quinoline was shown to have similar efficacies against all three different serotypes of S. pneumoniae, ATCC 49617™ (19F), ATCC BAA-1663™ (15B), and ATCC 700904™ (19A), in a resazurin-based high-throughput screen using the Korea Chemical Bank library. Further studies to identify a new lead with this scaffold, including tricyclic pyrrolo[3,2,1-ij]quinolone and pyrido[3,2,1-ij]quinolone derivatives, led to the identification of 6d, 7d and 12a. Compound 6d (IC50 = 0.92, 0.75, and 0.77 µM), 7d (IC50 = 0.57, 0.66, and 0.38 µM) and 12a (IC50 = 0.27, 1.03, and 0.62 µM) showed submicromolar IC50 values against 19F, 15B, and 19A, respectively, and thus serve as a starting point for further optimization. While some of compounds in this series exhibited acceptable pharmacokinetic profiles in preliminary in vivo rat experiments, the most active compound 12a showed poor solubility and high plasma protein binding. Our current research efforts are focused on optimizing compounds to improve physicochemical properties as well as potency. PMID: 32146051 [Pub...
Source: Bioorganic and Medicinal Chemistry Letters - Category: Chemistry Authors: Tags: Bioorg Med Chem Lett Source Type: research