The Discovery and Development of Thienopyrimidines as Inhibitors of Helicobacter pylori That Act through Inhibition of the Respiratory Complex I

• DOI: 10.1021/acsinfecdis.0c00300
• Publication Date: 2021-01-20T19:19:19Z
• Authors: Alex K. Mugengana; Nicole A. Vita; Autumn Brown Gandt; Kevin Moran; George Agyapong; Lalit K. Sharma; Elizabeth C. Grif...; Jiuyu Liu; Lei Yang; Ekaterina Gavrish; Kirk E. Hevener; Michael D. LaFleur; Richard E. Lee
• Keywords: 0301 basic medicine; Chemical Sciences not elsewhere classified; compound; vivo infection model; efficacy; Biochemistry; Helicobacter Infections; Mice; 03 medical and health sciences; Space Science; Environmental Sciences not elsewhere classified; . pylori; Animals; series; Pharmacology; Electron Transport Complex I; Helicobacter pylori; H . pylori infection; Helicobacter pylori infections; thienopyrimidine; Anti-Bacterial Agents; 3. Good health; ATP; Infectious Diseases; Pyrimidines; Medicine; side-chain elements optimized; Biological Sciences not elsewhere classified; SAR; H . pylori

The successful treatment of Helicobacter pylori infections is becoming increasingly difficult due to the rise resistance against current broad spectrum triple therapy regimens. In search for narrow-spectrum agents H. pylori, a high-throughput screen identified two structurally related thienopyrimidine compounds that selectively inhibited over commensal members gut microbiota. To develop structure–activity relationship (SAR) thienopyrimidines this study employed four series modifications in which systematic substitution core was explored and ultimately side-chain elements optimized from original hits were merged into lead compounds. During development series, mode action studies pylori's respiratory complex I subunit NuoD as target thienopyrimidines. As enzyme uniquely essential ATP synthesis homology model NuoB–NuoD binding interface generated help rationalize SAR guide further series. From these studies, emerged with increased potency improved safety indices, good overall pharmacokinetic profile exception high protein poor solubility. Although demonstrated efficacy an ex vivo infection model, had no mouse infection. Additional optimization pharmacological properties increase solubility free-drug levels at sequestered sites would potentially result gain efficacy. developed demonstrates can be targeted novel narrow thienopyrimines serve basis future advancement studies.