Modifications on C6 and C7 Positions of 3-Phenylquinolone Efflux Pump Inhibitors Led to Potent and Safe Antimycobacterial Treatment Adjuvants

摘要: Nontuberculous mycobacteria (NTM) are ubiquitous microbes belonging to the Mycobacterium genus. Among all NTM pathogens, M. avium is one of most frequent agents causing pulmonary disease, especially in immunocompromised individuals and cystic fibrosis patients. Recently, we reported first ad hoc designed efflux pump inhibitor (EPI; 1b) able strongly boost clarithromycin (CLA) MIC against different strains. Since 3-phenylquinolone derivative 1b suffered from toxicity issues toward human macrophages, herein report a two-pronged medicinal chemistry workflow for identifying new potent safe EPIs. Initially, followed computational approach exploiting our pharmacophore models screen FDA approved drugs in-house compounds identify "ready-to-use" EPIs and/or scaffolds be optimized terms EPI activity. Although nicardipine 2 was identified as EPI, molecules still issues. Therefore, based on promising activity 1b, undertook design, synthesis, biological evaluation 3-phenylquinolones differently functionalized at C6/C7 well N1 positions. 27 synthesized analogues, 11b, 12b, 16a exerted excellent concentrations below their CC50 cells, with being compound. Interestingly, also showed good avium-infected macrophages both alone combination CLA. The antimycobacterial observed only when tested ex vivo model suggests high therapeutic potential avium, which seems need functional pumps establish intracellular infections.