Preliminary structure−activity relationships analysis on N-(3,5-dichlorophenyl)-4,5-dihydronaphtho[1,2-d]thiazol-2-amine, a disruptor of mycobacterial energetics

The increasing emergence of drug-resistance among mycobacteria represents a serious global health threat, requiring novel and effective therapeutic strategies. The lack of innovation in the drug discovery approach and/or in the combination of the therapeutic cocktail makes inevitable the onset of resistance also for the newly marketed drugs such as bedaquiline and delamanid. Therefore, different therapeutic tools are urgently required. Adjuvant therapies (AT), that is those approaches aimed at boosting the existing treatment, rather than replacing it with another, have gained increasing consideration in the antibacterial landfill. Efflux Inhibitors (EIs) represent the most studied example of such an approach, as they can slow down the emergence of resistance and have positive effects on the duration of the treatment. Working toward this direction, we have recently reported the biological characterization of N-(3,5-dichlorophenyl)-4,5-dihydronaphtho[1,2-d]thiazol-2-amine (compound 1), a 2-aminothiazole derivative remarkably affecting Mycobacterium tuberculosis energetics. Despite the encouraging overall activity (MIC = 16 mu g/mL, RFF = 3.29), this compound poses several medicinal chemistry challenges concerning its toxicity and drug-likeness. Here we present a Structure-Activity Relationships around compound 1, with the disclosure of some derivatives with balanced efflux inhibitory characteristics, tolerable toxicity and drug-like physicochemical features.