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 µg/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.

分枝杆菌耐药性的日益出现对全球健康构成了严重威胁，需要新颖有效的治疗策略。药物发现方法和/或治疗混合物的组合缺乏创新，使得新上市的药物如贝达喹啉和德拉马尼也不可避免地出现耐药性。因此，迫切需要不同的治疗工具。辅助疗法（AT），即旨在加强现有治疗而不是用另一种治疗替代的方法，在抗菌垃圾填埋场中得到了越来越多的考虑。外排抑制剂（EI）代表了这种方法研究最多的例子，因为它们可以减缓耐药性的出现并对治疗持续时间产生积极影响。朝着这个方向努力，我们最近报道了N -(3,5-二氯苯基)-4,5-二氢萘并[1,2-d]噻唑-2-胺（化合物1）（一种 2-氨基噻唑衍生物）的生物学表征显着影响结核分枝杆菌能量学。尽管总体活性令人鼓舞（MIC = 16 µg/mL，RFF = 3.29），但该化合物在毒性和药物相似性方面提出了一些药物化学挑战。在这里，我们提出了化合物1 的构效关系，并公开了一些具有平衡的外排抑制特性、可耐受的毒性和类似药物的理化特性的衍生物。