New 2-(Quinolin-4-yloxy)acetamides: Synthesis, Antitubercular Evaluation, and Structure-Activity Relationships

Tuberculosis remains a significant global health concern, particularly due to the increasing prevalence of drug-resistant strains. In this work, a series of 2-(quinoline-4-yloxy)acetamides was synthesized and evaluated for antimycobacterial activity, aiming to advance the understanding of structure-activity relationships (SAR) within this scaffold. Variations at the quinoline core and the aryl moiety of the acetamide side chain resulted in distinct biological profiles, with SAR analysis revealing that small to moderate hydrophobic substituents at the 4-position of the aryl ring enhanced potency, while bulky or strongly electron-withdrawing groups reduced activity, likely due to steric or electronic effects. Notably, the lead compound exhibited a minimum inhibitory concentration of 0.80 µM against Mycobacterium tuberculosis H37Rv, representing more than a 2.8-fold increase in potency compared to isoniazid under identical experimental conditions. Furthermore, this molecule demonstrated no detectable cytotoxicity in HepG2 (human caucasian hepatocytes carcinoma) and Vero (African green monkey kidney) cell lines up to 20 µM, resulting in selectivity indices exceeding 25, and exhibited favorable solubility under acidic conditions (156 µM at pH 1.2). These findings indicate that the 2-(quinoline-4-yloxy)acetamide scaffold holds promise for further development and support the rational design of new candidates for the treatment of tuberculosis, potentially contributing to strategies aimed at overcoming the limitations of current therapies.