Preclinical Evaluation of Selene-Ethylenelacticamides in Tuberculosis: Effects Against Active, Dormant, and Resistant Mycobacterium Tuberculosis and In Vitro Toxicity Investigation

Selene-ethylenelacticamide derivatives have been suggested as promising scaffolds with leishmanicidal activity. In this work, we demonstrated, for the first time, the effectiveness of selene-ethylenelacticamide derivatives against mycobacteria. Firstly, selene-ethylenelacticamides inhibited the growth of laboratory strains of <i>Mycobacterium tuberculosis</i> with MIC values ranging from 10 to 20 µM. Importantly, three derivatives were active against two multi-drug-resistant clinical isolates of <i>M. tuberculosis</i> with MIC values similar to pan-sensitive strains. In addition, NC31 and NC34 displayed an improved activity compared to the group treated with isoniazid in the six-week nutrient-starved <i>M. tuberculosis</i> cultures. Moreover, in toxicity studies, NC34 did not significantly affect the viability of both Vero E6 and HepG2 cell lines. NC34 did not affect <i>Artemia salina</i> nauplii survival at concentrations lower than 100 µM. Importantly, NC34 displayed a synergistic effect when combined with rifampicin. Molecular docking simulations were used to evaluate <i>Mycobacterium tuberculosis</i> DprE1 and dihydrofolate reductase enzymes as putative targets of selene-ethylenelacticamides, mechanisms that could contribute to the antitubercular activity. Our findings reveal that NC34 may represent a hit for further drug optimization and for future preclinical development as a new anti-mycobacterial agent, especially in cases of resistant and/or dormant forms of tuberculosis.