In Vitro Activity of the Triazinyl Diazepine Compound FTSD2 Against Drug-Resistant Mycobacterium tuberculosis Strains

<b>Background/Objectives:</b> Compounds derived from pyrimido-diazepine have shown selective inhibition of the susceptible <i>Mycobacterium tuberculosis</i> strain H37Rv. However, there is a need for studies that evaluate the activity of these compounds against multidrug-resistant strains and clinical isolates. This study aims to evaluate the antitubercular potential of FTSD2 against drug-resistant strains of <i>M. tuberculosis</i>. <b>Methods:</b> The compound 4-(2,4-diamino-8-(4-methoxyphenyl)-8,9-dihydro-7H-pyrimido[4,5-b][1,4]diazepin-6-yl)-N-(2-(4-(dimethylamino)-6-(4-fluorophenyl)amino-1,3,5-triazin-2-yl)amino)ethyl)benzenesulfonamide (FTSD2) was tested against drug-resistant <i>M. tuberculosis</i> strains at minimal inhibitory and bactericidal concentrations (MIC and MBC). Kill curve assays were performed to assess bactericidal activity, and cytotoxicity was evaluated in human monocyte-derived macrophages and the RAW 264.7 murine macrophage cell line. Intracellular death assays, specifically macrophage infection assays, were also conducted to evaluate the effect of FTSD2 on intracellular <i>M. tuberculosis</i> growth. <b>Results:</b> FTSD2 inhibited the growth of drug-resistant <i>M. tuberculosis</i> at MIC and MBC values between 0.5 and 1 mg/L. Kill curve assays demonstrated concentration-dependent bactericidal activity. No cytotoxicity was observed in macrophages at concentrations below 64 mg/L. Additionally, FTSD2 significantly suppressed intracellular <i>M. tuberculosis</i> growth after 192 h. FTSD2 did not inhibit the growth of nontuberculous mycobacteria, including <i>M. avium</i>, <i>M. abscessus</i>, <i>M. fortuitum</i>, <i>M. chelonae</i>, and <i>M. smegmatis</i> at 50 mg/L. <b>Conclusions:</b> FTSD2 exhibits strong potential as a leading compound for the development of new antitubercular drugs, with selective activity against <i>M. tuberculosis</i> and minimal cytotoxic effects on macrophages. Further studies are needed to explore its mechanisms of action and therapeutic potential.