Exploring Benzo[h]chromene Derivatives as Agents against Protozoal and Mycobacterial Infections

<b>Background/Objectives:</b> In this study, the efficacy of benzo[h]chromene derivatives as antiprotozoal and antimycobacterial agents was explored. <b>Methods:</b> A total of twenty compounds, including benzo[h]chromene alkyl diesters and benzo[h]chromene-triazole derivatives, were synthesized and tested against <i>Trypanosoma cruzi</i>, <i>Leishmania braziliensis</i>, <i>L. infantum</i>, and strains of <i>Mycobacterium abscessus</i> and <i>Mycobacterium intracellulare</i> LIID-01. Notably, compounds <b>1a</b>, <b>1b</b>, <b>2a</b>, and <b>3f</b> exhibited superior activity against <i>Trypanosoma cruzi</i>, with IC₅₀ values of 19.2, 37.3, 68.7, and 24.7 µM, respectively, outperforming the reference drug benznidazole (IC₅₀: 54.7 µM). <b>Results:</b> Compounds <b>1b</b> and <b>3f</b> showed excellent selectivity indices against <i>Leishmania braziliensis</i>, with SI values of 19 and 18, respectively, suggesting they could be potential alternatives to the commonly used, but more selective, miltefosine (IC₅₀: 64.0 µM, SI: 43.0). Additionally, compounds <b>1a</b>, <b>1b</b>, and <b>3f</b> were most effective against <i>Leishmania infantum</i>, with IC₅₀ values of 24.9, 30.5, and 46.6 µM, respectively. Compounds <b>3f</b> and <b>3h</b> were particularly potent against various <i>Mycobacterium abscessus</i> strains, highlighting their significance given the inherent resistance of these bacteria to standard antimicrobials. <b>Conclusions:</b> The sensitivity of <i>Mycobacterium intracellulare</i> LIID-01 to these compounds also underscored their potential in managing infections by the Mycobacterium avium-intracellulare complex.