Pks13 was identified as a key enzyme involved in the final step of mycolic acid biosynthesis. We previously identified antitubercular coumestans that targeted Pks13-TE, and these compounds exhibited high potency both in vitro and in vivo. However, lead compound <b>8</b> presented potential safety concerns because it inhibits the hERG potassium channel in electrophysiology patch-clamp assays (IC<sub>50</sub> = 0.52 μM). By comparing the Pks13-TE-compound <b>8</b> complex and the ligand-binding pocket of the hERG ion channel, fluoro-substituted and oxazine-containing coumestans were designed and synthesized. Fluoro-substituted compound <b>23</b> and oxazine-containing coumestan <b>32</b> showed excellent antitubercular activity against both drug-susceptible and drug-resistant <i>Mtb</i> strains (MIC = 0.0039-0.0078 μg/mL) and exhibited limited hERG inhibition (IC<sub>50</sub> ≥ 25 μM). Moreover, <b>32</b> exhibited improved metabolic stability relative to parent compound <b>8</b> while showing favorable bioavailability in mouse models via serum inhibition titration assays.