Screening,Discovery, and Optimization of the NaturalAntitubercular Chlorflavonin from a Marine-Derived Fungal Library

Tuberculosis (TB), caused by the bacterium <i>Mycobacterium tuberculosis</i> (<i>Mtb</i>), is still a leading cause of mortality worldwide. Fifty-fungi from a marine-derived fungal library were screened for anti-<i>Mtb</i> activity, and an <i>Aspergillus candidus</i> strain with strong anti-<i>Mtb</i> activity was found. Three known flavones, chlorflavonin (<b>1</b>), dechlorflavonin (<b>2</b>), and bromoflavone (<b>3</b>), were isolated from this fungus. Chlorflavonin and bromoflavone showed inhibitory activity with MIC₉₀ values of 2.6 and 1.2 <i>μ</i>M, respectively. In combination with molecular docking, a series of new chlorflavonin derivatives (<b>4</b>–<b>41</b>) were rationally designed and semisynthesized. Three new derivatives substituted with (2)-chlorocinnamate (<b>14</b>), (3)-chlorocinnamate (<b>15</b>), and benzoate (<b>18</b>) at position 2′ showed MIC₉₀ values ranging from 0.7 to 1.0 <i>μ</i>M, having the potential to be further explored as antitubercular agents.