Exploring the Sponge Consortium <i>Plakortis symbiotica–Xestospongia deweerdtae</i> as a Potential Source of Antimicrobial Compounds and Probing the Pharmacophore for Antituberculosis Activity of Smenothiazole A by Diverted Total Synthesis

Fractionation of the bioactive CHCl₃–MeOH (1:1) extracts obtained from two collections of the sponge consortium <i>Plakortis symbiotica</i>–<i>Xestospongia deweerdtae</i> from Puerto Rico provided two new plakinidone analogues, designated as plakinidone B (<b>2</b>) and plakinidone C (<b>3</b>), as well as the known plakinidone (<b>1</b>), plakortolide F (<b>4</b>), and smenothiazole A (<b>5</b>). The structures of <b>1</b>–<b>5</b> were characterized on the basis of 1D and 2D NMR spectroscopic, IR, UV, and HRMS analysis. The absolute configurations of plakinidones <b>2</b> and <b>3</b> were established through chemical correlation methods, VCD/ECD experiments, and spectroscopic data comparisons. When assayed in vitro against <i>Mycobacterium tuberculosis</i> H₃₇Rv, none of the plakinidones <b>1</b>–<b>3</b> displayed significant activity, whereas smenothiazole A (<b>5</b>) was the most active compound, exhibiting an MIC value of 4.1 μg/mL. Synthesis and subsequent biological screening of <b>8</b>, a dechlorinated version of smenothiazole A, revealed that the chlorine atom in <b>5</b> is indispensable for anti-TB activity