Total Synthesis and Antimycobacterial Activity of Ascidiathiazones A and B and Analogues

We describe the total synthesis of the natural product ascidiathiazone A ( 1 ) and, for the first time, the total synthesis of ascidiathiazone B ( 2 ). Derivatives of both ascidiathiazone scaffolds were also prepared. The crystal structures of ascidiathiazone A ( 1 ) and B ( 2 ) and their saturated and unsaturated counterparts were also obtained, thereby unambiguously confirming the structures of the natural products. The antimycobacterial potential of the ascidiathiazones was also explored using Mycobacterium tuberculosis growth inhibition assays whereby ascidiathiazone A ( 1 ) exhibited an MIC = 1.6 μM and ascidiathiazone B ( 2 ) an MIC = 3 μM against M. tuberculosis mc 2 6230. Structure–activity studies showed that a more potent activity was observed when maintaining saturation in the thiazino[2,3- g ]quinoline or unsaturation in the [3,2- g ] scaffold, as per the compounds found in nature. The mode of action of these thiazones was found to be independent of respiratory type II NADH dehydrogenase (NDH-II). Taken together, the efficient syntheses of these compounds, combined with the previously determined low toxicity of ascidiathiazone A ( 1 ), bode well for the use of the ascidithiazones in therapeutic applications, including as a new class of antimycobacterial drug.