Thiadiazino-indole, thiadiazino-carbazole and benzothiadiazino-carbazole dioxides: synthesis, physicochemical and early ADME characterization of representatives of new tri-, tetra- and pentacyclic ring systems and their intermediates

Motivated by the in vivo anxiolytic activity of previously described 1,2,3-benzothiadiazine 1,1-dioxides, we aimed at elaborating a synthetic procedure for the preparation of their pyrrole-fused counterparts, 2,9-dihydro[1,2,3]thiadiazino[5,6-<i>g</i>]indole 1,1-dioxide derivatives. The simple and versatile process led, via Fischer indole cyclization of the corresponding hydrazones, to a wide structural variety of new tri-, tetra- and pentacyclic ring systems. The structural characterization of (<i>E</i>)- and (<i>Z</i>)-hydrazones was supported by 2D NMR techniques, while that of the target compounds by single-crystal X-ray measurements. The hydrazone intermediates and the new title compounds were subjected to a physicochemical and early ADME characterization study, in the framework of which log<i>P</i>, p<i>K</i> _a and log<i>k</i> values were calculated. Following that, kinetic solubility and in vitro gastrointestinal membrane-specific permeability measurements were carried out to assess the lead-likeness of the compounds. Subsequently, the metabolic stability of the most promising derivatives was also determined using human liver microsomes.