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
Gyöngyvér Pusztai, László Poszávácz, Anna Vincze, András Marton, Ahmed Qasim Abdulhussein, Judit Halász, András Dancsó, Gyula Simig, György Tibor Balogh, Balázs Volk
TL;DR
This paper describes the synthesis and characterization of new complex ring compounds with potential as drug candidates.
Contribution
A new synthetic method for creating tri-, tetra-, and pentacyclic ring systems with anxiolytic potential is developed.
Findings
A versatile synthetic route was developed for new ring systems via Fischer indole cyclization.
Physicochemical and early ADME properties of the compounds were characterized.
Kinetic solubility and permeability measurements indicated lead-likeness of some derivatives.
Abstract
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-g]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 (E)- and (Z)-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 logP, pKa and logk values were calculated. Following that, kinetic solubility and in vitro gastrointestinal…
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Taxonomy
TopicsSynthesis and Catalytic Reactions · Quinazolinone synthesis and applications · Synthesis and biological activity