Synthesis and Evaluation of the Biological Activity of New 3‑Amino‑4‑Aryl‑6‑Oxo‑4,5,6,7‑Tetrahydrothieno[2,3‑b]pyridines via the Thorpe–Ziegler Reaction

The paper presents an effective method for the synthesis of new 3-amino-4-aryl-6-oxo-4,5,6,7-tetrahydrothieno[2,3-b]pyridines using the tandem reaction of S-alkylation and subsequent Thorpe–Ziegler heterocyclization. The initial reagents were 4-aryl-6-oxo-3-cyano-1,4,5,6-tetrahydropyridine-2-thiolates of morpholinium (or N-methylmorpholinium) obtained from cyanothioacetamide, aromatic aldehydes and Meldrum acid. Their interaction with α-halocarbonyl compounds in an excess alcohol solution of potassium hydroxide made it possible to obtain target products with yields of 59-78%. The structure of all synthesized compounds has been confirmed by IR and NMR spectroscopy and elemental analysis; the spatial configuration of the chiral center of the C4 atom has been established.

An in-silico predictor analysis of pharmacokinetic parameters and bioavailability was performed for the obtained compounds. Calculations have shown that the physicochemical characteristics of the molecules meet the criteria of Lipinski's "rule of five", high gastrointestinal absorption and the ability to penetrate the blood-brain barrier are predicted. The assessment of the toxicological profile gave mixed results.

An experimental study of biological activity on sunflower seedlings revealed that some of the derivatives obtained have a pronounced antidote effect against the phytotoxic effect of the herbicide 2,4-D. The protective effect was assessed by increasing the length of the hypocotyls and roots in comparison with the herbicide-only treatment option.

Thus, the developed synthetic approach provides access to new heterocyclic compounds of interest as potential plant protectors in agrochemistry. The results obtained form the basis for further in-depth study of the biological activity and mechanisms of action of these derivatives.