Synthesis of the First Dihydroquercetin–Cytisine Conjugates

Chemical modification of natural biologically active compounds can expand their spectrum of activity and is a promising direction in new drug discovery [1]. Flavonoids are a large group of natural biologically active compounds, among which dihydroquercetin (DHQ) occupies a special place. It is isolated from Larix sibirica wood and exhibits powerful antioxidant, hepatoprotective, antitumor, immunomodulating, and other properties [2]. The broad spectrum of biological activity and low toxicity [2] classify DHQ as a lead compound for chemical modification in order to synthesize new hybrid polyfunctional pharmacologically active compounds. Alkaloids such as cytisine occupy a special place among numerous heterocyclic natural compounds. The pharmacological properties of cytisine, like nicotine, are typical of ganglionic toxins that excite the CNS and autonomic nervous system ganglia, reflexively strengthen breathing [3], and exhibit hypolipidemic activity [4]. Cytisine derivatives with isoflavones and coumarins were obtained earlier [5]. The reaction of DHQ and its close structural analogs with primary and secondary amines was used as an example to demonstrate [6, 7] that the Mannich reaction occurred at the 6-position of ring A and produced primarily the mono-substituted derivative if equimolar amounts of the reagents were used; the disubstituted derivative at the 6and 8-positions, with a two-fold excess of amine. The goal of the present work was to synthesize conjugates of DHQ (1) and cytisine (2) that were promising for discovering new pharmacologically active polyfunctional drugs.