Synthesis of acetylated glycosyl-containing thiourea derivatives based on the alkaloids cytisine and anabasine and the molecular structure of N-cytisino-N′-(2,3,4,6-tetraO-acetyl-β-D-glucopyranosyl)thiocarbamide

Abstract

Glycosylthiourea derivatives were synthesized from the alkaloids cytisine and anabasine and 1-deoxy-2,3,4,6-tetra-O-acetyl-E-D-glucopyranosylisothiocyanate. The structures of the synthesized compounds were proved using PMR spectroscopy, mass spectrometry, and an x-ray crystal structure analysis.Most thiourea derivatives are known to exhibit valuable pharmacological properties and are used as antituberculosis, antimicrobial, anti-ulcer, and other therapeutically active agents [1,2]. Thiourea derivatives containing natural biologically active compounds in their structure are especially interesting.In continuation of our research on the synthesis of various polyfunctional thiourea derivatives based on the alkaloids cytisine and anabasine [3][4][5][6], the preparation of glycosyl-containing thiourea derivatives of these alkaloids was planned because it is known that introducing biologically active compounds into the structure reduces sharply their toxicity, increases the water solubility, and prolongs the action of the drugs [7]. One of the oldest methods for synthesizing N-glycosylthioureas is the Fischer isothiocyanate method [8] based on the reaction of acetyl-substituted glycosylisothiocyanates with amines. A convenient preparative method for synthesizing the starting glycosylisothiocyanates, in addition to the method developed at the start of the last century by Fischer (from the corresponding glycosylbromides and silver thiocyanate), involves nucleophilic substitution of glycosylhalides by potassium thiocyanate under phase-transfer catalysis conditions in the presence of quaternary ammonium salts as proposed by Tashpulatov et al. [9]. Because the starting silver thiocyanate was expensive, the cheaper and more available lead thiocyanate was used to synthesize glycosylisothiocyanates [10]. Also, glycosylisothiocyanates were prepared in a melt of the starting glycosylbromides and potassium thiocyanate [11].We synthesized tetra-O-acetyl-D-D-glucopyranosylbromide (acetobromoglucose, ABG) by a simplified method developed by us that differed markedly from that described before [12] in order to prepare glycosylthiourea derivatives of several alkaloids. The method is classical for its simplicity and higher yields and purities. The resulting ABG (1) underwent a substitution reaction with a 1.5-fold excess of lead thiocyanate.

Synthesis and Crystal Structure of N-Ethyl-N-Cytisinocarbothioamide

“…The addition of ethyl isothiocyanate to cytisine gives compound 1 containing the carbothioamide group, where the second N15 nitrogen atom with a planar trigonal configuration is also involved in conjugation with the C=S bond (Table 1). This configuration of N1 and N2 nitrogen atoms of the carbothioamide group is also observed in three cytisine derivatives: N-adamantylcytisine-12-thiocarbamide (6) [18], N-cytisinyl-N′-(2,3,4,6-tetrakis(O-acetyl)-β-D-glucopyranosil)thiocarbamide monohydrate (7) [19], cytisine-N-(2-hydroxyethyl)thiocarbamide (8) [20]. However, the C(sp 3 )-N1-C=S torsion angle greatly deviates from zero in the molecules of 1, 6-8, compared to the respective angle in the molecules of 2-5.…”

Synthesis, Structure and Molecular Docking of New 4,5-Dihydrothiazole Derivatives Based on 3,5-Dimethylpyrazole and Cytisine and Salsoline Alkaloids

“…Isothiocyanate method [ 61 ] is one of the preparatively convenient methods allowing introducing thiourea or thioureide fragments into many aromatic and heterocyclic amines, including physiologically active alkaloids. It has been shown by us earlier on numerous examples [ 62 , 63 , 64 , 65 ].…”

Synthesis, Structure and Molecular Docking of New 4,5-Dihydrothiazole Derivatives Based on 3,5-Dimethylpyrazole and Cytisine and Salsoline Alkaloids

“…Isothiocyanate method [61] is one of the preparatively convenient methods allowing introducing thiourea or thioureide fragments into many aromatic and heterocyclic amines, including physiologically active alkaloids. It has been shown by us earlier on numerous examples [62][63][64][65].…”