Synthesis of thiourea derivatives of the alkaloid anabasine and crystal structure of N-(anabasino1-thiocarbonyl)furan-2-carboxamide

Abstract

A series of new N-acylsubstituted thioureas, the compositions and structures of which were determined by IR and PMR spectroscopy and mass spectrometry, were synthesized from the alkaloid anabasine. The crystal structure of one of the products, N-(anabasino-1-thiocarbonyl)furan-2-carboxamide, was confirmed by x-ray structure analysis. It was also shown that this compound exhibited moderate antibacterial activity.Anabasine was discovered in 1929 by Orekhov A. P. from Anabasis aphilla and acts as a respiratory and cardiac stimulant. It is used in practical medicine as anabasine hydrochloride as an anti-smoking agent [1,2]. It was also broadly used previously as an insecticide for pests of such industrial cultures as cotton, fruit trees, and vegetables and gourds [3,4].Introducing a sulfur atom into physiologically active compounds not only decreases their overall toxicity due to the facile oxidizability of its derivatives in vivo but also produces other types of bioactivity. Also, it is known that most thiourea derivatives possess valuable pharmacological properties and are used as antituberculosis, antitumor, antimicrobial, anti-ulcer, and other therapeutic agents [5][6][7].We have previously synthesized thiourea derivatives of the alkaloids cytisine, 1-ephedrine, and d-pseudoephedrine with unsaturated and aromatic acyl derivatives.In continuation of that work we synthesized acyl-substituted thiourea derivatives based on anabasine by a convenient preparative isothiocyanate method. Isothiocyanates are very reactive compounds and react with amines under rather mild conditions.The starting isothiocyanates were synthesized by a convenient preparative in situ method (without isolation) by heating the corresponding acid chlorides (benzoylchloride, p-methylbenzoylchloride, p-bromobenzoylchloride, 2-furancarboxylic acid chloride) with KSCN in acetone. Further reaction of the resulting isothiocyanate lutions with anabasine under mild conditions formed 1-4.The products were white (or slightly yellowish) crystalline compounds that were soluble in polar organic solvents.

Synthesis and crystal structure of 5-methyl-2-(N-anabasinyl)-5,6-dihydro-1,3-thiazin-4-one from the alkaloid anabasine

“…The pyridine ring is planar within ±0.007 A° and is oriented axially (C3C7C8C9 torsion angle = -70.6°) relative to the piperidine ring, in contrast with anabasine O,O-diethylthiophosphate, where it is oriented equatorially. Such an orientation of the pyridine ring has been observed previously in N-anabasino(2-vinyloxyethylamino)methanethione [9] and N-(anabasino-1-carbonothioyl)furan-2-carboxamide [2]. In our opinion, such an orientation is due to non-bonded repulsion between the bulky substituent and the pyridine ring.…”

“…Its structure was proved by IR and PMR spectroscopy, mass spectrometry, and an x-ray structure analysis.Keywords: anabasine alkaloid, methacryloylisothiocyanate, intramolecular heterocyclization, 5,6-dihydro-1,3-thiazin-4-one, x-ray structure analysis.We have previously synthesized thiourea derivatives of the alkaloids cytisine, anabasine, d-pseudoephedrine, and l-ephedrine [1][2][3]. Many thiourea derivatives based on these alkaloids are excellent synthons for synthesizing new heterocyclic derivatives [4,5].…”

“…We have previously synthesized thiourea derivatives of the alkaloids cytisine, anabasine, d-pseudoephedrine, and l-ephedrine [1][2][3]. Many thiourea derivatives based on these alkaloids are excellent synthons for synthesizing new heterocyclic derivatives [4,5].…”

“…The piperidine ring adopted an ideal chair conformation ('C s 8 = 0.7 A° ), like in anabasine O,O-diethylthiophosphate [8], N-anabasino(2-vinyloxyethylamino)methanethione [9], and N-(anabasino-1-carbonothioyl)furan-2-carboxamide [2]. The pyridine ring is planar within ±0.007 A° and is oriented axially (C3C7C8C9 torsion angle = -70.6°) relative to the piperidine ring, in contrast with anabasine O,O-diethylthiophosphate, where it is oriented equatorially.…”

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

“…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.…”