Synthesis and biological activity of 3,4-dihydropyrimidin-2-thione aminomethylene derivatives based on the alkaloid cytisine

Abstract

547.94: 547.853 3,4-Dihydropyrimidin-2-thiones derivatized by the alkaloid cytisine were synthesized by Mannich aminomethylation. The compositions and structures of the products were confirmed by mass spectrometry and PMR and 1 H-1 H NOESY spectroscopy. One of the products showed pronounced antimicrobial activity.Keywords: alkaloid cytisine, PMR and 1 H-1 H NOESY spectroscopy, antimicrobial activity.Incorporation into the structure of plant alkaloids of other pharmacophores, including physiologically active heterocyclic compounds, many of which are analogs of natural nucleotides, is known to be a basic approach to the chemical design of new biologically active compounds. The alkaloid cytisine, which exhibits analeptic and antismoking activity, occupies a special place among a multitude of natural alkaloids [1]. Furthermore, the presence of a free secondary amine in cytisine facilitates the incorporation into its structure of various functional groups and heterocycles. The number of publications on the synthesis of heterocyclic N-derivatives of cytisine has increased in the last decade. Among these, compounds with types of biological activity that are uncharacteristic of cytisine itself are constantly being discovered. Until now many cytisine derivatives with various heterocylic groups such as coumarin [2,3]; 1,2,3-triazole [4]; 1,2,4-thiadiazole [5]; 1,3-thiazoline [6]; 2,5-dimercapto-1,3,4-thiadiazole [7]; barbituric acid [8]; pyridine [9]; 1,4-dihydropyridine [10]; and phenothiazine [11] were prepared.The Mannich reaction, which is widely used in organic chemistry to synthesize a variety of practically important compounds, is a convenient method for preparing new N-derivatives of cytisine in addition to the broadly used nucleophilic substitution and addition reactions of cytisine [2][3][4][5][6][7][9][10][11].The starting synthons for preparing new N-heterocyclic cytisine derivatives were 3,4-dihydropyrimidin-(1H)-2-thione derivatives, which were obtained via three-component condensation using a Biginelli reaction. The number of publications on the chemistry of 4-aryl-3,4-dihydropyrimidin-2-ones and 4-aryl-3,4-dihydropyrimidin-2-thiones has recently increased significantly in the scientific literature. This is due to not only their preparative availability but also the manifestation by them of a broad spectrum of pharmacological activity such as analgesic, antibacterial, antihypertensive, etc. [12][13][14].Because the starting 3,4-dihydropyrimidin-(1H)-2-thiones (1 and 2) had two reaction centers with nucleophilic N atoms (in the ring) and the S atom, which also exhibited a certain nucleophilicity and participated in possible thione-thiol tautomerism, it seemed interesting to us to study the possible involvement of these thiones in the Mannich synthesis as an

Mannich bases in medicinal chemistry and drug design

“…Thus, pyrimidine-2-thione Mannich base 145 ( Fig. 26) was obtained using natural alkaloid cytosine as amine reagent in aminomethylation, and its evaluation as antibacterial agent showed that it is a potent growth inhibitor of S. aureus and B. subtilis, and it has weak activity against P. aeruginosa and E. coli [209]. Double Mannich bases 146 ( Fig.…”

Biginelli Reaction Mediated Synthesis of Antimicrobial Pyrimidine Derivatives and Their Therapeutic Properties

“…Kulakov synthesized new 3,4-dihydropyrimidin-2-thiones 28 in two steps: (i) a Biginelli reaction to obtain compounds 27 and (ii) an aminomethylation Mannich reaction to obtain 3,4-dihydropyrimidin-2-thiones grafted with alkaloid cytisine ( Scheme 9 ) [ 78 ]. The bioscreening of 28a revealed its pronounced antibacterial activity against the Gram-positive strains S. aureus and B. subtilis , weak activity against Gram-negative strains P. aeruginosa and E. coli , in addition to the fungus C. albicans .…”

Cytisine derivatives as new anti-Escherichia coli agents: in silico and in vitro studies

“…Among the various derivatives of cytisine, compounds are constantly found with other types of biological activity that are not characteristic of itself (antispasmodic, antiarrhythmic, hepatoprotective, analgesic, cholinergic, insecticidal, antioxidant, etc. ), which attracts attention and encourages the synthesis and study of its new derivatives [9,10]. Small doses of cytisine strongly arouse breathing and increase blood pressure.…”