1,2,4-Thiadiazole derivatives of cytisine

Saprykina, V. A.; Виноградова, В. И.; Ambartsumova, R. F.; Ibragimov, T. F.; Sultankulov, A.; Shakhidoyatov, Kh. M.

doi:10.1007/s10600-005-0042-x

Cited by 14 publications

(12 citation statements)

References 4 publications

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“…On the other hand, the chiral 3,7-diazobicyclo[3.3.1]nonane skeleton is interesting for studying structural features of substituted cytisines [3][4][5][6]. Until now, a large number of cytisine derivatives with various groups on the N atom have been synthesized [7][8][9][10][11][12], including acryloyl groups [13], thiazoles, benzthiazoles [11], and 1,2,4-thiadiazole groups [12]. In continuation of our research on transformations of 1 [11,12] and in order to find biologically active compounds in this series, we synthesized acyl derivatives via acylation of 1 with acetic anhydride and acid chlorides.…”

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“…Until now, a large number of cytisine derivatives with various groups on the N atom have been synthesized [7][8][9][10][11][12], including acryloyl groups [13], thiazoles, benzthiazoles [11], and 1,2,4-thiadiazole groups [12]. In continuation of our research on transformations of 1 [11,12] and in order to find biologically active compounds in this series, we synthesized acyl derivatives via acylation of 1 with acetic anhydride and acid chlorides. The acylating agents were acetic anhydride; benzoyl-and o-bromo-and p-nitrobenzoyl chlorides; and crotonyl and cinnamoyl chlorides.…”

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Structural features of N-acylcytisines

et al. 2009

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747.945+547.79+548.737 G. Genzhemuratova, M. G. Levkovich, and Kh. M. ShakhidoyatovN-Acyl cytisine derivatives were synthesized by acylation with acetic anhydride; benzoyl and o-bromo-and p-nitrobenzoyl chlorides; and crotonyl and cinnamoyl chlorides. The structures of the synthesized compounds were studied using IR, PMR, and x-ray structure analysis (XSA). PMR spectra of the N-acylcytisines in solution typically had two rotational isomers around the N12-CO bond. Conformational analysis was performed using XSA for the position of the acyl group relative to the cytisine core. Bond lengths and angles of the acyl groups involved in the conjugation were analyzed.The broad spectrum of biological activity of cytisine (1) and its derivatives [1, 2] makes them a promising class for practical application. On the other hand, the chiral 3,7-diazobicyclo[3.3.1]nonane skeleton is interesting for studying structural features of substituted cytisines [3][4][5][6]. Until now, a large number of cytisine derivatives with various groups on the N atom have been synthesized [7][8][9][10][11][12], including acryloyl groups [13], thiazoles, benzthiazoles [11], and 1,2,4-thiadiazole groups [12]. In continuation of our research on transformations of 1 [11,12] and in order to find biologically active compounds in this series, we synthesized acyl derivatives via acylation of 1 with acetic anhydride and acid chlorides. The acylating agents were acetic anhydride; benzoyl-and o-bromo-and p-nitrobenzoyl chlorides; and crotonyl and cinnamoyl chlorides. The reaction with acetic anhydride occurred with an excess of it. Acylation by the acid chlorides occurred in anhydrous toluene under reflux: R = -ÑH 3 (2); -Ñ 6 H 5 (3); -Ñ 6 H 4 -Br-o (4); -C 6 H 4 -NO 2 -n (5); -CH=CH-C 6 H 5 (6); -CH=CH-CH 3 (7) Acylation of 1 by acid chlorides was carried out without a HCl acceptor. Atom N12 of ring C played this role. Structures of 2-7 were confirmed by IR and PMR spectra and by an x-ray structure analysis (XSA) for N-o-bromobenzoylcytisine (4), N-p-nitrobenzoylcytisine (5), and N-crotonylcytisine (6).IR spectra contained absorption bands at 1643-1653 cm -1 (ν CO ) and 1634-1647 (ν CO ). The physicochemical properties of 2, 3, and 7 agreed with those published. PMR spectra of the N-acylcytisines in solution characteristically showed several rotational isomers around the N12-CO and CO-R bonds. They could produce spectra of several conformers or simply give very broad spectral lines because the barriers to rotation were small. In several instances resonances could not be unambiguously assigned.

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Structural features of N-acylcytisines

et al. 2009

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“…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.…”

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“…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].…”

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

Кулаков

2011

Chem Nat Compd

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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

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Modified coumarins. 20. Furocoumarin derivatives of cytisine

et al. 2006

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Cytisine derivatives modified by furocoumarins were synthesized using activated esters.Many important natural compounds are based on the furocoumarin structure [1]. Highly active pharmacological compounds are known among natural and synthetic furocoumarins [2].On the other hand, the alkaloid cytisine and its derivatives possess a broad spectrum of biological activity [3,4]. Therefore, a large number of publications on the chemical modification and study of the properties of cytisine have appeared [5][6][7][8]. Thus, addition to cytisine of a furocoumarin ring as a substituent is interesting both to the chemistry of alkaloids and coumarins and to the targeted search for new biologically active compounds.Starting furocoumarins 1-12 that contain a carboxylic acid were prepared by the MacLeod method [9, 10]. Cytisine was N-acylated using activated esters [11], a method that is widely employed in peptide synthesis. The carboxylic acid was activated as the highly reactive N-hydroxysuccinimide ester [12]. Activated esters were prepared by reacting the corresponding acids 1-12 and N-hydroxysuccinimide (SuOH) in absolute dioxane using diisopropylcarbodiimide (DIC) as the condensing agent. Condensation of the resulting activated esters with cytisine in dioxane at room temperature gives in high yields the N-acyl cytisine derivatives 13-24, the molecules of which contain furocoumarin moieties. 1, 13: R 1 = Me, R 2 = R 3 = H, n = 1; 2, 14: R 1 = R 3 = Me, R 2 = H, n = 1; 3, 15: R 1 = R 2 = Me, R 3 = H, n = 1; 4, 16: R 1 = R 2 = R 3 = Me, n = 1; 5,17: R 1 R 2 = (CH 2 ) 4 , R 3 = H, n = 1; 6, 18: R 1 R 2 = (CH 2 ) 4 , R 3 = Me, n = 1; 7, 19: R 1 = Me, R 2 = R 3 = H, n = 2; 8, 20: R 1 = R 3 = Me, R 2 = H, n = 2; 9, 21: R 1 = R 2 = Me, R 3 = H, n = 2; 10, 22: R 1 = R 2 = R 3 = Me, n = 2; 11, 23: R 1 R 2 = (CH 2 ) 4 , R 3 = H, n = 2; 12, 24: R 1 R 2 = (CH 2 ) 4 , R 3 = Me, n = 2 C 30 H 30 N 2 O 5 , mp 287-289°C. PMR spectrum (300 MHz, DMSO-d 6 , δ, ppm, J/Hz): 1.84 (2H, m, CH 2 -7″), 1.93 (2H, m, CH 2

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1,2,4-Thiadiazole derivatives of cytisine

Cited by 14 publications

References 4 publications

Structural features of N-acylcytisines

Structural features of N-acylcytisines

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

Modified coumarins. 20. Furocoumarin derivatives of cytisine

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