A. V. Koval’skaya

Synthesis and neuropharmacological activity of N -1-adamantylcytisine-12-carbamide and its 12-thiocarbonyl analog

The neuropharmacological activity of two (–)-cytisine derivatives with adamantyl fragments was studied. It was shown that N-1-adamantylcytisine-12-thiocarbamide exhibited in tests in vivo a pronounced mnestic effect, increased the lifespan of laboratory animals under hypoxic conditions, and also enhanced in vitro binding of transcription factors NFAT and NF-κB to the DNA sequences corresponding to them.

Synthesis and specific nootropic activity of (–)-cytisine derivatives with carbamide and thiocarbamide moieties in their structure

N-(methylcytisinyl)-N′-substituted ureas, N-substituted cytisine-12-carbamides, and cytisine-12-thiocarbamide were prepared by reaction of (–)-cytisine with urea and thiourea and of (–)-cytisine and its 12-N-methyl-3-amino derivative with isocyanates. Their specific nootropic activity was studied in vivo. The therapeutic index was determined for the lead compound. Promising candidates for further pharmacological testing were found.

Synthesis of 3- and 5-Amino Derivatives of Methylcytisine

Synthetic approaches to 3- and 5-amino derivatives of methylcytisine via its nitration with subsequent reduction and a four-step synthetic sequence of exhaustive bromination, regioselective debromination, nitration and one-pot catalytic reduction of the nitro group, and debromination were proposed.

SEARCH FOR COMPOUNDS WITH ANTIVIRAL ACTIVITY AMONG SYNTHETIC ()-CYTISINE DERIVATIVES

The antiviral activity of several amides and thio- and carboxamides of (-)-cytisine in addition to bromination and nitration products of its 2-pyridone core was studied. Compounds with a selectivity index close to 10 were found.

New (−)−Cytisine Derivatives with Nootropic Activity

The mnestic and antihypoxic effects of new derivatives of the quinolizidine alkaloid (−)-cytisine on acquisition of a conditioned passive avoidance reflex (CPAR) were studied in rats; effects on normobaric (jar) hypoxia were studied in mice. Screening studies showed that the benzamide and the N-(12-methylcytidin-3-yl)-N′-phenylurea not only improved learning and memory, but also increased the resistance of the brain to hypoxia.

Synthesis and Nootropic Activity of new 3-Amino-12- N -Methylcytisine Derivatives

Reductive alkylation of 3-amino-12-N-methylcytisine by aromatic aldehydes synthesized a series of secondary amines. The nootropic activity of the synthesized compounds was studied in vivo (mnestic and antihypoxic properties) and in vitro (antiradical properties and ability to affect transcription factor HIF-1 DNA-binding activity). The cytotoxicity of the synthesized compounds was assessed. The lead compound was identified.

Synthesis and Molecular Structure of N-{(1R,5S)-3-Methyl-8-Oxo-1,3,4,5,6,8-Hexahydro-2H-1,5-Methanopyrido[1,2-α] [1,5]Diazocin-9-yl}Acetamide

Compound 2 was isolated by column chromatography over SiO2 in 67% yield and had mp 171–172°C (MeOH) and [ ]D 20 –16.0° (c 0.72, CHCl3). The crystal and molecular structure of 2 were established by an x-ray crystal structure analysis (XSA), for which crystals of 2 were grown by slow crystallization from MeOH. The asymmetric unit of the unit cell of 2 contained two molecules (2a and 2b) that had very similar structures. Figure 1 shows a general view of the symmetry independent molecules 2a and 2b. The compound crystallized in chiral space group P21 and contained two chiral centers (1R,5S). The absolute configuration was the same as that of starting (–)-cytisine. The diazabicyclononane had a chair–half-chair conformation, which is often observed in similar compounds [6–10]. The amide was practically coplanar with the aromatic ring. As we supposed, the trans-orientation of the C9–N1 (C9 –N1 in the second independent molecule) was explained mainly by steric considerations. Thus, the acidic amide proton and the carbonyl O1 atom were oriented on the same side. This favored the formation of the H-bonded dimer. In fact, the two symmetrically independent 2a and 2b were joined in the crystal structure into a dimer through N1–H1...O1 (H...O 2.37 A° , N...O 3.235(2) A° , 1, i.e., when the crystal structure consisted of more than a single independent molecule [11–14]. Apparently, this was due to limitations imposed by the symmetry, which prevented the molecules from adopting the optimum orientation relative to each other. Crystals of C14H19N3O2 (MW 261.32) at 100 K were monoclinic, a = 11.4769(10), b = 9.4595(8), c = 12.9183(11) A ° , = 106.697(2)°, V = 1343.4(2) A° 3, space group P21, Z = 4, dcalc = 1.292 mg/m 3. A data set of 19,378 reflections was collected on a Bruker Smart Apex2 CCD diffractometer ( Mo K -radiation, 2 max = 64°). The starting set of measured intensities was processed using the SAINT and SADABS programs included in the APEX2 program suite [15]. The structure was solved by direct methods and was refined by anisotropic full-matrix least-squares methods over Fhkl for non-hydrogen atoms. The H atoms were placed in geometrically calculated positions with the exception of the amide H, the position of which was located in a difference electron-density synthesis. Then, the N–H distance was normalized to 0.90 A° . The H atoms were refined using a rider model. A total of 4910 independent reflections (Rint = 0.0395) were used in the refinement. The refinement over all independent reflections gave wR2 = 0.1019 [R1 = 0.0422 over 4267 reflections with I > 2 (I)]. All calculations were performed using the SHELXTL programs [16]. Atomic coordinates and thermal factors were deposited in the Cambridge Crystallographic Data Centre (CCDC 981034). Thus, the structure of N-[(1R,5S)-3-methyl-8-oxo-1,3,4,5,6,8-hexahydro-2H-1,5-methanopyrido[1,2-a][1,5]diazocin9-yl]acetamide was characterized for the first time by an XSA. The existence of two symmetrically independent molecules in its crystal structure was explained. 1) Institute of Elementorganic Compounds, Russian Academy of Sciences, 119991, GSP-1, Moscow, B-334, Ul. Vavilova, 28; 2) Institute of Organic Chemistry, Ufa Scientific Center, Russian Academy of Sciences, 450054, Ufa, Prosp. Oktyabrya, 71, e-mail: tsipisheva@anrb.ru.; Translated from Khimiya Prirodnykh Soedinenii, No. 3, May–June, 2014, pp. 501–502, original article submitted January 17, 2014. N N

Amines, Amides, and Thio- and Carboxamides of (–)-Cytisine as Nfat Transcription Factor Modulators

A library of derivatives of the quinolizidine alkaloid (–)-cytisine with amine, amide, and thio- and carboxamides in the 3-, 5-, and 12-positions were synthesized. Their activity with respect to NFAT transcription factor was studied. It was shown that NFAT modulation activity was a function of the nature of the substituent.

Synthesis of Several 3,5- and 3-Substituted Thermopsine Derivatives

In continuation of research on functionalization of the 2-pyridone core of quinolizidine alkaloids [1, 2], we synthesized 3,5-dibromo-, 3-bromo-, 3-nitro-, 5-nitro-, and 3-amino-derivatives of the quinolizidine alkaloid thermopsine (1). Thermopsine (1) was obtained in S. Yu. Yunusov Institute of the Chemistry of Plant Substances (Tashkent). Its physicochemical constants agreed with those in the literature [3]. Bromination of 1 according to the literature [1] produced 3,5-dibromo-derivative 2 in 73% yield. Compound 2 was converted by zinc dust in HCl into 3-bromo-derivative 3 in 90% yield. Nitration of 1 in conc. H2SO4 as before [2] gave 3-nitrothermopsine 4 and 5-nitrothermopsine 5 in a 7:1 ratio in 60% overall yield. Then, compound 4 was reduced by H2 over Pd catalyst into amine 5 in quantitative yield. The structures of 2–5 were elucidated using PMR and 13C NMR spectroscopy.

Synthesis and Cytotoxic Activity of Conjugates of (–)-Cytisine and Thermopsin Amine Derivatives with 1,3-Dimethyl-5-Formyluracil

New conjugates of the quinolizidine alkaloids (–)-cytisine and thermopsin were synthesized by alkylating their 9-amino derivatives with 1,3-dimethyl-5-formyluracil. The cytotoxic properties of the synthesized conjugates against cell lines HEK293, HepG2, and Jurkat were studied. Screening identified the lead compound 5-{[(3-benzyl-8-oxo-1,3,4,5,6,8-hexahydro-2H-1,5-methanopyrido[1,2-a][1,5]diazocin-9-yl)amino]methyl}-1,3-dimethylpyrimidine-2,4-(1H,3H)-dione, which suppressed metabolic activity of lymphoblastic leukemia cells with inhibitory concentration (IC50) 20.6 ± 2.1 μM (IC50 of reference compound 5-fluorouracil was 18.5 ± 3.3 μM).