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Direct thionation of quinolizidine alkaloids (-)-cytisine, methylcytisine, thermopsine and some of their carbonyl derivatives was realized. It was established that carrying out of the reaction in the boiling toluene with 0.5 eq. of Lawesson's reagent (LR) is most effective for synthesis of thio analogues of methyl-, allyl-, benzylcytisine and thermopsine. It was found, that formation of thioamides is preferable in the case with starting 3-carboxamides of (-)-cytisine or 2-oxo and 4-oxo derivatives of methylcytisine; and an excess of LR is needed for their exhaustive thionation. It was shown, that thionation of 'cytisine substituted' urea and thiourea, as well as Diels-Alder adducts of methylcitisine with phenylmaleimide on basis of this approach was not quite successful: only thionation of the 2-pyridone core has occurred. It should be noted that transformation of urea and thiourea is complicated by side reactions leading to low yields of thio products, and the result of LR interaction with mentioned above diastereomeric Diels-Alder adducts depends on their stereochemistry and thermodynamic stability under reaction conditions.

Novel derivatives of quinolizidine alkaloid ( - )-cytisine were synthesised. ADME properties, cytotoxicity against HEK293 cells and activity against viruses of influenza A/California/07/09(H1N1)pdm09 virus (IAV) and human parainfluenza virus type 3 (HPIV3) were evaluated. It was shown, that 9-carboxamides of methylcytisine (with phenyl and allyl urea's fragments) are most active compounds against IAV probably due to predicted in silico peculiarity of their interactions with the 4R7B active site of IAV neuraminidase. Indexes of selectivity (SI) calculated as ratio of CC 50 /IC 50 of these ureas are 47 and 59 correspondingly. It was also found, that derivatives obtained from allyl isocyanate and ( - )-cytisine or 9,11-dibromocytisine are able to inhibit a reproduction of HPIV3 with SI = 58 and 95. Moreover, last compound - (1  R ,5 R )- N -allyl-9,11-dibromo-8-oxo-1,5,6,8-tetrahydro-2 H -1,5-methanopyrido[1,2- a ][1,5]diazocine-3(4 H )-carboxamide with two bromine atom in 2-pyridone core of starting ( - )-cytisine molecule, demonstrated high activity against HPIV3 (SI = 95) and moderate activity against IAV (SI = 16).

The first direct synthesis of 3- N -methyl-9-formylcytisine via electrophylic formylation is described. It is established, that Vilsmeier-Haack and Gatterman variants of this reaction are unsuccessful in the case with 3-substituted (-)-cytisine derivatives, but Duff procedure (with hexamethylenetetramine in trifluoroacetic acid) gives a possibility to obtain the target pseudo aromatic aldehyde with the 69% yield. Convenient precursors for [4 + 2]- or [3 + 2]-cycloaddition reactions are obtained by means of condensation of synthesized 3- N -methyl-9-formylcytisine with acetone, nitromethane and phosphorous ylides with yields from 70 to 87%. Alternative aprroach to alkenyl products and to 9-alkynyl-3-methylcytisine is realized using the Heck and Sonogashira cross-coupling reactions of methyl vinyl ketone, cyclohexenone or trimethylsilylacetylene with 9-bromo-3-methylcytisine (55, 70 and 60% accordingly). It is shown, that interaction of 3- N -methyl-9-formylcytisine with hydroxylamines leads to corresponding nitrone (93%) and oxime (70%). All individual compounds are isolated by column chromatography and completely characterized on the basis of NMR spectroscopy data.

We performed screening of nootropic properties of 10 new derivatives of quinolizidine alkaloid (-)-cytisine. Compounds with β-endo stereochemistry were more active than α-endo-isomers. Under stress conditions (3aR,4S,8S,12R,12aS,12bR)-10-methyl-2-phenyloctahydro-1H-4,12a-etheno-8,12-methanopyrrolo[3',4':3,4]pyrido[1,2-a] [1,5]diazocine-1,3,5(4H)-trione enhanced memory and had a positive effect on cognitive functions of rats. According to molecular docking data, the nootropic activity of the compound can be associated with its affinity for the glutamate-binding subunits GluK1 and GluR2 of the kainate and AMPA receptor, respectively.

Background and Objectives: Neurodegenerative diseases and inflammation are always linked to each other; therefore the elaboration of new chemical compounds, which interact with pharmacological targets involved into these two processes, can become one of ways of correction of these types of human CNS pathology. In the field of this problem the anti-inflammatory activity of ten 3-amino derivatives of quinolizidine alkaloid (.)-cytisine (the data about nootropic activity of these compounds are outlined by us previously) was studied by using in vivo, in vitro and in silico approaches., Methods: The anti-inflammatory activity of novel compounds was investigated on carrageenan- induced model of inflammation in Rat paw following an established protocol. COX-1 (ovin) and COX-2 (human recombinant) inhibition activities of tested compounds assessed using a COX Fluorescent Inhibitor Screening Assay Kit. And as part of an in silico screening the leading compounds were docked into the tyrosine sites of COX-1/COX-2 enzymes (PDB code: 1DIY and 1CVU)., Results: It was established that ability of 3-(2-hydroxyphenyl)amino, 3-(4-hydroxyphenyl) amino and 3-(3-phenylprop-2-en-1-yl)amino derivatives of 12-N-metylcytisine to inhibit the carrageenan-induced paw oedema in rats is comparable with reference drug diclofenac. The results of in vitro COX-1/COX-2 inhibition assay showed no significant activity of tested compounds, except compounds with 2-hydroxyphenyl, 3-phenylprop-2-en-1-yl, furyl and thiophenyl fragments which slightly reduce the activity of COX-2., Conclusion: The tendency to occurrence of anti-inflammatory properties of synthesized derivatives of quinolizidine alkaloid (-)-cytisine can be explained on the basis of molecular docking results, which assume the possibility of interaction of more potent compounds with key amino acids of COX-1/COX-2 active sites., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

The first example of aza-Michael reaction of 12-N-carboxamide of quinolizidine alkaloid (-)-cytisine with α,β-unsaturated ketones, dimethyl acetylenedicarboxylate and β-nitrostyrene under high pressure condition has been described. It has been shown that the [4+2]-cycloaddition takes place in the case with N-phenylmaleimide.