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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.Keywords: ()-cytisine, H1N1 flu virus.Some plants that exhibit antiviral properties are known to bear alkaloids. Thus, several genera of the family Fabaceae, e.g., Sophora, Acacia, and Caragana, yield extracts that are highly active against hepatitis C (HCV), hepatitis B (HBV), Herpes simplex 1 (HSV-1), and several other viruses [1][2][3][4][5].The search for new antiviral agents should be conducted among representatives of the most common structural groups of quinolizidine alkaloids, including ()-cytisine, because plants of the family Fabaceae are the principal producers of them [6] and the aforementioned antiviral properties may be associated with them.The pharmacological profiles of ()-cytisine itself and its derivatives are very broad. Neuropharmacological, antiinflammatory, analeptic, and antidiabetic activity was established for them [7]. An example of a study of the antiviral properties of ()-cytisine itself and several of its synthetic derivatives was published [8].We synthesized two groups of derivatives of ()-cytisine and N-methylcytisine that contained substituents on the secondary N atom and in the 2-pyridone core in order to discover compounds with antiviral activity and to establish the structure-activity relationship.The transformation products of the ()-cytisine secondary amine were amides of m-fluoro-, m-bromo-, and p-chlorobenzoic acids (1-3) that were prepared by the hydroxysuccinimide method as before [9]. The syntheses of thio-and carboxamides 4 and 5, substituted ureas 6 and 7, nitro derivatives 9 and 10, carbamide 12, and dibromo derivative 8 were described by us previously [10,11]. Dinitro derivative 11 was synthesized by repeated nitration of 9. Table 1 summarizes results from the study of the toxicity and antiviral activity of cytisine derivatives 1-12. According to the results, starting alkaloid ()-cytisine had low toxicity and antiviral activity. Transformation products of the ()-cytisine secondary amine, i.e., amides of m-fluoro-, m-bromo-, and p-chlorobenzoic acids 1-3, differed in toxicity and activity. This indicated that the nature of the corresponding acid and the halogen atom and its position on the aromatic ring affected the antiviral properties.

Allapinine (lappaconitine hydrobromide) is a drug for the treatment of cardiac arrhythmias, it shows IC class antiarrhythmics properties. Its action mechanism is associated with blockade of Na(+)-channels with subsequent inhibition of the depolarization rate and, consequently, of the slowing and reducing the excitability of the cardiac conduction system. At the moment, it is not established, what factors are associated with side effects of Allapinine, and therefore it seems important to study the molecular mechanisms of its action. The target genes were identified in a rat model of aconitine-induced arrhythmia using a commercial kit "Rat Neuroscience Ion Channels & Transporters RT2 Profiler PCR Array" (SABioscienses). Comparison of the expression of 84 genes in the experimental (aconitine arrhythmias/Allapinine) and control (aconitine arrhythmias/saline) animals revealed changes in the mRNA level of 18 genes. It has been shown an increase in mRNA levels of genes encoding various types of K(+)-channels (kcna6, kcnj1, kcnj4, kcnq2, kcnq4), Ca(2+)-channel (cacna 1g), vesicular acetylcholine transporter (slc 18a3). Decrease in the mRNA level was observed for genes encoding the Na(+)-channel (scn8a), K(+)-channels (kcne 1, kcns 1), membrane transporters (atp4a, slc6a9). Taken together, it appears that the effect of Allapinine on aconitine--induced arrhythmias is due to modulation of genes encoding Na(+)-, K(+)-, Ca(2+)-channels, conducting ionic currents (I(Na), I(to), I(Ks), I(K1), I(CaT)), which are involved in the formation of different phases of the action potential. The effect of the drug on the mRNA levels of genes encoding the acetylcholine and glycine transporters, suggesting the participation of these neurotransmitters in the mechanisms of anti-arrhythmic properties of the Allapinine.

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Novel derivatives of quinolizidine alkaloid (-)-cytisine were synthesized. Main ADME properties, cytotoxicity against HEK293 cell line and activity against viruses of influenza A/California/7/09(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 (SI of ribavirin is 67, and SI of rimantadin is 5). 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 (SI of ribavirin is 192 in this case). Moreover, last compound -(1R,5R)- N-allyl-9,11-dibromo-8-oxo-1,5,6,8-tetrahydro-2H-1,5-methanopyrido[1,2-a][1,5]diazocine-3(4H)-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).

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