Search for compounds with antiviral activity among synthetic (-)-cytisine derivatives

Abstract

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.

Synthesis of Camphecene and Cytisine Conjugates Using Click Chemistry Methodology and Study of Their Antiviral Activity

“…The immediate conjugation of azides 5 – 8 with propargyl ether 9 was performed using [2+3] cycloaddition of organic azides to compounds with terminal triple bond. This reaction is well‐known since the middle of the past century, in recent time it became one of the popular methods of preparative organic chemistry, in particular for constructing molecular systems with different kinds of biological activity, due to the works by Sharpless . The reaction of azides 5 – 8 with ether 9 was conducted by the previously described procedure .…”

“…The use of cytisine as one of pharmacophoric blocks is purposeful because it has a rather wide pharmacologic profile, [15,16] including antiviral. [17] Direct conjugation of cytisine with camphor was carried out by click chemistry methodology assuming coppercatalyzed [2 + 3] cycloaddition of azides to alkynes. [18] It should be noted that click chemistry approach was used not only as an instrument for conjugation of different portions of molecule but also for possible increase in biological activity due to introduction of 1,2,3-triazole fragment, which is a well-known pharmacophore.…”

“…With the aim to continue our work to extend the library of compounds showing antiviral activity, we synthesized new hybrid molecules based on (+)‐camphor derivatives and (−)‐cytisine, an alkaloid of quinolizidine series, and studied their antiviral properties. The use of cytisine as one of pharmacophoric blocks is purposeful because it has a rather wide pharmacologic profile, including antiviral . Direct conjugation of cytisine with camphor was carried out by click chemistry methodology assuming copper‐catalyzed [2+3] cycloaddition of azides to alkynes .…”

Activity of Thermopsis schischkinii Alkaloids Against Influenza A(H1N1)pdm09 Virus

“…The reference drugs were rimantadine and ribavirin. The experimental method was described before in detail [7,18].…”

“…The selectivity indices (SI), which were ratios of CTD 50 /EC 50 values, for fraction 4 with the lowest median EC 50 (1 Pg/mL) and for fraction 5 (3.1 Pg/mL) indicated that they had high anti-influenza activity (SI for 4, 300; for 5, 97) that was statistically significantly greater than those of the reference drugs (SI of rimantadine, 5; of ribavirin, 147) [7]. The A/California/07/09(H1N1)pdm09 virus that was used in the work is known to be rimantadine-resistant.…”