Synthesis and biological activity of N-benzyl derivatives of cytisine

Rakhimov, Sh. B.; Виноградова, В. И.; Mirzaev, Yu. R.; Vypova, N. L.; Kazantseva, D. S.

doi:10.1007/s10600-006-0181-8

Cited by 11 publications

(5 citation statements)

References 3 publications

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“…1). 12 N methylcytisine, benzilcytisine and benzoilcytisine (2)-(4), and compounds (10) and (11) were synthesized according to published method ologies [8,[33][34][35][36][37]. Derivation of compounds (5)- (9) and (12)- (22) has been described previously [38][39][40][41].…”

Section: Resultsmentioning

confidence: 99%

Search for (-)-cytisine derivatives as potential inhibitors of NF-κB and STAT1

et al. 2015

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Design and synthesis ofnew derivatives of (-)-cytisine with a wide spectrum of pharmacological activity, represents the potential therapeutic interest for development of drug candidates for neurodegenerative disorders, inflammatory diseases, and treatment of nicotine addiction. We used HEK293 cell line transiently transfected with N F-κB and STATI luciferase reporter constructs to screen the (-)-cytisine derivatives for their potency to modulate basal and induced NF-κB and STAT1 activity. Currently, NF-κB, STAT1 and components of their signaling pathways are considered as attractive targets for pharmacological intervention, primarily in chronic inflammation, cancer, autoimmune, neurodegenerative and infectious diseases. The library of compounds included the derivatives of (-)-cytisine with amino-, amide-, thio- and carboxamide groups at 3, 5 and 12 position of the starting molecule, as well as some bimolecular derivatives. Our experimental data revealed compounds with moderate activating as well as inhibitory effects for basal NF-κB and STATI activity (IC50 or EC50 values are mainly in the micromolar range). The structure-activity relationship analysis demonstrated that the character of activity (activation or inhibition of NFκ-B and STAT1) is determined by the topology of the substituents at the (-)-cytisine molecule, whereas the nature of the substituents mainly contributes to severity of the effect (introduction of aromatic and adamantyl substituents, as well as thionyl or keto groups are of the principal importance). When evaluating the effect of (-)-cytisine derivatives on activity of NF-κB and STATI, induced by specific agents (TNFα and IFNγ, respectively) we observed that some compounds inhibited basal and stimulated activity of NF-κB and STAT1, another compounds showed the dual effect (an increase of basal- and a decrease of stimulated NF-κB activity) and several compounds increase both basal and induced activity of NF-κB and STAT1. Thus, obtained results suggest that one of the possible mechanisms of biological action of (-)-cytisine derivatives is their ability to influence the components of NF-κB and STAT1-dependent signaling pathways.

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Section: Resultsmentioning

confidence: 99%

Search for (-)-cytisine derivatives as potential inhibitors of NF-κB and STAT1

et al. 2015

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“…All molecular structures (8) were constructed using the Hyperchem 6.01 software package a and optimized by applying Austin Model 1 (AM1) (26) hamiltonian (with Polak‐Ribiere algorithm and termination condition 0.001 kcal/mol).…”

Section: Methodsmentioning

confidence: 99%

“…Cytisine (Chart 1) is a tricyclic representative of quinolizidine alkaloids that is mainly known as a nicotinic acetylcholine receptor (n‐AChR) partial agonist with high affinity for the neuronal α4β2 subtype (5,6). Although a pharmacological profile of cytisine itself has been extensively studied, structure–activity relationship investigations are still somewhat limited (7,8). This can be explained by the complex tricyclic structure of the alkaloids that represents a significant challenge for synthetic chemists.…”

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confidence: 99%

“…To fill in this gap, we aimed to prepare cytisine‐based compounds with potential pharmacological properties to be evaluated. In our previous reports, we described synthetic routes for cytisine alkylation by substituted benzaldehydes (8). Next, additionally to in vivo toxicity, N ‐cholinolytic, and spasmolytic activities, the effect of N‐benzylated cytisine derivatives on blood clotting system was examined in vitro and in vivo (8,18,19).…”

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confidence: 99%

“…In our previous reports, we described synthetic routes for cytisine alkylation by substituted benzaldehydes (8). Next, additionally to in vivo toxicity, N ‐cholinolytic, and spasmolytic activities, the effect of N‐benzylated cytisine derivatives on blood clotting system was examined in vitro and in vivo (8,18,19). We now report in vitro cytotoxicity of these compounds against Leishmania donovani.…”

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confidence: 99%

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Structure–Activity Relationship Investigations Of Leishmanicidal N‐Benzylcytisine Derivatives

et al. 2011

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In vitro leishmanicidal activity of 16 N-benzylcytisine derivatives has been evaluated using Leishmania donovani axenic amastigotes. In general, halogen (bromo-, chloro-) derivatives appeared to be more toxic against parasites than their parent compounds. Quantum-chemical calculations helped to recognize certain patterns in the structure of frontier orbitals related to bioactivity of compounds. Thus, the presence of halogen atom is shown to have a significant effect on both distribution and the energy of LUMOs thereby on potent activity that was also confirmed by Quantitative-Structure Activity Relationship (QSAR) analysis. Experimentally and theoretically observed structure-cytotoxicity relationships are described.

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

et al. 2015

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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.Nootropic agents are a significant component in the therapy of neurodegenerative diseases, consequences of injuries and concussions, and brain dysfunctions caused by alcoholism and acute neural infections owing their broad spectrum of activity and proven positive clinical outcomes. Nootropic agents for human health are applied mainly to the prevention of stress and maintenance of functionality in critical situations and with heightened physical and intellectual exertion [1][2][3][4].The mechanism of action of many nootropic agents is due to nootropic and mnestic properties themselves in addition to antioxidant and antihypoxic activity [5]. Therefore, both in vivo screening tests [conditioned passive-avoidance response (CPAR), normobaric hypercapnic hypoxia] and the potential protective activity of tested compounds in in vitro cell models for antiradical properties and the ability to influence the hypoxia-induced DNA-binding activity of transcription factor HIF-1 should be assessed [6,7].We demonstrated earlier that several carboxamides obtained from 3-amino-12-N-methylcytisine (1) and the corresponding isocyanates had nootropic properties that were comparable or superior to those of the reference drug piracetam [8]. A library of secondary amines 2-11 was prepared via one-pot syntheses using reductive alkylation of 1 with hetero-and aromatic aldehydes (the azomethines formed in the first step were reduced by NaBH 4 without isolation as before [9]) in order to determine nootropic activity as a function of the 2-pyridone substituent. Compounds 2-11 were obtained in 56-97% yields. Their structures were established by NMR ( 1 H, 13 C, 15 N) spectroscopy.

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Synthesis and biological activity of N-benzyl derivatives of cytisine

Abstract: The reductive alkylation of cytisine by various aromatic aldehydes was studied. Preliminary pharmacological investigations of the synthesized compounds were performed.

Cited by 11 publications

References 3 publications

Search for (-)-cytisine derivatives as potential inhibitors of NF-κB and STAT1

Search for (-)-cytisine derivatives as potential inhibitors of NF-κB and STAT1

Structure–Activity Relationship Investigations Of Leishmanicidal N‐Benzylcytisine Derivatives

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

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