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1.
Bioorg Med Chem Lett ; 99: 129623, 2024 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-38242331

RESUMO

Dengue virus (DENV) is a significant global health threat, causing millions of cases worldwide each year. Developing antiviral drugs for DENV has been a challenging endeavor. Our previous study identified anti-DENV properties of two (-)-cytisine derivatives contained substitutions within the 2-pyridone core from a pool of 19 (-)-cytisine derivatives. This study aimed to expand on the previous research by investigating the antiviral potential of N-methylcytisine thio (mCy thio) derivatives against DENV, understanding the molecular mechanisms of antiviral activity for the active thio derivatives. The inhibitory assays on DENV-2-induced cytopathic effect and infectivity revealed that mCy thio derivatives 3 ((1R,5S)-3-methyl-1,2,3,4,5,6-hexahydro-8H-1,5-methanopyrido[1,2-a][1,5]diazocine-8-thione) and 6 ((1S,5R)-3-methyl-2-thioxo-1,2,3,4,5,6-hexahydro-8H-1,5-methanopyrido[1,2-a][1,5]diazocin-8-one) were identified as the active compounds against both DENV-1 and DENV-2. Derivative 6 displayed robust antiviral activity against DENV-2, with EC50 values ranging from 0.002 to 0.005 µM in different cell lines. Derivative 3 also exhibited significant antiviral activity against DENV-2. The study found that these compounds are effective at inhibiting DENV-2 at both the entry stage (including virus attachment) and post-entry stages of the viral life cycle. The study also investigated the inhibition of the DENV-2 NS2B-NS3 protease activity by these compounds. Derivative 6 demonstrated notably stronger inhibition compared to mCy thio 3, revealing its dual antiviral action at both the entry and post-entry stages. Molecular docking simulations indicated that mCy thio derivatives 3 and 6 bind to the domain I and III of the DENV E protein, as well as the active of NS2B-NS3 protease, suggesting their molecular interactions with the virus. The study demonstrates the antiviral efficacy of N-methylcytisine thio derivatives against DENV. It provides valuable insights into the potential interactions between these compounds and viral target proteins, which could be useful in the development of antiviral drugs for DENV.


Assuntos
Vírus da Dengue , Alcaloides Quinolizidínicos , Simulação de Acoplamento Molecular , Proteínas do Envelope Viral , Peptídeo Hidrolases , Serina Endopeptidases/metabolismo , Antivirais/farmacologia , Antivirais/metabolismo , Inibidores de Proteases/farmacologia , Proteínas não Estruturais Virais
2.
Nat Prod Res ; : 1-6, 2023 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-37874662

RESUMO

On the basis of typical for secondary amino group reactions a number of derivatives of alkaloid (+)-salsolidine was synthesised. Cytotoxic properties of obtained compounds towards the HEK293, A549, MCF-7 and SH-SY5Y cell lines have been evaluated. As a result of the screening, the hit compound - 2-(chloroacetyl)-6,7-dimethoxy-1-methyl-1,2,3,4-tetrahydroisoquinoline (11) was identified, that inhibited the metabolic activity of A-549, MCF-7 and SH-SY5Y tumour cell lines with the IC50 values of 3.83 ± 0.78 µM, 5.84 ± 1.62 µM and 2.89 ± 0,92 µM correspondingly. Based on the effect of 11 on the cell cycle progression and the molecular docking data, it was preliminary assumed that the cytotoxic activity of the 11 can be realised through its interaction with the active site of the cyclin-dependent kinase CDK9 (PDB code 3BLR).

3.
Int J Mol Sci ; 24(16)2023 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-37628818

RESUMO

The utility of sterically hindered phenols (SHPs) in drug design is based on their chameleonic ability to switch from an antioxidant that can protect healthy tissues to highly cytotoxic species that can target tumor cells. This work explores the biological activity of a family of 45 new hybrid molecules that combine SHPs equipped with an activating phosphonate moiety at the benzylic position with additional urea/thiourea fragments. The target compounds were synthesized by reaction of iso(thio)cyanates with C-arylphosphorylated phenols containing pendant 2,6-diaminopyridine and 1,3-diaminobenzene moieties. The SHP/urea hybrids display cytotoxic activity against a number of tumor lines. Mechanistic studies confirm the paradoxical nature of these substances which combine pronounced antioxidant properties in radical trapping assays with increased reactive oxygen species generation in tumor cells. Moreover, the most cytotoxic compounds inhibited the process of glycolysis in SH-SY5Y cells and caused pronounced dissipation of the mitochondrial membrane of isolated rat liver mitochondria. Molecular docking of the most active compounds identified the activator allosteric center of pyruvate kinase M2 as one of the possible targets. For the most promising compounds, 11b and 17b, this combination of properties results in the ability to induce apoptosis in HuTu 80 cells along the intrinsic mitochondrial pathway. Cyclic voltammetry studies reveal complex redox behavior which can be simplified by addition of a large excess of acid that can protect some of the oxidizable groups by protonations. Interestingly, the re-reduction behavior of the oxidized species shows considerable variations, indicating different degrees of reversibility. Such reversibility (or quasi-reversibility) suggests that the shift of the phenol-quinone equilibrium toward the original phenol at the lower pH may be associated with lower cytotoxicity.


Assuntos
Neuroblastoma , Fenóis , Humanos , Animais , Ratos , Fenóis/farmacologia , Antioxidantes/farmacologia , Fenol , Ureia , Espécies Reativas de Oxigênio , Simulação de Acoplamento Molecular , Apoptose
4.
Int J Mol Sci ; 24(11)2023 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-37298694

RESUMO

Novel monoterpene-based hydroxamic acids of two structural types were synthesized for the first time. The first type consisted of compounds with a hydroxamate group directly bound to acyclic, monocyclic and bicyclic monoterpene scaffolds. The second type included hydroxamic acids connected with the monoterpene moiety through aliphatic (hexa/heptamethylene) or aromatic linkers. An in vitro analysis of biological activity demonstrated that some of these molecules had powerful HDAC6 inhibitory activity, with the presence of a linker area in the structure of compounds playing a key role. In particular, it was found that hydroxamic acids containing a hexa- and heptamethylene linker and (-)-perill fragment in the Cap group exhibit excellent inhibitory activity against HDAC6 with IC50 in the submicromolar range from 0.56 ± 0.01 µM to 0.74 ± 0.02 µM. The results of the study of antiradical activity demonstrated the presence of moderate ability for some hydroxamic acids to scavenge 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2ROO• radicals. The correlation coefficient between the DPPH radical scavenging activity and oxygen radical absorbance capacity (ORAC) value was R2 = 0.8400. In addition, compounds with an aromatic linker based on para-substituted cinnamic acids, having a monocyclic para-menthene skeleton as a Cap group, 35a, 38a, 35b and 38b, demonstrated a significant ability to suppress the aggregation of the pathological ß-amyloid peptide 1-42. The 35a lead compound with a promising profile of biological activity, discovered in the in vitro experiments, demonstrated neuroprotective effects on in vivo models of Alzheimer's disease using 5xFAD transgenic mice. Together, the results obtained demonstrate a potential strategy for the use of monoterpene-derived hydroxamic acids for treatment of various aspects of Alzheimer's disease.


Assuntos
Doença de Alzheimer , Animais , Camundongos , Doença de Alzheimer/tratamento farmacológico , Ácidos Hidroxâmicos/química , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Histona Desacetilases/uso terapêutico , Inibidores de Histona Desacetilases/química , Camundongos Transgênicos , Peptídeos beta-Amiloides , Relação Estrutura-Atividade
5.
Nat Prod Res ; 36(14): 3538-3543, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33397149

RESUMO

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.


Assuntos
Alcaloides , Quinolizidinas , Compostos Organotiofosforados , Tioureia , Ureia
6.
Bioorg Med Chem Lett ; 54: 128437, 2021 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-34737087

RESUMO

Dengue virus (DENV) causes about 50-100 million cases per year worldwide. However, there is still a big challenge in developing antiviral drugs against DENV infection. Some derivatives of alkaloid (-)-cytisine, like other alkaloid analogs, have been proposed for their antiviral potential. This study investigated antiviral activity and mechanisms of the cytisine derivatives, and discovered the structure-activity relationship against DENV. The antiviral assays were performed using one strain of DENV1 and DENV2, and two cell lines Vero E6 and A549. The structure-activity relationship of the effective compounds was also evaluated using combination of time-of-addition/removal assay and molecular docking. Compounds 3, 4, 12 (N-allylcytisine-3-thiocarbamide), 16, and 20 exhibited the high antiviral activity with IC50 values of lower than 3 µM against DENV1 and DENV2. Of them, the derivative 12 showed the highest antiviral activities against DENV1 (IC50 = 0.14 µM) and DENV-2 (IC50 = <0.1 µM), exhibiting the potent inhibition on virus attachment and entry stages. Meanwhile, the compounds 4 and 20 had a strong inhibition at the post-entry stage (IC50 = <0.1 µM). A correlation between the experimental pIC50 values and predicted pKi calculated by docking of compounds into DENV E protein was significant, correlating with the impact of compound 12 on the attachment stage, but compounds 4, and 20 on post-entry stage. The results provided the insight into the directions of synthetic modifications of starting (-)-cytisine as the inhibitors of DENV E protein at attachment and entry stages of DENV life cycle.


Assuntos
Alcaloides/farmacologia , Antivirais/farmacologia , Vírus da Dengue/efeitos dos fármacos , Alcaloides/síntese química , Alcaloides/química , Antivirais/síntese química , Antivirais/química , Azocinas/síntese química , Azocinas/química , Azocinas/farmacologia , Relação Dose-Resposta a Droga , Testes de Sensibilidade Microbiana , Estrutura Molecular , Quinolizinas/síntese química , Quinolizinas/química , Quinolizinas/farmacologia , Relação Estrutura-Atividade
7.
Pharmaceutics ; 13(11)2021 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-34834312

RESUMO

Hydroxamic acids are one of the most promising and actively studied classes of chemical compounds in medicinal chemistry. In this study, we describe the directed synthesis and effects of HDAC6 inhibitors. Fragments of adamantane and natural terpenes camphane and fenchane, combined with linkers of various nature with an amide group, were used as the CAP groups. Accordingly, 11 original target compounds were developed, synthesized, and exposed to in vitro and in vivo biological evaluations, including in silico methods. In silico studies showed that all synthesized compounds were drug-like and could penetrate through the blood-brain barrier. According to the in vitro testing, hydroxamic acids 15 and 25, which effectively inhibited HDAC6 and exhibited anti-aggregation properties against ß-amyloid peptides, were chosen as the most promising substances to study their neuroprotective activities in vivo. All in vivo studies were performed using 5xFAD transgenic mice simulating Alzheimer's disease. In these animals, the Novel Object Recognition and Morris Water Maze Test showed that the formation of hippocampus-dependent long-term episodic and spatial memory was deteriorated. Hydroxamic acid 15 restored normal memory functions to the level observed in control wild-type animals. Notably, this effect was precisely associated with the ability to restore lost cognitive functions, but not with the effect on motor and exploratory activities or on the level of anxiety in animals. Conclusively, hydroxamic acid 15 containing an adamantane fragment linked by an amide bond to a hydrocarbon linker is a possible potential multitarget agent against Alzheimer's disease.

8.
Int J Mol Sci ; 22(11)2021 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-34064275

RESUMO

Sigma-1 receptor (chaperone Sigma1R) is an intracellular protein with chaperone functions, which is expressed in various organs, including the brain. Sigma1R participates in the regulation of physiological mechanisms of anxiety (Su, T. P. et al., 2016) and reactions to emotional stress (Hayashi, T., 2015). In 2006, fabomotizole (ethoxy-2-[2-(morpholino)-ethylthio]benzimidazole dihydrochloride) was registered in Russia as an anxiolytic (Seredenin S. and Voronin M., 2009). The molecular targets of fabomotizole are Sigma1R, NRH: quinone reductase 2 (NQO2), and monoamine oxidase A (MAO-A) (Seredenin S. and Voronin M., 2009). The current study aimed to clarify the dependence of fabomotizole anxiolytic action on its interaction with Sigma1R and perform a docking analysis of fabomotizole interaction with Sigma1R. An elevated plus maze (EPM) test revealed that the anxiolytic-like effect of fabomotizole (2.5 mg/kg i.p.) administered to male BALB/c mice 30 min prior EPM exposition was blocked by Sigma1R antagonists BD-1047 (1.0 mg/kg i.p.) and NE-100 (1.0 mg/kg i.p.) pretreatment. Results of initial in silico study showed that fabomotizole locates in the active center of Sigma1R, reproducing the interactions with the site's amino acids common for established Sigma1R ligands, with the ΔGbind value closer to that of agonist (+)-pentazocine in the 6DK1 binding site.


Assuntos
Ansiolíticos/farmacologia , Ansiedade/tratamento farmacológico , Benzimidazóis/farmacologia , Chaperonas Moleculares/metabolismo , Morfolinas/farmacologia , Receptores sigma/metabolismo , Animais , Anisóis/farmacologia , Sítios de Ligação/fisiologia , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Etilenodiaminas/farmacologia , Ligantes , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Propilaminas/farmacologia , Federação Russa , Receptor Sigma-1
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