Evaluation of Neurotropic Activity and Molecular Docking Study of New Derivatives of pyrano[4″,3″:4′,5′]pyrido[3′,2′:4,5]thieno[3,2-<i>d</i>]pyrimidines on the Basis of pyrano[3,4-<i>c</i>]pyridines
Background: Heterocyclic compounds and their fused analogs, which contain pharmacophore fragments such as pyridine, thiophene and pyrimidine rings, are of great interest due to their broad spectrum of biological activity. Chemical compounds containing two or more pharmacophore groups due to addition...
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MDPI AG
2022-05-01
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| Online Access: | https://www.mdpi.com/1420-3049/27/11/3380 |
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| author | Shushanik Sh. Dashyan Eugene V. Babaev Ervand G. Paronikyan Armen G. Ayvazyan Ruzanna G. Paronikyan Lernik S. Hunanyan |
| author_facet | Shushanik Sh. Dashyan Eugene V. Babaev Ervand G. Paronikyan Armen G. Ayvazyan Ruzanna G. Paronikyan Lernik S. Hunanyan |
| author_sort | Shushanik Sh. Dashyan |
| collection | DOAJ |
| description | Background: Heterocyclic compounds and their fused analogs, which contain pharmacophore fragments such as pyridine, thiophene and pyrimidine rings, are of great interest due to their broad spectrum of biological activity. Chemical compounds containing two or more pharmacophore groups due to additional interactions with active receptor centers usually enhance biological activity and can even lead to a new type of activity. The search for new effective neurotropic drugs in the series of derivatives of heterocycles containing pharmacophore groups in organic, bioorganic and medical chemistry is a serious problem. Methods: Modern methodology of drugs involves synthesis, physicochemical study, molecular modeling and selection of active compounds through virtual screening and experimental evaluation of the biological activity of new chimeric compounds with pharmacophore fragments. For the synthesis of new compounds, classical organic methods were used and developed. For the evaluation of neurotropic activity of new synthesized compounds, some biological methods were used according to indicators characterizing anticonvulsant, sedative and antianxiety activity as well as side effects. For docking analysis, various soft ware packages and methods were used. Results: As a result of multistep reactions, 11 new, tri- and tetracyclic heterocyclic systems were obtained. The studied compounds exhibit protection against pentylenetetrazole (PTZ) seizures as well as some psychotropic effects. The biological assays evidenced that nine of the eleven studied compounds showed a high anticonvulsant activity by antagonism with pentylenetetrazole. The toxicity of the compounds is low, and they do not induce muscle relaxation in the studied doses. According to the study of psychotropic activity, it was found that the selected compounds have an activating behavior and anxiolytic effects on the “open field” and “elevated plus maze” (EPM) models. The data obtained indicate the anxiolytic (antianxiety) activity of the derivatives of tricyclic thieno[2,3-<i>b</i>]pyridines and tetracyclic pyridothieno[3,2-<i>d</i>]pyrimidin-8-ones, especially pronounced in compounds <b>3b</b>–<b>f</b> and <b>4e</b>. The studied compounds increase the latent time of first immobilization on the “forced swimming” (FS) model and exhibit antidepressant effects; compounds <b>3e</b> and <b>3f</b> especially exhibit these effects, similarly to diazepam. Docking studies revealed that compounds <b>3c</b> and <b>4b</b> bound tightly in the active site of γ-aminobutyric acid type A (GABA<sub>A</sub>) receptors with a value of the scoring function that estimates free energy of binding (∆G) at −10.0 ± 5 kcal/mol. Compound <b>4e</b> showed the best affinity ((∆G) at −11.0 ± 0.54 kcal/mol) and seems to be an inhibitor of serotonin (SERT) transporter. Compounds <b>3c</b>–<b>f</b> and <b>4e</b> practically bound with the groove of T4L of 5HT_1A and blocked it completely, while the best affinity observed was in compound <b>3f</b> ((∆G) at −9.3 ± 0.46 kcal/mol). Conclusions: The selected compounds have an anticonvulsant, activating behavior and anxiolytic effects and at the same time exhibit antidepressant effects. |
| first_indexed | 2024-03-10T01:05:31Z |
| format | Article |
| id | doaj.art-85ab2d37a5564f65afd669547520f275 |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-10T01:05:31Z |
| publishDate | 2022-05-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-85ab2d37a5564f65afd669547520f2752023-11-23T14:27:49ZengMDPI AGMolecules1420-30492022-05-012711338010.3390/molecules27113380Evaluation of Neurotropic Activity and Molecular Docking Study of New Derivatives of pyrano[4″,3″:4′,5′]pyrido[3′,2′:4,5]thieno[3,2-<i>d</i>]pyrimidines on the Basis of pyrano[3,4-<i>c</i>]pyridinesShushanik Sh. Dashyan0Eugene V. Babaev1Ervand G. Paronikyan2Armen G. Ayvazyan3Ruzanna G. Paronikyan4Lernik S. Hunanyan5Scientific Technological Center of Organic and Pharmaceutical Chemistry of National Academy of Sciences of Republic of Armenia, Ave. Azatutyan 26, Yerevan 0014, ArmeniaFaculty of Chemistry, Moscow State University, 1, GSP-1, 1-3 Leninskiye Gory, 119991 Moscow, RussiaScientific Technological Center of Organic and Pharmaceutical Chemistry of National Academy of Sciences of Republic of Armenia, Ave. Azatutyan 26, Yerevan 0014, ArmeniaScientific Technological Center of Organic and Pharmaceutical Chemistry of National Academy of Sciences of Republic of Armenia, Ave. Azatutyan 26, Yerevan 0014, ArmeniaScientific Technological Center of Organic and Pharmaceutical Chemistry of National Academy of Sciences of Republic of Armenia, Ave. Azatutyan 26, Yerevan 0014, ArmeniaLaboratory of Structural Bioinformatics, Institute of Biomedicine and Pharmacy, Russian-Armenian University, 123 H. Emin Str., Yerevan 0051, ArmeniaBackground: Heterocyclic compounds and their fused analogs, which contain pharmacophore fragments such as pyridine, thiophene and pyrimidine rings, are of great interest due to their broad spectrum of biological activity. Chemical compounds containing two or more pharmacophore groups due to additional interactions with active receptor centers usually enhance biological activity and can even lead to a new type of activity. The search for new effective neurotropic drugs in the series of derivatives of heterocycles containing pharmacophore groups in organic, bioorganic and medical chemistry is a serious problem. Methods: Modern methodology of drugs involves synthesis, physicochemical study, molecular modeling and selection of active compounds through virtual screening and experimental evaluation of the biological activity of new chimeric compounds with pharmacophore fragments. For the synthesis of new compounds, classical organic methods were used and developed. For the evaluation of neurotropic activity of new synthesized compounds, some biological methods were used according to indicators characterizing anticonvulsant, sedative and antianxiety activity as well as side effects. For docking analysis, various soft ware packages and methods were used. Results: As a result of multistep reactions, 11 new, tri- and tetracyclic heterocyclic systems were obtained. The studied compounds exhibit protection against pentylenetetrazole (PTZ) seizures as well as some psychotropic effects. The biological assays evidenced that nine of the eleven studied compounds showed a high anticonvulsant activity by antagonism with pentylenetetrazole. The toxicity of the compounds is low, and they do not induce muscle relaxation in the studied doses. According to the study of psychotropic activity, it was found that the selected compounds have an activating behavior and anxiolytic effects on the “open field” and “elevated plus maze” (EPM) models. The data obtained indicate the anxiolytic (antianxiety) activity of the derivatives of tricyclic thieno[2,3-<i>b</i>]pyridines and tetracyclic pyridothieno[3,2-<i>d</i>]pyrimidin-8-ones, especially pronounced in compounds <b>3b</b>–<b>f</b> and <b>4e</b>. The studied compounds increase the latent time of first immobilization on the “forced swimming” (FS) model and exhibit antidepressant effects; compounds <b>3e</b> and <b>3f</b> especially exhibit these effects, similarly to diazepam. Docking studies revealed that compounds <b>3c</b> and <b>4b</b> bound tightly in the active site of γ-aminobutyric acid type A (GABA<sub>A</sub>) receptors with a value of the scoring function that estimates free energy of binding (∆G) at −10.0 ± 5 kcal/mol. Compound <b>4e</b> showed the best affinity ((∆G) at −11.0 ± 0.54 kcal/mol) and seems to be an inhibitor of serotonin (SERT) transporter. Compounds <b>3c</b>–<b>f</b> and <b>4e</b> practically bound with the groove of T4L of 5HT_1A and blocked it completely, while the best affinity observed was in compound <b>3f</b> ((∆G) at −9.3 ± 0.46 kcal/mol). Conclusions: The selected compounds have an anticonvulsant, activating behavior and anxiolytic effects and at the same time exhibit antidepressant effects.https://www.mdpi.com/1420-3049/27/11/3380pyrano[3,4-<i>c</i>]pyridinesthieno[2,3-<i>b</i>]pyridinethieno[3,2-<i>d</i>]pyrimidinonesneurotrophic activitydocking analysis |
| spellingShingle | Shushanik Sh. Dashyan Eugene V. Babaev Ervand G. Paronikyan Armen G. Ayvazyan Ruzanna G. Paronikyan Lernik S. Hunanyan Evaluation of Neurotropic Activity and Molecular Docking Study of New Derivatives of pyrano[4″,3″:4′,5′]pyrido[3′,2′:4,5]thieno[3,2-<i>d</i>]pyrimidines on the Basis of pyrano[3,4-<i>c</i>]pyridines Molecules pyrano[3,4-<i>c</i>]pyridines thieno[2,3-<i>b</i>]pyridine thieno[3,2-<i>d</i>]pyrimidinones neurotrophic activity docking analysis |
| title | Evaluation of Neurotropic Activity and Molecular Docking Study of New Derivatives of pyrano[4″,3″:4′,5′]pyrido[3′,2′:4,5]thieno[3,2-<i>d</i>]pyrimidines on the Basis of pyrano[3,4-<i>c</i>]pyridines |
| title_full | Evaluation of Neurotropic Activity and Molecular Docking Study of New Derivatives of pyrano[4″,3″:4′,5′]pyrido[3′,2′:4,5]thieno[3,2-<i>d</i>]pyrimidines on the Basis of pyrano[3,4-<i>c</i>]pyridines |
| title_fullStr | Evaluation of Neurotropic Activity and Molecular Docking Study of New Derivatives of pyrano[4″,3″:4′,5′]pyrido[3′,2′:4,5]thieno[3,2-<i>d</i>]pyrimidines on the Basis of pyrano[3,4-<i>c</i>]pyridines |
| title_full_unstemmed | Evaluation of Neurotropic Activity and Molecular Docking Study of New Derivatives of pyrano[4″,3″:4′,5′]pyrido[3′,2′:4,5]thieno[3,2-<i>d</i>]pyrimidines on the Basis of pyrano[3,4-<i>c</i>]pyridines |
| title_short | Evaluation of Neurotropic Activity and Molecular Docking Study of New Derivatives of pyrano[4″,3″:4′,5′]pyrido[3′,2′:4,5]thieno[3,2-<i>d</i>]pyrimidines on the Basis of pyrano[3,4-<i>c</i>]pyridines |
| title_sort | evaluation of neurotropic activity and molecular docking study of new derivatives of pyrano 4 3 4 5 pyrido 3 2 4 5 thieno 3 2 i d i pyrimidines on the basis of pyrano 3 4 i c i pyridines |
| topic | pyrano[3,4-<i>c</i>]pyridines thieno[2,3-<i>b</i>]pyridine thieno[3,2-<i>d</i>]pyrimidinones neurotrophic activity docking analysis |
| url | https://www.mdpi.com/1420-3049/27/11/3380 |
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