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-d]pyrimidines on the Basis of pyrano[3,4-c]pyridines
Abstract
:1. Introduction
2. Results and Discussion
2.1. Chemistry
2.2. Biological Assays
2.3. Molecular Docking
2.3.1. Docking and Conformational Analysis of GABAA Receptor Complexation
2.3.2. Docking and Conformational Analysis of SERT Complexation
2.3.3. Docking and Conformational Analysis of 5HT_1A Complexation
3. Materials and Methods
3.1. Chemistry
3.1.1. General Information
3.1.2. Methods for the Synthesis of Ethyl 1-Amino-5-(3,5-dimethyl-1H-pyrazol-1-yl)-8,8-dimethyl-8,9-dihydro-6H-pyrano[4,3-d]thieno[2,3-b]pyridine-2-carboxylate (3a)
3.1.3. General Method for the Preparation of Compounds 3b–f
3.1.4. Method for the Synthesis of 5-(3,5-Dimethyl-1H-pyrazol-1-yl)-2,2-dimethyl-1,4-dihydro-2H-pyrano[4″,3″:4′,5′]pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidin-8(9H)-one (4a)
3.1.5. General Method for the Preparation of Compounds 4b–f
3.2. Biological Evaluation
3.2.1. Evaluation of the Anticonvulsant Activity of the Synthesized Compounds
3.2.2. Evaluation of the Psychotropic Properties of the Synthesized Compounds
3.2.3. Evaluation of Incoordination of Movements in the Rotating Rod Test
3.3. Docking Studies
3.3.1. Design of Molecular Models
3.3.2. Molecular Docking
3.3.3. Binding Constant Calculation
3.3.4. Conformational Analysis and Visualization
3.3.5. Statistical Analysis
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Sample Availability
References
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Compound | R | Yield (%) 1 |
---|---|---|
3a | COOEt | Method (A) 81/Method (B) 78 |
3b | CN | 89 |
3c | CONHC6H5 | 98 |
3d | CONH-2,4-(OMe)2C6H3 | 92 |
3e | CONH-3,4-Cl2C6H3 | 90 |
3f | CONH(CH2)2C6H5 | 89 |
Compound | R | Yield (%) 1 |
---|---|---|
4a | H | 82 |
4b | C6H5 | 92 |
4c | 2,4-(OMe)2C6H3 | 91 |
4d | 3,4-Cl2C6H3 | 89 |
4e | (CH2)2C6H5 | 84 |
Compounds (50 mg/kg) | Antagonism with PTZ * | Myorelaxation (TD50, mg/kg) * | MTD, (mg/kg) | PI | |
---|---|---|---|---|---|
% | (ED50, mg/kg) * | ||||
3a | 40 | − | >500 | 1100 | − |
3b | 60 | 34.0 (22.6 ÷ 57.0) | 560.0 (455 ÷ 689) | 1050 | 16.5 |
3c | 60 | 36.0 (24.0 ÷ 54.0) | 525 (437.5 ÷ 630) | 1150 | 14.6 |
3d | 60 | 35.0 (21.8 ÷ 56.0) | 540.0 (439 ÷ 664) | 1300 | 15.4 |
3e | 80 | 26.0 (21.7 ÷ 31.2) | 580.0 (475 ÷ 708) | 1350 | 22.3 |
3f | 60 | 44.0 (33.8 ÷ 57.2) | 600.0 (500 ÷ 720) | 1500 | 13.6 |
4a | 40 | − | >500 | 1350 | - |
4b | 60 | 37.0 (30.8 ÷ 44.4) | 565.0 (463 ÷ 689) | 1200 | 15 |
4c | 60 | 44.0 (24.4 ÷ 65.6) | 528.0 (432.7÷644) | 1400 | 12 |
4d | 60 | 37.5 (20.8 ÷ 67.5) | 505.0 (417 ÷ 611) | 1250 | 13.5 |
4e | 60 | 40.0 (23.5 ÷ 68.0) | 545.0 (450.4÷660) | 1250 | 13.6 |
Ethosuximide (200 mg/kg) | 60 | 155.0 (117.5 ÷ 205) | 520.0 (426 ÷ 634) | 1000 | 3.4 |
Diazepam (2 mg/kg) | 80 | 0.5 (0.4 ÷ 0.7) | 2.7 (1.4 ÷ 5.5) | 200 | 5.4 |
Compounds | Dose, mg/kg | Amount (Absolute Data over 5 min) * | ||
---|---|---|---|---|
Horizontal Displacement | Vertical Displacement | Cells | ||
Control | – | 25.8 ± 3.5 | 6.1 ± 1.1 | 0.5 ± 0.02 |
3b | 50 | 26.4 ± 3.6 | 3.3 ± 0.6 ** | 2.6 ± 0.6 ** |
3c | 50 | 42.6 ± 6.3 ** | 6.8 ± 1.2 | 1.2 ± 0.06 ** |
3d | 50 | 44.8 ± 5.2 ** | 9.6 ± 1.9 ** | 2.8 ± 0.5 ** |
3e | 50 | 24.4 ± 3.7 | 2.8 ± 0.7 ** | 2.8 ± 0.53 ** |
3f | 50 | 58.2 ± 6.1 ** | 7.0 ± 2.2 | 2.4 ± 0.8 ** |
4b | 50 | 40.4 ± 7.5 ** | 4.5± 0.9 | 0.9 ± 0.05 ** |
4c | 50 | 43.8 ± 4.1 ** | 6.2 ± 1.8 | 2.2 ± 0.6 ** |
4d | 50 | 34.2 ± 4.8 ** | 5.2 ± 0.7 | 2.2 ± 0.3 ** |
4e | 50 | 50.4 ± 7.3 ** | 7.1 ± 3.0 | 2.5 ± 0.7 ** |
Ethosuximide | 200 | 26.8 ± 3.8 | 5.8 ± 1.9 | 0.6 ± 0.08 |
Diazepam | 2 | 33.6 ± 4.2 ** | 6.4 ± 1.0 | 3.2 ± 0.9 ** |
Compound (50 mg/kg) | Time Spent in Closed Arms, /s/ * | Number of Entries into the Closed Arms * | Time Spent in the Center, /s/ * | Time Spent in the Open Arms, /s/ * |
---|---|---|---|---|
Control | 278.2 (262 ÷ 294.0) | 7.0 (5.83 ÷ 8.4) | 21.8 (11.0 ÷ 32.6) | – |
3b | 207.2 (180.1÷233.6) ** | 7.6 (5.2 ÷ 10.0) | 87.8 (73.2 ÷105.4) ** | 5.0 (4.34 ÷ 5.75) ** |
3c | 220.6 (186.9 ÷ 260.3) ** | 3.6 (2.9 ÷ 4.3) | 74.2 (61,3 ÷89.8) ** | 5.2 (4.3 ÷ 6.24) ** |
3d | 200.6 (171 ÷ 230.3) ** | 3.0 (2.2 ÷ 3.8) ** | 88.0 (70.1÷105.9) ** | 11.4 (6.3 ÷ 16.5) ** |
3e | 152.2 (112.4÷192) ** | 5.6 (4.66 ÷ 6.72) | 138.0 (115 ÷165.6) ** | 9.8 (8.3 ÷ 11.6) ** |
3f | 177.2 (137.8 ÷ 216.6) ** | 4.2 (3.5 ÷ 4.9) ** | 113.4 (94.5 ÷ 136) ** | 9.4 (7.9 ÷ 11.51) ** |
4b | 197.4 (143.0÷251.8) ** | 5.6 (3.5 ÷ 7.7) | 96.4 (79 ÷ 117.6) ** | 6.2 (3.0 ÷ 9.4) ** |
4c | 167.0 (144.4 ÷ 189.6) ** | 5.0 (3.2 ÷ 6.8) | 130 (107.5 ÷152.5) ** | 3.0 (2.6 ÷ 3.45) ** |
4d | 208.0 (179.2 ÷ 236.8) ** | 4.0 (3.1 ÷ 4.9) ** | 82.0 (53.9 ÷ 110.1) ** | 10.0 (8.3 ÷ 12) ** |
4e | 216.2 (183.2 ÷ 255.1) ** | 6.2 (5.1 ÷ 7.3) | 79.8 (66.2 ÷ 93.4) ** | 4.0 (3.48 ÷ 4.6) ** |
Ethosux. 200 mg/kg | 245.2 (212.9 ÷ 277.5) | 8.1 (5.6 ÷ 10.6) | 52.8 (19.7 ÷ 85.9) | – |
Diazep. 2 mg/kg | 257.5 (226.2÷ 288.8) | 5.5 (4.58 ÷ 6.6) | 42.5 (34.8 ÷ 51.9) ** | 57 (47.5 ÷ 68.4) ** |
Compound | Dose, mg/kg | Latent Period I Immobilization, /s/ * | Total Time of Immobilization /s/ * | Total Time of Active Swimming, /s/ * |
---|---|---|---|---|
Control | – | 92 (80.0 ÷ 105.8) | 81 (59.3 ÷ 102.7) | 282 (245.2 ÷ 324.3) |
3b | 50 | 71.0 (60.6 ÷ 81.4) | 195.0 (141.0 ÷ 249.0) | 165.0 (132 ÷ 206.3) |
3c | 50 | 97.0 (70.8 ÷ 123.2) | 136.0 (92.2 ÷ 179.8) | 224.0 (180.2 ÷ 267.8) |
3d | 50 | 91.0 (66.0 ÷ 116.0) | 142.0 (108.4 ÷ 175.6) | 218.0 (184.4 ÷ 251.6) |
3e | 50 | 172.0 (143.0 ÷206.4) ** | 48.0 (40.0 ÷ 57.6) ** | 312.0 (276.1 ÷ 352.6) |
3f | 50 | 121.0 (108.0 ÷ 135.5) ** | 20.0 (16.5 ÷ 24.2) ** | 340.0 (283.3 ÷ 408.0) |
4b | 50 | 78.0 (58.0 ÷ 100.0) | 141.0 (116.0 ÷ 166.0) | 219.0 (193.2 ÷ 244.8) |
4c | 50 | 70.0(58.1 ÷ 81.9) | 159.0 (140.9 ÷ 177.1) | 201.0 (150.2 ÷ 251.8) |
4d | 50 | 124.0 (110.7 ÷ 138.9) ** | 177.0 (149.9 ÷ 204.1) | 183.0 (155.9 ÷210.1) |
4e | 50 | 104.0 (67.2 ÷ 140.8) | 96.0 (73.7÷ 118.3) | 264.0 (202.0 ÷ 326.0) |
Ethosux. | 200 | 105 (87.5 ÷ 104.4) | 98 (75.3 ÷ 127.4) | 262 (199.9 ÷ 324.1) |
Diazep. | 2 | 174 (144 ÷ 204) ** | 24 (13.9 ÷ 34.1) ** | 336 (282.6 ÷ 389.4) |
Structure ID: | Complexation Energy kcal/mol | Root-Mean-Square Deviation (RMSD) | Binding Constant, Kb |
---|---|---|---|
3a | −8.3 ± 0.41 | 1.35 | 1.1 × 106 |
3c | −10.0 ± 0.5 | 1.92 | 2.2 × 107 |
3d | −9.3 ± 0.46 | 1.92 | 6.0 × 106 |
3e | −9.8 ± 0.49 | 1.68 | 1.5 × 107 |
4b | −10.0 ± 0.5 | 0.83 | 2.2 × 107 |
4c | −8.8 ± 0.44 | 1.08 | 2.9 × 106 |
4d | −9.8 ± 0.49 | 1.81 | 1.5 × 107 |
Diazepam | −7.5 ± 0.37 | 1.20 | 2.9 × 105 |
Structure ID | Complexation Energy kcal/mol | Root-Mean-Square Deviation (RMSD) | Binding Constant, Kb |
---|---|---|---|
2 | −7.8 ± 0.39 | 1.73 | 5.2 × 105 |
3c | −10.3 ± 0.51 | 1.86 | 3.2 × 107 |
3d | −9.1 ± 0.45 | 1.87 | 4.2 × 106 |
3e | −10.3 ± 0.51 | 0.92 | 3.0 × 107 |
3f | −10.8 ± 0.54 | 1.08 | 7.8 × 107 |
4b | −10.2 ± 0.51 | 0.62 | 2.7 × 107 |
4d | −9.8 ± 0.49 | 1.36 | 1.4 × 107 |
4e | −11.0 ± 0.54 | 1.41 | 9.7 × 107 |
Structure ID: | Complexation Energy kcal/mol | RMSD | Binding Constant, Kb |
---|---|---|---|
3a | −6.8 ± 0.34 | 1.98 | 9.8 × 104 |
3c | −8.9 ± 0.44 | 1.40 | 3.1 × 106 |
3d | −9.1 ± 0.45 | 1.95 | 4.2 × 106 |
3e | −8.9 ± 0.44 | 1.86 | 3.3 × 106 |
3f | −9.3 ± 0.46 | 0.92 | 6.0 × 106 |
4a | −8.1 ± 0.4 | 1.49 | 8.0 × 105 |
4e | −8.7 ± 0.43 | 1.17 | 2.5 × 106 |
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Dashyan, S.S.; Babaev, E.V.; Paronikyan, E.G.; Ayvazyan, A.G.; Paronikyan, R.G.; Hunanyan, L.S. 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-d]pyrimidines on the Basis of pyrano[3,4-c]pyridines. Molecules 2022, 27, 3380. https://doi.org/10.3390/molecules27113380
Dashyan SS, Babaev EV, Paronikyan EG, Ayvazyan AG, Paronikyan RG, Hunanyan LS. 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-d]pyrimidines on the Basis of pyrano[3,4-c]pyridines. Molecules. 2022; 27(11):3380. https://doi.org/10.3390/molecules27113380
Chicago/Turabian StyleDashyan, Shushanik Sh., Eugene V. Babaev, Ervand G. Paronikyan, Armen G. Ayvazyan, Ruzanna G. Paronikyan, and Lernik S. Hunanyan. 2022. "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-d]pyrimidines on the Basis of pyrano[3,4-c]pyridines" Molecules 27, no. 11: 3380. https://doi.org/10.3390/molecules27113380